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In myasthenia gravis, antibodies pass open-label tests
PHOENIX – . The two drugs, rozanolixizumab (Rystiggo, UCB) and efgartigimod PH20 (Vyvgart, Argenx SE), received Food and Drug Administration approval in June 2023 and December 2021, respectively, for the treatment of MG.
The neonatal Fc receptor binds to IgG within cells and recycles it back into the blood, leading to increased serum levels. The antibodies bind to the neonatal Fc receptor and promote its degradation, therefore preventing IgG recycling without interfering with its production. They do not affect the levels of other immunoglobulin isotypes.
At the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM), researchers presented data from an open-label extension study following the phase 3 MycarinG trial of rozanolixizumab and the ADAPT-SC+ study of efgartigimod.
In the MycarinG study, rozanolixizumab “showed both statistically significant and clinically meaningful improvements in multiple endpoints,” said Vera Bril, MD, during a presentation of the results.
Rozanolixizumab is approved for MG patients who are anti–acetylcholine receptor (AchR) or anti–muscle-specific tyrosine kinase (MuSK) antibody positive. Efgartigimod is approved for MG patients who are AChR positive.
After completing MycarinG, patients were eligible to enroll in one of two open-label studies, one of each dose.
The new efficacy analysis focused on 110 patients who underwent two or more consecutive symptom-driven treatment cycles. A safety analysis focused on 188 patients who received at least one cycle of treatment.
“The post hoc analysis showed that the clinically meaningful improvements in the generalized myasthenia gravis symptoms were maintained over time for the cohort across rozanolixizumab cycles, while individual patients move through the consecutive treatment cycles, rozanolixizumab had an acceptable safety profile that was maintained across repeated treatments cycles. This is consistent with previous results of rozanolixizumab,” said Dr. Bril, who is a clinical investigator at University of Toronto
A reduction in steroid use?
During the Q&A session, George Small, MD, asked if the study had shown a reduction in steroid use among patients with MG.
As clinical associate director of neurology at Allegheny Medical Center, Pittsburgh, he has overseen the care of several hundred patients with generalized MG, as well as participated in clinical trials. “Many physicians use steroids for very quick responses in their patients. I love steroids and I hate steroids. I’ve helped save people’s lives with them, but I’ve also probably hastened their demise, unfortunately, because of the long-term side effects of the medications. Many neurologists in the community will over-utilize steroids because they don’t have access to these more expensive therapies. I look forward to both using these medications more as they become FDA approved and being an advocate for them, because it is my belief that they help decrease the use of steroids,” said Dr. Small in an interview.
Even if new medications do reduce steroid use, there remains a hurdle with insurance companies. “I’ve felt I’ve been forced to use treatments that I know may not be efficacious in the short term in order to get authorization for more expensive therapies that I use now. I’ve had patients admitted to the hospital as I’ve tried to jump through hoops that the insurance companies demanded,” said Dr. Small.
Clinical improvements seen
In the MycarinG study, patients received weekly injections of 7 mg/kg, 10 mg/kg rozanolixizumab, or placebo over a 6-week period. Both treatment groups had reductions in Myasthenia Gravis Activities of Daily Living (MG-ADL) scores compared with placebo.
MG-ADL and Quantitative Myasthenia Gravis (QMG) scores were consistent across treatment cycles. The mean MG-ADL score dropped by about 4 points at week 6. At around week 10, the mean improvement declined to 2 points, and then by week 14 it increased to 3 points, where it remained consistent out to 50 weeks. A similar pattern was seen in QMG scores, with an approximate 5-point drop at 6 weeks, then about a 1.5-point improvement at 10 weeks, then a mean decrease of around 4 points that stayed stable out to 50 weeks.
Over all cycles of treatment, 89.9% of patients experienced a treatment-emergent adverse event, including 22.3% who had a serious TEAE; the study dropout rate because of TEAEs was 15.4%.
In the ADAPT-SC study, 110 patients were randomized to 10 mg/kg intravenous efgartigimod or 1,000 mg efgartigimod PH20, which is formulated with recombinant human hyaluronidase to allow for rapid administration of larger volumes. After completion of ADAPT-SC, 105 patients from both groups and an additional 79 patients entered the open-label extension study with 1,000 mg efgartigimod PH20.
The study included 141 patients who were AChR-Ab positive and 38 who were AChR-Ab negative. In the first cycle, 34.6% experienced an injection-site reaction, which steadily dropped to 11.5% by the sixth cycle. After each cycle of treatment, the mean change in MG-ADL from study baseline at week 4 was between 4.1 and 4.7 points. The mean change in Myasthenia Gravis Quality of Life 15-Item Questionnaire revisited from study baseline at week 4 was between 5.1 and 6.5 points. The mean change in EuroQoL 5-dimension, 5-level visual analog scale was between 12.3 and 16.0 points at week 4.
MyCarinG was funded by UCB Pharma. ADAPT-SC was funded by Argenx SE. Dr. Bril has financial relationships with Behring, Argenyx, Alexion, Immunovant, Alnylam, Akcea, Takeda, Sanofi, Ionis, Roche, Novo Nordisk, Octapharma, Momenta, Pfizer, CSL Behring, Grifols, Powell Mansfield, UCB, and Viela Bio. Dr. Small is on the speaker’s bureau for Alexion.
PHOENIX – . The two drugs, rozanolixizumab (Rystiggo, UCB) and efgartigimod PH20 (Vyvgart, Argenx SE), received Food and Drug Administration approval in June 2023 and December 2021, respectively, for the treatment of MG.
The neonatal Fc receptor binds to IgG within cells and recycles it back into the blood, leading to increased serum levels. The antibodies bind to the neonatal Fc receptor and promote its degradation, therefore preventing IgG recycling without interfering with its production. They do not affect the levels of other immunoglobulin isotypes.
At the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM), researchers presented data from an open-label extension study following the phase 3 MycarinG trial of rozanolixizumab and the ADAPT-SC+ study of efgartigimod.
In the MycarinG study, rozanolixizumab “showed both statistically significant and clinically meaningful improvements in multiple endpoints,” said Vera Bril, MD, during a presentation of the results.
Rozanolixizumab is approved for MG patients who are anti–acetylcholine receptor (AchR) or anti–muscle-specific tyrosine kinase (MuSK) antibody positive. Efgartigimod is approved for MG patients who are AChR positive.
After completing MycarinG, patients were eligible to enroll in one of two open-label studies, one of each dose.
The new efficacy analysis focused on 110 patients who underwent two or more consecutive symptom-driven treatment cycles. A safety analysis focused on 188 patients who received at least one cycle of treatment.
“The post hoc analysis showed that the clinically meaningful improvements in the generalized myasthenia gravis symptoms were maintained over time for the cohort across rozanolixizumab cycles, while individual patients move through the consecutive treatment cycles, rozanolixizumab had an acceptable safety profile that was maintained across repeated treatments cycles. This is consistent with previous results of rozanolixizumab,” said Dr. Bril, who is a clinical investigator at University of Toronto
A reduction in steroid use?
During the Q&A session, George Small, MD, asked if the study had shown a reduction in steroid use among patients with MG.
As clinical associate director of neurology at Allegheny Medical Center, Pittsburgh, he has overseen the care of several hundred patients with generalized MG, as well as participated in clinical trials. “Many physicians use steroids for very quick responses in their patients. I love steroids and I hate steroids. I’ve helped save people’s lives with them, but I’ve also probably hastened their demise, unfortunately, because of the long-term side effects of the medications. Many neurologists in the community will over-utilize steroids because they don’t have access to these more expensive therapies. I look forward to both using these medications more as they become FDA approved and being an advocate for them, because it is my belief that they help decrease the use of steroids,” said Dr. Small in an interview.
Even if new medications do reduce steroid use, there remains a hurdle with insurance companies. “I’ve felt I’ve been forced to use treatments that I know may not be efficacious in the short term in order to get authorization for more expensive therapies that I use now. I’ve had patients admitted to the hospital as I’ve tried to jump through hoops that the insurance companies demanded,” said Dr. Small.
Clinical improvements seen
In the MycarinG study, patients received weekly injections of 7 mg/kg, 10 mg/kg rozanolixizumab, or placebo over a 6-week period. Both treatment groups had reductions in Myasthenia Gravis Activities of Daily Living (MG-ADL) scores compared with placebo.
MG-ADL and Quantitative Myasthenia Gravis (QMG) scores were consistent across treatment cycles. The mean MG-ADL score dropped by about 4 points at week 6. At around week 10, the mean improvement declined to 2 points, and then by week 14 it increased to 3 points, where it remained consistent out to 50 weeks. A similar pattern was seen in QMG scores, with an approximate 5-point drop at 6 weeks, then about a 1.5-point improvement at 10 weeks, then a mean decrease of around 4 points that stayed stable out to 50 weeks.
Over all cycles of treatment, 89.9% of patients experienced a treatment-emergent adverse event, including 22.3% who had a serious TEAE; the study dropout rate because of TEAEs was 15.4%.
In the ADAPT-SC study, 110 patients were randomized to 10 mg/kg intravenous efgartigimod or 1,000 mg efgartigimod PH20, which is formulated with recombinant human hyaluronidase to allow for rapid administration of larger volumes. After completion of ADAPT-SC, 105 patients from both groups and an additional 79 patients entered the open-label extension study with 1,000 mg efgartigimod PH20.
The study included 141 patients who were AChR-Ab positive and 38 who were AChR-Ab negative. In the first cycle, 34.6% experienced an injection-site reaction, which steadily dropped to 11.5% by the sixth cycle. After each cycle of treatment, the mean change in MG-ADL from study baseline at week 4 was between 4.1 and 4.7 points. The mean change in Myasthenia Gravis Quality of Life 15-Item Questionnaire revisited from study baseline at week 4 was between 5.1 and 6.5 points. The mean change in EuroQoL 5-dimension, 5-level visual analog scale was between 12.3 and 16.0 points at week 4.
MyCarinG was funded by UCB Pharma. ADAPT-SC was funded by Argenx SE. Dr. Bril has financial relationships with Behring, Argenyx, Alexion, Immunovant, Alnylam, Akcea, Takeda, Sanofi, Ionis, Roche, Novo Nordisk, Octapharma, Momenta, Pfizer, CSL Behring, Grifols, Powell Mansfield, UCB, and Viela Bio. Dr. Small is on the speaker’s bureau for Alexion.
PHOENIX – . The two drugs, rozanolixizumab (Rystiggo, UCB) and efgartigimod PH20 (Vyvgart, Argenx SE), received Food and Drug Administration approval in June 2023 and December 2021, respectively, for the treatment of MG.
The neonatal Fc receptor binds to IgG within cells and recycles it back into the blood, leading to increased serum levels. The antibodies bind to the neonatal Fc receptor and promote its degradation, therefore preventing IgG recycling without interfering with its production. They do not affect the levels of other immunoglobulin isotypes.
At the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM), researchers presented data from an open-label extension study following the phase 3 MycarinG trial of rozanolixizumab and the ADAPT-SC+ study of efgartigimod.
In the MycarinG study, rozanolixizumab “showed both statistically significant and clinically meaningful improvements in multiple endpoints,” said Vera Bril, MD, during a presentation of the results.
Rozanolixizumab is approved for MG patients who are anti–acetylcholine receptor (AchR) or anti–muscle-specific tyrosine kinase (MuSK) antibody positive. Efgartigimod is approved for MG patients who are AChR positive.
After completing MycarinG, patients were eligible to enroll in one of two open-label studies, one of each dose.
The new efficacy analysis focused on 110 patients who underwent two or more consecutive symptom-driven treatment cycles. A safety analysis focused on 188 patients who received at least one cycle of treatment.
“The post hoc analysis showed that the clinically meaningful improvements in the generalized myasthenia gravis symptoms were maintained over time for the cohort across rozanolixizumab cycles, while individual patients move through the consecutive treatment cycles, rozanolixizumab had an acceptable safety profile that was maintained across repeated treatments cycles. This is consistent with previous results of rozanolixizumab,” said Dr. Bril, who is a clinical investigator at University of Toronto
A reduction in steroid use?
During the Q&A session, George Small, MD, asked if the study had shown a reduction in steroid use among patients with MG.
As clinical associate director of neurology at Allegheny Medical Center, Pittsburgh, he has overseen the care of several hundred patients with generalized MG, as well as participated in clinical trials. “Many physicians use steroids for very quick responses in their patients. I love steroids and I hate steroids. I’ve helped save people’s lives with them, but I’ve also probably hastened their demise, unfortunately, because of the long-term side effects of the medications. Many neurologists in the community will over-utilize steroids because they don’t have access to these more expensive therapies. I look forward to both using these medications more as they become FDA approved and being an advocate for them, because it is my belief that they help decrease the use of steroids,” said Dr. Small in an interview.
Even if new medications do reduce steroid use, there remains a hurdle with insurance companies. “I’ve felt I’ve been forced to use treatments that I know may not be efficacious in the short term in order to get authorization for more expensive therapies that I use now. I’ve had patients admitted to the hospital as I’ve tried to jump through hoops that the insurance companies demanded,” said Dr. Small.
Clinical improvements seen
In the MycarinG study, patients received weekly injections of 7 mg/kg, 10 mg/kg rozanolixizumab, or placebo over a 6-week period. Both treatment groups had reductions in Myasthenia Gravis Activities of Daily Living (MG-ADL) scores compared with placebo.
MG-ADL and Quantitative Myasthenia Gravis (QMG) scores were consistent across treatment cycles. The mean MG-ADL score dropped by about 4 points at week 6. At around week 10, the mean improvement declined to 2 points, and then by week 14 it increased to 3 points, where it remained consistent out to 50 weeks. A similar pattern was seen in QMG scores, with an approximate 5-point drop at 6 weeks, then about a 1.5-point improvement at 10 weeks, then a mean decrease of around 4 points that stayed stable out to 50 weeks.
Over all cycles of treatment, 89.9% of patients experienced a treatment-emergent adverse event, including 22.3% who had a serious TEAE; the study dropout rate because of TEAEs was 15.4%.
In the ADAPT-SC study, 110 patients were randomized to 10 mg/kg intravenous efgartigimod or 1,000 mg efgartigimod PH20, which is formulated with recombinant human hyaluronidase to allow for rapid administration of larger volumes. After completion of ADAPT-SC, 105 patients from both groups and an additional 79 patients entered the open-label extension study with 1,000 mg efgartigimod PH20.
The study included 141 patients who were AChR-Ab positive and 38 who were AChR-Ab negative. In the first cycle, 34.6% experienced an injection-site reaction, which steadily dropped to 11.5% by the sixth cycle. After each cycle of treatment, the mean change in MG-ADL from study baseline at week 4 was between 4.1 and 4.7 points. The mean change in Myasthenia Gravis Quality of Life 15-Item Questionnaire revisited from study baseline at week 4 was between 5.1 and 6.5 points. The mean change in EuroQoL 5-dimension, 5-level visual analog scale was between 12.3 and 16.0 points at week 4.
MyCarinG was funded by UCB Pharma. ADAPT-SC was funded by Argenx SE. Dr. Bril has financial relationships with Behring, Argenyx, Alexion, Immunovant, Alnylam, Akcea, Takeda, Sanofi, Ionis, Roche, Novo Nordisk, Octapharma, Momenta, Pfizer, CSL Behring, Grifols, Powell Mansfield, UCB, and Viela Bio. Dr. Small is on the speaker’s bureau for Alexion.
AT AANEM 2023
FDA okays drug for Duchenne muscular dystrophy
Duchenne muscular dystrophy (DMD) in patients as young as age 2 years, the company has announced Vamorolone is a structurally unique steroidal anti-inflammatory drug that potently inhibits proinflammatory NFkB pathways via high-affinity binding to the glucocorticoid receptor.
“Corticosteroids have been a first line treatment for DMD for many years, but their utility has always been limited by the side effect profile, which includes weight gain, short stature, and decreased bone density, among others,” Sharon Hesterlee, PhD, chief research officer for the Muscular Dystrophy Association, said in a statement.
The approval of vamorolone “provides people living with Duchenne, and their families, a powerful tool to treat the disease, while limiting some negative side effects associated with corticosteroids,” Dr. Hesterlee added.
The approval was based on data from the phase 2b VISION-DMD study, supplemented with safety information collected from three open-label studies.
Vamorolone was administered at doses ranging from 2-6 mg/kg/d for a period of up to 48 months.
Vamorolone demonstrated efficacy similar to that of traditional corticosteroids, with data suggesting a reduction in adverse events – notably related to bone health, growth trajectory, and behavior.
Vamorolone had received orphan drug status for DMD, as well as fast track and rare pediatric disease designations. It will be made available in the United States by Catalyst Pharmaceuticals.
A version of this article first appeared on Medscape.com .
Duchenne muscular dystrophy (DMD) in patients as young as age 2 years, the company has announced Vamorolone is a structurally unique steroidal anti-inflammatory drug that potently inhibits proinflammatory NFkB pathways via high-affinity binding to the glucocorticoid receptor.
“Corticosteroids have been a first line treatment for DMD for many years, but their utility has always been limited by the side effect profile, which includes weight gain, short stature, and decreased bone density, among others,” Sharon Hesterlee, PhD, chief research officer for the Muscular Dystrophy Association, said in a statement.
The approval of vamorolone “provides people living with Duchenne, and their families, a powerful tool to treat the disease, while limiting some negative side effects associated with corticosteroids,” Dr. Hesterlee added.
The approval was based on data from the phase 2b VISION-DMD study, supplemented with safety information collected from three open-label studies.
Vamorolone was administered at doses ranging from 2-6 mg/kg/d for a period of up to 48 months.
Vamorolone demonstrated efficacy similar to that of traditional corticosteroids, with data suggesting a reduction in adverse events – notably related to bone health, growth trajectory, and behavior.
Vamorolone had received orphan drug status for DMD, as well as fast track and rare pediatric disease designations. It will be made available in the United States by Catalyst Pharmaceuticals.
A version of this article first appeared on Medscape.com .
Duchenne muscular dystrophy (DMD) in patients as young as age 2 years, the company has announced Vamorolone is a structurally unique steroidal anti-inflammatory drug that potently inhibits proinflammatory NFkB pathways via high-affinity binding to the glucocorticoid receptor.
“Corticosteroids have been a first line treatment for DMD for many years, but their utility has always been limited by the side effect profile, which includes weight gain, short stature, and decreased bone density, among others,” Sharon Hesterlee, PhD, chief research officer for the Muscular Dystrophy Association, said in a statement.
The approval of vamorolone “provides people living with Duchenne, and their families, a powerful tool to treat the disease, while limiting some negative side effects associated with corticosteroids,” Dr. Hesterlee added.
The approval was based on data from the phase 2b VISION-DMD study, supplemented with safety information collected from three open-label studies.
Vamorolone was administered at doses ranging from 2-6 mg/kg/d for a period of up to 48 months.
Vamorolone demonstrated efficacy similar to that of traditional corticosteroids, with data suggesting a reduction in adverse events – notably related to bone health, growth trajectory, and behavior.
Vamorolone had received orphan drug status for DMD, as well as fast track and rare pediatric disease designations. It will be made available in the United States by Catalyst Pharmaceuticals.
A version of this article first appeared on Medscape.com .
Stiff person syndrome: When a rare disorder hits the headlines
When, in 2022, singer and international celebrity Celine Dion announced what she called her “one-in-a-million diagnosis” of stiff person syndrome, clinicians and medical scientists who specialize in the disorder took a deep breath. Scott D. Newsome, DO, professor of neurology and director of the Johns Hopkins Stiff Person Syndrome Center, Baltimore – a glass-half-full kind of person – saw in Ms. Dion’s worrying announcement a huge opportunity nonetheless: To raise awareness about the rare cluster of disorders known collectively as stiff person spectrum disorders (SPSD).
“Even at the clinician level, if you don’t know the hallmark signs and symptoms, you could possibly misdiagnose it,” Dr. Newsome said in an interview.
But misdiagnosis can go either way; increased awareness of SPSD can have a downside. Thirty years ago, when Marinos C. Dalakas, MD, first began studying SPSD, the diagnosis was frequently missed – “because people were not aware of it,” he said. But now, Dr. Dalakas, professor of neurology and director of the division of neuromuscular diseases in the department of neurology at Thomas Jefferson University and the Jefferson Hospital for Neuroscience, both in Philadelphia, said overdiagnosis is also a concern, particularly with increased public awareness.
“Just this last month I saw two patients who told me: ‘I read about it, and I believe I have symptoms of stiff person,’ ” he said.
These days, most patients in whom SPSD is suspected end up with an alternate diagnosis. In a recent retrospective study that Dr. Dalakas coauthored, of 173 patients who had been referred to the Mayo Clinic in Rochester, Minn., with suspected SPSD,1 Dr. Dalakas and colleagues determined that only 48 (27.7%) actually had the disorder – meaning that the rest might have been unnecessarily exposed to immunosuppressive SPSD therapies and that treatment for their actual disorder (most often, a functional neurologic disorder or nonneurologic condition) was delayed.
At the root of both underdiagnosis and overdiagnosis of SPSD is the heterogeneity of the condition and a lack of definitive diagnostic markers.
SPSD has been considered an autoimmune disorder for a long time, and observations by Dr. Dalakas and others have shown that as many as 35% of cases co-occur with another autoimmune disease, such as vitiligo, celiac disease, rheumatologic disease, type 1 diabetes mellitus, and thyroid disease (Grave’s disease and Hashimoto’s thyroiditis).2 A more recent study by his group observed an even higher rate (42%) of comorbid autoimmunity, with autoimmune thyroid disease being most common. However, although most cases of SPDS are characterized by an elevated level of glutamic acid decarboxylase (GAD)65-IgG, these autoantibodies are not specific to SPSD (low levels are also seen in diabetes, thyroid disease, healthy controls, etc.). Some SPSD patients have less common autoantibodies and a minority has no autoantibodies. Dr. Newsome said seronegative cases and the antibody presence and titers not being associated with disease severity or treatment response are clues that “SPSD does not appear to be a primary antibody-mediated condition and that there must be other immune factors at play.”
Autoimmune process drives SPSD
Autoimmunity, even if not detected by serologic studies, is believed to inhibit expression of gamma aminobutyric acid (GABA) receptors, which, in turn, results in stiffness and spasms. Although what are known as “Dalakas criteria,” proposed in 2009,2 describe the “classic” SPSD phenotype, encompassing roughly three-quarters of SPSD patients, there have now been other phenotypes proposed under SPSD, including isolated forms (stiff limb or trunk syndrome) and “nonclassic” phenotypes like SPS-plus (classic features plus brain stem and/or cerebellar involvement),3 overlap syndromes (for example, classic features with refractory epilepsy/limbic encephalitis), and probably the most severe phenotype, progressive encephalomyelitis with rigidity and myoclonus.
Early and aggressive therapy with benzodiazepines and other GABA-ergic agonists, as well as immune-based treatments, is considered critical to slowing progression of SPSD. However, the insidious onset of what is often a cluster of vague, nonspecific symptoms is a challenge for clinicians to recognize.
“When a patient comes in with muscular spasms, with stiffness in the back, in the legs, and it’s unexplained and it’s not due to spinal cord disease, or multiple sclerosis ... think SPSD,” said Dr. Dalakas. “Check antibodies – that’s the first thing to do.”
Antibody positivity is most helpful at high levels, he added; low titers can be present in autoimmune diabetes and other conditions, as previously mentioned. The real challenge? When a patient is seronegative.
Embarking on a diagnostic odyssey
Patients “bounce from one clinician to the next looking for answers,” said Dr. Newsome. “Patients will often start with their general practitioner and be referred to physical therapy, rheumatology, or orthopedics, and other specialists, which could include neurology and/or psychiatry, among others. SPSD is often not considered as a possible diagnosis until the patient develops more concrete symptoms and/or objective signs on exam. Of course, considering this diagnosis starts at knowing that it exists.”
Task-specific phobias and exaggerated acoustic startle or sensory reflex are specific symptoms that can red-flag some SPSD patients, said Dr. Dalakas. “Impaired GABA is also important for fears and anxiety. So, when you have a reduction of GABA you have more phobic neuroses – fear of crossing the street, fear of speaking in public, and they get very tense and they cannot perform.
“If the GABA-ergic pathways are dysfunctional, then there’s a relative hyper-excitability within the nervous system,” said Dr. Newsome. “This can be evaluated with electromyography. “The muscles are unhinged and going crazy: Agonists and antagonists are contracting together, which is abnormal. We will also assess for continuous motor unit potential activity within individual muscles – angry muscles just continuously firing. In our experience, this finding appears to be a pretty specific sign of SPS, especially in the torso.” Importantly, the sudden contraction of muscles along with stiffness can lead to traumatic falls, causing major orthopedic and brain injury.
In early stages of SPSD, a careful history and clinical exam is critical to try to shorten what Dr. Newsome calls the patient’s “diagnostic odyssey.”
“It behooves the clinician to put their hands on the patient. Check their back, their abdomen – try to feel for rigidity, paraspinal muscle spasms, and tightness. These regions of the body often have a ropey feel to them, which is due to chronic muscle spasms and tightness. Most [SPSD] patients will have this present in the thoracolumbar area,” he explained. “Check for hyperlordosis, as this is a hallmark sign on exam in SPSD. Additionally, patients can have rigidity and spasticity in their legs or arms. Also, patients with nonclassical phenotypes can present with a variety of other symptoms and findings on exam, including ataxia, nystagmus, ophthalmoparesis, and dysarthria.”
Lumbar puncture can sometimes reveal signs of inflammation, such as an elevated white blood cell count and oligoclonal bands in spinal fluid.
“The classic teaching was that you can only see such findings in conditions like multiple sclerosis, but that’s not the case,” said Dr. Newsome. “You can see these findings in other autoimmune conditions, including SPSD. Hence, as part of the workup, we will have patients undergo lumbar punctures to assess for these markers of autoimmunity.”
Other mimics of SPSD, including multiple sclerosis, tumors, and spinal stenosis, should be ruled out with MRI of the brain and spine.
Treatment options
Because of wide variability in signs and symptoms of the disorder, treatment of SPSD is a highly individualized cocktail of interventions, which might include immunotherapy and GABA-ergic agonists, as well as nonmedication treatments. The response to these agents can be difficult to quantify.
Benzodiazepines (diazepam, clonazepam, baclofen) along with other oral symptomatic treatments are often recommended as first-line therapy because of their ability to enhance GABA.4
First-line immunotherapy is usually intravenous immunoglobulin, steroids, or plasmapheresis. Second- and third-line agents include rituximab, mycophenolate mofetil, azathioprine, cyclophosphamide, and combination immune treatments.
Dr. Newsome and Dr. Dalakas have independently published a step-by-step therapeutic approach to SPSD.3,5 But in patients with paraneoplastic stiff person syndrome, eradication of their cancer is critical, although, per Dr. Newsome, “this does not always cure SPS and most of these patients still have residual disability.”
But immune-based therapies are only part of what should be a multipronged treatment approach, said Dr. Newsome. He also strongly advocates for non-pharmacological interventions, such as selective physical therapy (stretching, ultrasound, and gait and balance training), heat therapy, aquatherapy, deep-tissue massage or myofascial techniques, osteopathic or chiropractic manipulation, acupuncture, and acupressure.3
Because SPSD is considered a progressive disorder for some, a reasonable goal of treatment is to prevent worsening, said Dr. Newsome. This can take time: “We don’t expect the treatments to work overnight. It involves consecutive months and, sometimes, a couple of years of immune treatment before you start to see it impact the person’s life favorably.”
Patients who are not well informed about the long-term goal of treatments might be tempted to abandon the treatments prematurely because they don’t see immediate results, Dr. Newsome added. Encouraging realistic expectations is also important, without dashing hopes.
“I have patients who were marathon runners, and they want to get back to doing marathons. I would love nothing more than for people to get back to their pre-SPSD levels of function. But this may not be a realistic goal. However, this does not mean that quality of life can’t be helped.”
Nevertheless, Dr. Newsome encourages clinicians to reassess regularly, especially because lack of disease biomarkers makes it hard to objectively monitor the impact of therapy.
“It’s always a good rule of thumb, especially in the rare disease space, to step back and ask: ‘Are we on the right treatment path or not?’ If we’re not, then it is important to make sure you have the correct diagnosis. Even when you have a patient who fits the textbook and you, yourself, diagnosed them, it is important to continue to re-evaluate the diagnosis over time, especially if there is consideration of changing treatments. It is also important to make sure there is not something else on top of the stiff person syndrome that is working in parallel to worsen their condition.”
Be alert for comorbidity
Undiagnosed comorbid conditions that can complicate SPSD include Parkinson’s disease or myasthenia gravis, to name a couple, which Dr. Newsome has seen more than once. “We’ve seen a few people over the years who have both SPSD and another autoimmune or degenerative neurological condition.”
Diabetes also co-occurs in approximately 30% of people with SPSD, said Dr. Dalakas. “Endocrinologists should also be aware of this connection.”
Paraneoplastic stiff person syndrome is thought to be triggered by cancer, which might not have been diagnosed, making it important to work up patients for malignancy – particularly breast cancer, small cell lung cancer, lymphoma, and thymoma, Dr. Newsome advised.
Although most cases of SPSD are diagnosed in mid-life, the disorder can occur in teenagers and the elderly.
“It’s not the first thing you think of when a 70-year-old patient comes with neck pain, so it’s missed more often, and the prognosis is worse,” Dr. Dalakas warned.
What does the future hold?
Like Dr. Newsome, Dr. Dalakas is encouraged when SPSD hits the headlines because, generally, awareness facilitates diagnosis and research. (Both clinicians serve on the medical advisory board of The Stiff Person Syndrome Research Foundation.)
“We are looking for better therapies that target immune factors,” said Dr. Dalakas. “There are several of those that are relevant, so we need to select the best immune marker that we think plays a role in the antibody production,” he said.
“There’s a lot of hope – at least I have a lot of hope for what the future holds with SPSD,” added Dr. Newsome. “More research is needed and it starts with awareness of SPSD.”
Dr. Newsome discloses that he has received consulting fees for serving on scientific advisory boards of Biogen, Genentech, Bristol Myers Squibb, EMD Serono, Jazz Pharmaceuticals, Novartis, Horizon Therapeutics, TG Therapeutics; is the study lead principal investigator for a Roche clinical trial; and has received research funding (paid directly to his employing institution) from Biogen, Roche, Lundbeck, Genentech, The Stiff Person Syndrome Research Foundation, National Multiple Sclerosis Society, U.S. Department of Defense, and Patient-Centered Outcomes Research Institute. Dr. Dalakas reports nothing relevant to disclose.
References
1. Chia NH et al. Ann Clin Transl Neurol. 2023;10(7):1083-94. doi: 10.1002/acn3.51791.
2. Dalakas MC.. Curr Treat Options Neurol. 2009;11(2):102-10. doi: 10.1007/s11940-009-0013-9.
3. Newsome SD and Johnson T. J Neuroimmunol. 2022;369:577915. doi: 10.1016/j.jneuroim.2022.577915.
4. Ortiz JF et al. Cureus. 2020;12(12):e11995. doi: 10.7759/cureus.11995.
5. Dalakas CD. Neurol Neuroimmunol Neuroinflamm. 2023;10(3):e200109. doi: 10.1212/NXI.0000000000200109.
When, in 2022, singer and international celebrity Celine Dion announced what she called her “one-in-a-million diagnosis” of stiff person syndrome, clinicians and medical scientists who specialize in the disorder took a deep breath. Scott D. Newsome, DO, professor of neurology and director of the Johns Hopkins Stiff Person Syndrome Center, Baltimore – a glass-half-full kind of person – saw in Ms. Dion’s worrying announcement a huge opportunity nonetheless: To raise awareness about the rare cluster of disorders known collectively as stiff person spectrum disorders (SPSD).
“Even at the clinician level, if you don’t know the hallmark signs and symptoms, you could possibly misdiagnose it,” Dr. Newsome said in an interview.
But misdiagnosis can go either way; increased awareness of SPSD can have a downside. Thirty years ago, when Marinos C. Dalakas, MD, first began studying SPSD, the diagnosis was frequently missed – “because people were not aware of it,” he said. But now, Dr. Dalakas, professor of neurology and director of the division of neuromuscular diseases in the department of neurology at Thomas Jefferson University and the Jefferson Hospital for Neuroscience, both in Philadelphia, said overdiagnosis is also a concern, particularly with increased public awareness.
“Just this last month I saw two patients who told me: ‘I read about it, and I believe I have symptoms of stiff person,’ ” he said.
These days, most patients in whom SPSD is suspected end up with an alternate diagnosis. In a recent retrospective study that Dr. Dalakas coauthored, of 173 patients who had been referred to the Mayo Clinic in Rochester, Minn., with suspected SPSD,1 Dr. Dalakas and colleagues determined that only 48 (27.7%) actually had the disorder – meaning that the rest might have been unnecessarily exposed to immunosuppressive SPSD therapies and that treatment for their actual disorder (most often, a functional neurologic disorder or nonneurologic condition) was delayed.
At the root of both underdiagnosis and overdiagnosis of SPSD is the heterogeneity of the condition and a lack of definitive diagnostic markers.
SPSD has been considered an autoimmune disorder for a long time, and observations by Dr. Dalakas and others have shown that as many as 35% of cases co-occur with another autoimmune disease, such as vitiligo, celiac disease, rheumatologic disease, type 1 diabetes mellitus, and thyroid disease (Grave’s disease and Hashimoto’s thyroiditis).2 A more recent study by his group observed an even higher rate (42%) of comorbid autoimmunity, with autoimmune thyroid disease being most common. However, although most cases of SPDS are characterized by an elevated level of glutamic acid decarboxylase (GAD)65-IgG, these autoantibodies are not specific to SPSD (low levels are also seen in diabetes, thyroid disease, healthy controls, etc.). Some SPSD patients have less common autoantibodies and a minority has no autoantibodies. Dr. Newsome said seronegative cases and the antibody presence and titers not being associated with disease severity or treatment response are clues that “SPSD does not appear to be a primary antibody-mediated condition and that there must be other immune factors at play.”
Autoimmune process drives SPSD
Autoimmunity, even if not detected by serologic studies, is believed to inhibit expression of gamma aminobutyric acid (GABA) receptors, which, in turn, results in stiffness and spasms. Although what are known as “Dalakas criteria,” proposed in 2009,2 describe the “classic” SPSD phenotype, encompassing roughly three-quarters of SPSD patients, there have now been other phenotypes proposed under SPSD, including isolated forms (stiff limb or trunk syndrome) and “nonclassic” phenotypes like SPS-plus (classic features plus brain stem and/or cerebellar involvement),3 overlap syndromes (for example, classic features with refractory epilepsy/limbic encephalitis), and probably the most severe phenotype, progressive encephalomyelitis with rigidity and myoclonus.
Early and aggressive therapy with benzodiazepines and other GABA-ergic agonists, as well as immune-based treatments, is considered critical to slowing progression of SPSD. However, the insidious onset of what is often a cluster of vague, nonspecific symptoms is a challenge for clinicians to recognize.
“When a patient comes in with muscular spasms, with stiffness in the back, in the legs, and it’s unexplained and it’s not due to spinal cord disease, or multiple sclerosis ... think SPSD,” said Dr. Dalakas. “Check antibodies – that’s the first thing to do.”
Antibody positivity is most helpful at high levels, he added; low titers can be present in autoimmune diabetes and other conditions, as previously mentioned. The real challenge? When a patient is seronegative.
Embarking on a diagnostic odyssey
Patients “bounce from one clinician to the next looking for answers,” said Dr. Newsome. “Patients will often start with their general practitioner and be referred to physical therapy, rheumatology, or orthopedics, and other specialists, which could include neurology and/or psychiatry, among others. SPSD is often not considered as a possible diagnosis until the patient develops more concrete symptoms and/or objective signs on exam. Of course, considering this diagnosis starts at knowing that it exists.”
Task-specific phobias and exaggerated acoustic startle or sensory reflex are specific symptoms that can red-flag some SPSD patients, said Dr. Dalakas. “Impaired GABA is also important for fears and anxiety. So, when you have a reduction of GABA you have more phobic neuroses – fear of crossing the street, fear of speaking in public, and they get very tense and they cannot perform.
“If the GABA-ergic pathways are dysfunctional, then there’s a relative hyper-excitability within the nervous system,” said Dr. Newsome. “This can be evaluated with electromyography. “The muscles are unhinged and going crazy: Agonists and antagonists are contracting together, which is abnormal. We will also assess for continuous motor unit potential activity within individual muscles – angry muscles just continuously firing. In our experience, this finding appears to be a pretty specific sign of SPS, especially in the torso.” Importantly, the sudden contraction of muscles along with stiffness can lead to traumatic falls, causing major orthopedic and brain injury.
In early stages of SPSD, a careful history and clinical exam is critical to try to shorten what Dr. Newsome calls the patient’s “diagnostic odyssey.”
“It behooves the clinician to put their hands on the patient. Check their back, their abdomen – try to feel for rigidity, paraspinal muscle spasms, and tightness. These regions of the body often have a ropey feel to them, which is due to chronic muscle spasms and tightness. Most [SPSD] patients will have this present in the thoracolumbar area,” he explained. “Check for hyperlordosis, as this is a hallmark sign on exam in SPSD. Additionally, patients can have rigidity and spasticity in their legs or arms. Also, patients with nonclassical phenotypes can present with a variety of other symptoms and findings on exam, including ataxia, nystagmus, ophthalmoparesis, and dysarthria.”
Lumbar puncture can sometimes reveal signs of inflammation, such as an elevated white blood cell count and oligoclonal bands in spinal fluid.
“The classic teaching was that you can only see such findings in conditions like multiple sclerosis, but that’s not the case,” said Dr. Newsome. “You can see these findings in other autoimmune conditions, including SPSD. Hence, as part of the workup, we will have patients undergo lumbar punctures to assess for these markers of autoimmunity.”
Other mimics of SPSD, including multiple sclerosis, tumors, and spinal stenosis, should be ruled out with MRI of the brain and spine.
Treatment options
Because of wide variability in signs and symptoms of the disorder, treatment of SPSD is a highly individualized cocktail of interventions, which might include immunotherapy and GABA-ergic agonists, as well as nonmedication treatments. The response to these agents can be difficult to quantify.
Benzodiazepines (diazepam, clonazepam, baclofen) along with other oral symptomatic treatments are often recommended as first-line therapy because of their ability to enhance GABA.4
First-line immunotherapy is usually intravenous immunoglobulin, steroids, or plasmapheresis. Second- and third-line agents include rituximab, mycophenolate mofetil, azathioprine, cyclophosphamide, and combination immune treatments.
Dr. Newsome and Dr. Dalakas have independently published a step-by-step therapeutic approach to SPSD.3,5 But in patients with paraneoplastic stiff person syndrome, eradication of their cancer is critical, although, per Dr. Newsome, “this does not always cure SPS and most of these patients still have residual disability.”
But immune-based therapies are only part of what should be a multipronged treatment approach, said Dr. Newsome. He also strongly advocates for non-pharmacological interventions, such as selective physical therapy (stretching, ultrasound, and gait and balance training), heat therapy, aquatherapy, deep-tissue massage or myofascial techniques, osteopathic or chiropractic manipulation, acupuncture, and acupressure.3
Because SPSD is considered a progressive disorder for some, a reasonable goal of treatment is to prevent worsening, said Dr. Newsome. This can take time: “We don’t expect the treatments to work overnight. It involves consecutive months and, sometimes, a couple of years of immune treatment before you start to see it impact the person’s life favorably.”
Patients who are not well informed about the long-term goal of treatments might be tempted to abandon the treatments prematurely because they don’t see immediate results, Dr. Newsome added. Encouraging realistic expectations is also important, without dashing hopes.
“I have patients who were marathon runners, and they want to get back to doing marathons. I would love nothing more than for people to get back to their pre-SPSD levels of function. But this may not be a realistic goal. However, this does not mean that quality of life can’t be helped.”
Nevertheless, Dr. Newsome encourages clinicians to reassess regularly, especially because lack of disease biomarkers makes it hard to objectively monitor the impact of therapy.
“It’s always a good rule of thumb, especially in the rare disease space, to step back and ask: ‘Are we on the right treatment path or not?’ If we’re not, then it is important to make sure you have the correct diagnosis. Even when you have a patient who fits the textbook and you, yourself, diagnosed them, it is important to continue to re-evaluate the diagnosis over time, especially if there is consideration of changing treatments. It is also important to make sure there is not something else on top of the stiff person syndrome that is working in parallel to worsen their condition.”
Be alert for comorbidity
Undiagnosed comorbid conditions that can complicate SPSD include Parkinson’s disease or myasthenia gravis, to name a couple, which Dr. Newsome has seen more than once. “We’ve seen a few people over the years who have both SPSD and another autoimmune or degenerative neurological condition.”
Diabetes also co-occurs in approximately 30% of people with SPSD, said Dr. Dalakas. “Endocrinologists should also be aware of this connection.”
Paraneoplastic stiff person syndrome is thought to be triggered by cancer, which might not have been diagnosed, making it important to work up patients for malignancy – particularly breast cancer, small cell lung cancer, lymphoma, and thymoma, Dr. Newsome advised.
Although most cases of SPSD are diagnosed in mid-life, the disorder can occur in teenagers and the elderly.
“It’s not the first thing you think of when a 70-year-old patient comes with neck pain, so it’s missed more often, and the prognosis is worse,” Dr. Dalakas warned.
What does the future hold?
Like Dr. Newsome, Dr. Dalakas is encouraged when SPSD hits the headlines because, generally, awareness facilitates diagnosis and research. (Both clinicians serve on the medical advisory board of The Stiff Person Syndrome Research Foundation.)
“We are looking for better therapies that target immune factors,” said Dr. Dalakas. “There are several of those that are relevant, so we need to select the best immune marker that we think plays a role in the antibody production,” he said.
“There’s a lot of hope – at least I have a lot of hope for what the future holds with SPSD,” added Dr. Newsome. “More research is needed and it starts with awareness of SPSD.”
Dr. Newsome discloses that he has received consulting fees for serving on scientific advisory boards of Biogen, Genentech, Bristol Myers Squibb, EMD Serono, Jazz Pharmaceuticals, Novartis, Horizon Therapeutics, TG Therapeutics; is the study lead principal investigator for a Roche clinical trial; and has received research funding (paid directly to his employing institution) from Biogen, Roche, Lundbeck, Genentech, The Stiff Person Syndrome Research Foundation, National Multiple Sclerosis Society, U.S. Department of Defense, and Patient-Centered Outcomes Research Institute. Dr. Dalakas reports nothing relevant to disclose.
References
1. Chia NH et al. Ann Clin Transl Neurol. 2023;10(7):1083-94. doi: 10.1002/acn3.51791.
2. Dalakas MC.. Curr Treat Options Neurol. 2009;11(2):102-10. doi: 10.1007/s11940-009-0013-9.
3. Newsome SD and Johnson T. J Neuroimmunol. 2022;369:577915. doi: 10.1016/j.jneuroim.2022.577915.
4. Ortiz JF et al. Cureus. 2020;12(12):e11995. doi: 10.7759/cureus.11995.
5. Dalakas CD. Neurol Neuroimmunol Neuroinflamm. 2023;10(3):e200109. doi: 10.1212/NXI.0000000000200109.
When, in 2022, singer and international celebrity Celine Dion announced what she called her “one-in-a-million diagnosis” of stiff person syndrome, clinicians and medical scientists who specialize in the disorder took a deep breath. Scott D. Newsome, DO, professor of neurology and director of the Johns Hopkins Stiff Person Syndrome Center, Baltimore – a glass-half-full kind of person – saw in Ms. Dion’s worrying announcement a huge opportunity nonetheless: To raise awareness about the rare cluster of disorders known collectively as stiff person spectrum disorders (SPSD).
“Even at the clinician level, if you don’t know the hallmark signs and symptoms, you could possibly misdiagnose it,” Dr. Newsome said in an interview.
But misdiagnosis can go either way; increased awareness of SPSD can have a downside. Thirty years ago, when Marinos C. Dalakas, MD, first began studying SPSD, the diagnosis was frequently missed – “because people were not aware of it,” he said. But now, Dr. Dalakas, professor of neurology and director of the division of neuromuscular diseases in the department of neurology at Thomas Jefferson University and the Jefferson Hospital for Neuroscience, both in Philadelphia, said overdiagnosis is also a concern, particularly with increased public awareness.
“Just this last month I saw two patients who told me: ‘I read about it, and I believe I have symptoms of stiff person,’ ” he said.
These days, most patients in whom SPSD is suspected end up with an alternate diagnosis. In a recent retrospective study that Dr. Dalakas coauthored, of 173 patients who had been referred to the Mayo Clinic in Rochester, Minn., with suspected SPSD,1 Dr. Dalakas and colleagues determined that only 48 (27.7%) actually had the disorder – meaning that the rest might have been unnecessarily exposed to immunosuppressive SPSD therapies and that treatment for their actual disorder (most often, a functional neurologic disorder or nonneurologic condition) was delayed.
At the root of both underdiagnosis and overdiagnosis of SPSD is the heterogeneity of the condition and a lack of definitive diagnostic markers.
SPSD has been considered an autoimmune disorder for a long time, and observations by Dr. Dalakas and others have shown that as many as 35% of cases co-occur with another autoimmune disease, such as vitiligo, celiac disease, rheumatologic disease, type 1 diabetes mellitus, and thyroid disease (Grave’s disease and Hashimoto’s thyroiditis).2 A more recent study by his group observed an even higher rate (42%) of comorbid autoimmunity, with autoimmune thyroid disease being most common. However, although most cases of SPDS are characterized by an elevated level of glutamic acid decarboxylase (GAD)65-IgG, these autoantibodies are not specific to SPSD (low levels are also seen in diabetes, thyroid disease, healthy controls, etc.). Some SPSD patients have less common autoantibodies and a minority has no autoantibodies. Dr. Newsome said seronegative cases and the antibody presence and titers not being associated with disease severity or treatment response are clues that “SPSD does not appear to be a primary antibody-mediated condition and that there must be other immune factors at play.”
Autoimmune process drives SPSD
Autoimmunity, even if not detected by serologic studies, is believed to inhibit expression of gamma aminobutyric acid (GABA) receptors, which, in turn, results in stiffness and spasms. Although what are known as “Dalakas criteria,” proposed in 2009,2 describe the “classic” SPSD phenotype, encompassing roughly three-quarters of SPSD patients, there have now been other phenotypes proposed under SPSD, including isolated forms (stiff limb or trunk syndrome) and “nonclassic” phenotypes like SPS-plus (classic features plus brain stem and/or cerebellar involvement),3 overlap syndromes (for example, classic features with refractory epilepsy/limbic encephalitis), and probably the most severe phenotype, progressive encephalomyelitis with rigidity and myoclonus.
Early and aggressive therapy with benzodiazepines and other GABA-ergic agonists, as well as immune-based treatments, is considered critical to slowing progression of SPSD. However, the insidious onset of what is often a cluster of vague, nonspecific symptoms is a challenge for clinicians to recognize.
“When a patient comes in with muscular spasms, with stiffness in the back, in the legs, and it’s unexplained and it’s not due to spinal cord disease, or multiple sclerosis ... think SPSD,” said Dr. Dalakas. “Check antibodies – that’s the first thing to do.”
Antibody positivity is most helpful at high levels, he added; low titers can be present in autoimmune diabetes and other conditions, as previously mentioned. The real challenge? When a patient is seronegative.
Embarking on a diagnostic odyssey
Patients “bounce from one clinician to the next looking for answers,” said Dr. Newsome. “Patients will often start with their general practitioner and be referred to physical therapy, rheumatology, or orthopedics, and other specialists, which could include neurology and/or psychiatry, among others. SPSD is often not considered as a possible diagnosis until the patient develops more concrete symptoms and/or objective signs on exam. Of course, considering this diagnosis starts at knowing that it exists.”
Task-specific phobias and exaggerated acoustic startle or sensory reflex are specific symptoms that can red-flag some SPSD patients, said Dr. Dalakas. “Impaired GABA is also important for fears and anxiety. So, when you have a reduction of GABA you have more phobic neuroses – fear of crossing the street, fear of speaking in public, and they get very tense and they cannot perform.
“If the GABA-ergic pathways are dysfunctional, then there’s a relative hyper-excitability within the nervous system,” said Dr. Newsome. “This can be evaluated with electromyography. “The muscles are unhinged and going crazy: Agonists and antagonists are contracting together, which is abnormal. We will also assess for continuous motor unit potential activity within individual muscles – angry muscles just continuously firing. In our experience, this finding appears to be a pretty specific sign of SPS, especially in the torso.” Importantly, the sudden contraction of muscles along with stiffness can lead to traumatic falls, causing major orthopedic and brain injury.
In early stages of SPSD, a careful history and clinical exam is critical to try to shorten what Dr. Newsome calls the patient’s “diagnostic odyssey.”
“It behooves the clinician to put their hands on the patient. Check their back, their abdomen – try to feel for rigidity, paraspinal muscle spasms, and tightness. These regions of the body often have a ropey feel to them, which is due to chronic muscle spasms and tightness. Most [SPSD] patients will have this present in the thoracolumbar area,” he explained. “Check for hyperlordosis, as this is a hallmark sign on exam in SPSD. Additionally, patients can have rigidity and spasticity in their legs or arms. Also, patients with nonclassical phenotypes can present with a variety of other symptoms and findings on exam, including ataxia, nystagmus, ophthalmoparesis, and dysarthria.”
Lumbar puncture can sometimes reveal signs of inflammation, such as an elevated white blood cell count and oligoclonal bands in spinal fluid.
“The classic teaching was that you can only see such findings in conditions like multiple sclerosis, but that’s not the case,” said Dr. Newsome. “You can see these findings in other autoimmune conditions, including SPSD. Hence, as part of the workup, we will have patients undergo lumbar punctures to assess for these markers of autoimmunity.”
Other mimics of SPSD, including multiple sclerosis, tumors, and spinal stenosis, should be ruled out with MRI of the brain and spine.
Treatment options
Because of wide variability in signs and symptoms of the disorder, treatment of SPSD is a highly individualized cocktail of interventions, which might include immunotherapy and GABA-ergic agonists, as well as nonmedication treatments. The response to these agents can be difficult to quantify.
Benzodiazepines (diazepam, clonazepam, baclofen) along with other oral symptomatic treatments are often recommended as first-line therapy because of their ability to enhance GABA.4
First-line immunotherapy is usually intravenous immunoglobulin, steroids, or plasmapheresis. Second- and third-line agents include rituximab, mycophenolate mofetil, azathioprine, cyclophosphamide, and combination immune treatments.
Dr. Newsome and Dr. Dalakas have independently published a step-by-step therapeutic approach to SPSD.3,5 But in patients with paraneoplastic stiff person syndrome, eradication of their cancer is critical, although, per Dr. Newsome, “this does not always cure SPS and most of these patients still have residual disability.”
But immune-based therapies are only part of what should be a multipronged treatment approach, said Dr. Newsome. He also strongly advocates for non-pharmacological interventions, such as selective physical therapy (stretching, ultrasound, and gait and balance training), heat therapy, aquatherapy, deep-tissue massage or myofascial techniques, osteopathic or chiropractic manipulation, acupuncture, and acupressure.3
Because SPSD is considered a progressive disorder for some, a reasonable goal of treatment is to prevent worsening, said Dr. Newsome. This can take time: “We don’t expect the treatments to work overnight. It involves consecutive months and, sometimes, a couple of years of immune treatment before you start to see it impact the person’s life favorably.”
Patients who are not well informed about the long-term goal of treatments might be tempted to abandon the treatments prematurely because they don’t see immediate results, Dr. Newsome added. Encouraging realistic expectations is also important, without dashing hopes.
“I have patients who were marathon runners, and they want to get back to doing marathons. I would love nothing more than for people to get back to their pre-SPSD levels of function. But this may not be a realistic goal. However, this does not mean that quality of life can’t be helped.”
Nevertheless, Dr. Newsome encourages clinicians to reassess regularly, especially because lack of disease biomarkers makes it hard to objectively monitor the impact of therapy.
“It’s always a good rule of thumb, especially in the rare disease space, to step back and ask: ‘Are we on the right treatment path or not?’ If we’re not, then it is important to make sure you have the correct diagnosis. Even when you have a patient who fits the textbook and you, yourself, diagnosed them, it is important to continue to re-evaluate the diagnosis over time, especially if there is consideration of changing treatments. It is also important to make sure there is not something else on top of the stiff person syndrome that is working in parallel to worsen their condition.”
Be alert for comorbidity
Undiagnosed comorbid conditions that can complicate SPSD include Parkinson’s disease or myasthenia gravis, to name a couple, which Dr. Newsome has seen more than once. “We’ve seen a few people over the years who have both SPSD and another autoimmune or degenerative neurological condition.”
Diabetes also co-occurs in approximately 30% of people with SPSD, said Dr. Dalakas. “Endocrinologists should also be aware of this connection.”
Paraneoplastic stiff person syndrome is thought to be triggered by cancer, which might not have been diagnosed, making it important to work up patients for malignancy – particularly breast cancer, small cell lung cancer, lymphoma, and thymoma, Dr. Newsome advised.
Although most cases of SPSD are diagnosed in mid-life, the disorder can occur in teenagers and the elderly.
“It’s not the first thing you think of when a 70-year-old patient comes with neck pain, so it’s missed more often, and the prognosis is worse,” Dr. Dalakas warned.
What does the future hold?
Like Dr. Newsome, Dr. Dalakas is encouraged when SPSD hits the headlines because, generally, awareness facilitates diagnosis and research. (Both clinicians serve on the medical advisory board of The Stiff Person Syndrome Research Foundation.)
“We are looking for better therapies that target immune factors,” said Dr. Dalakas. “There are several of those that are relevant, so we need to select the best immune marker that we think plays a role in the antibody production,” he said.
“There’s a lot of hope – at least I have a lot of hope for what the future holds with SPSD,” added Dr. Newsome. “More research is needed and it starts with awareness of SPSD.”
Dr. Newsome discloses that he has received consulting fees for serving on scientific advisory boards of Biogen, Genentech, Bristol Myers Squibb, EMD Serono, Jazz Pharmaceuticals, Novartis, Horizon Therapeutics, TG Therapeutics; is the study lead principal investigator for a Roche clinical trial; and has received research funding (paid directly to his employing institution) from Biogen, Roche, Lundbeck, Genentech, The Stiff Person Syndrome Research Foundation, National Multiple Sclerosis Society, U.S. Department of Defense, and Patient-Centered Outcomes Research Institute. Dr. Dalakas reports nothing relevant to disclose.
References
1. Chia NH et al. Ann Clin Transl Neurol. 2023;10(7):1083-94. doi: 10.1002/acn3.51791.
2. Dalakas MC.. Curr Treat Options Neurol. 2009;11(2):102-10. doi: 10.1007/s11940-009-0013-9.
3. Newsome SD and Johnson T. J Neuroimmunol. 2022;369:577915. doi: 10.1016/j.jneuroim.2022.577915.
4. Ortiz JF et al. Cureus. 2020;12(12):e11995. doi: 10.7759/cureus.11995.
5. Dalakas CD. Neurol Neuroimmunol Neuroinflamm. 2023;10(3):e200109. doi: 10.1212/NXI.0000000000200109.
The dawning age of therapy for Friedreich ataxia
It took 160 years but, in February 2023, the Food and Drug Administration approved the first drug specifically designed to treat the rare neuromuscular disease Friedreich ataxia (FA). The disease, first described in 1863 by German physician Nikolaus Friedreich, has an estimated incidence of 1 in 50,000 worldwide. It is the most common form of hereditary ataxia, accounting for approximately 50% of all cases of ataxia and approximately 75% of cases among patients younger than 25 years in the United States.1
FA typically presents in childhood or early adolescence; in some patients, symptoms manifest in the middle of the third decade of life. Patients exhibit symptoms such as ataxia that becomes worse over time, gait ataxia, impaired sensation in the extremities that can spread centrally, loss of normal reflexes, especially in the knees, speech disorders (dysarthria), muscle spasticity, scoliosis, and dysphagia.
Severity of disease ranges from relatively mild to completely disabling. Symptoms are progressive; patients almost inevitably require ambulatory support or a wheelchair. They might develop diabetes mellitus and can lose hearing and vision as the disease progresses. Hypertrophic cardiomyopathy is the most common cause of death among FA patients. Some patients who have less severe features might live into their 60s – even beyond that age.2There is no cure for FA. Until recently, no therapy was available other than supportive care to address associated neuromuscular, cardiovascular, and metabolic complications.
Making the diagnosis
Genetic testing can provide a definitive diagnosis of FA. (The genetic etiology of the disease is described later in this article.)
In addition to genetic screening, the workup includes a thorough medical history and physical examination that focuses on problems with balance, proprioception, absence of reflexes, and neurological signs. Tests include electromyography, nerve-conduction studies, electrocardiography, a metabolic profile, and MRI of the brain and spinal cord.
MRI utility in FA. In a paper published in July 2023 in Brain Communications, investigators from the University of Minnesota, Minneapolis, reported that various MRI techniques can be combined to detect early-stage alterations and disease progression in patients with FA.3 The researchers compared images taken at baseline and at 1, 2, and 3 years in 28 FA patients and 20 age- and gender-matched controls.
They observed that, compared with controls, patients with FA had lower cerebellar white matter volume but not lower cerebellar gray matter volume; larger cerebellar peduncle, thalamus, and brain stem structures; and a higher volume of the fourth ventricle. Using diffusion-tensor imaging and fixel-based analysis of diffusion MRI metrics, they also detected microstructural differences in several brain regions – especially in the cerebellum and corticospinal tract.
“Over time, many of these macrostructural and microstructural alterations progressed, especially cerebellar gray- and white-matter volume and microstructures of the superior cerebellar peduncle, the posterior limb of the internal capsule, and the superior corona radiata,” the investigators reported. In addition, “linear regressions showed significant associations between many of those imaging metrics and clinical scales.”
Pathophysiological basis of FA
The underlying genetic pathology of FA was first described in 1996 by investigators from the University of Valencia (Spain). They reported that FA is caused by a mutation in FXN (formerly X25), a gene that encodes for the protein frataxin, which is important for producing mitochondrial adenosine triphosphate and managing iron stores.4
The mutation results in multiple guanine-adenine-adenine repeats in FXN, or, in a few cases, a point mutation or deletion in 1 allele of FXN, with multiple GAA repeats in the other allele. A hallmark of FA is impairment of cellular antioxidative defense mechanisms – a major cause of disease progression.
The GAA repeat leads to methylation of the promoter region of FXN. This results in production and accumulation in cells of an abnormal, ineffective form of frataxin and oxidative damage to cells, particularly those that require larger amounts of energy, such as cells in the brain, heart, and pancreas.
“You would expect that the cells would be revving up all of their endogenous defenses,” David Lynch, MD, PhD, director of the Friedreich ataxia program at Children’s Hospital of Philadelphia, explained in an interview. “These oxidative damage responses are controlled by a DNA response element called the antioxidant response element, and it’s activated by the transcription factor Nrf2 [nuclear factor erythroid 2–related factor 2].”
Treatment options have been limited
Omaveloxolone. Dr. Lynch is principal investigator for the MOXIe trial of the safety, pharmacodynamics, and efficacy of omaveloxolone (marketed as Skyclarys [Reata Pharmaceuticals]),5 which received FDA orphan drug, fast track, priority review, and rare pediatric disease designations for the treatment of FA and, in February 2023, formal FDA approval.6 Development of this drug, which activates Nrf2 and induces antioxidant target genes, arose from basic science investigation into mechanisms by which cells respond to stresses.
“Omaveloxolone works on the Nrf2 pathway, which is, paradoxically, deficient in FA,” Dr. Lynch said. “This pathway should be active all the time. You would expect that, in cells from Friedreich ataxia in a person or an animal model of the disease, you’d see that Nrf2 would be very active but, in fact, what you find is the opposite,” Dr. Lynch explained. “It’s relatively inefficient, it’s localized in the cell, and the antioxidant response element genes – the things we all use to protect ourselves from mitochondrial damage – are all relatively turned off.”
In the first phase of MOXIe, 103 patients with FA were randomly assigned to receive either omaveloxolone, 15 mg orally (51 patients), or placebo (52 patients) for 48 weeks.
The primary endpoint was change in the modified Friedreich’s Ataxia Rating Scale (mFARS) score at 48 weeks. The scale is a clinically validated neurological instrument that evaluates upper- and lower-limb coordination, upright stability, and bulbar function.
Patients assigned to placebo had worsening of function at 48 weeks (mean increase in mFARS score, 0.85). In contrast, patients assigned to omaveloxolone had a mean decrease in the mFARS score of –1.56, indicating improvement. The between-group difference of –2.41 points was statistically significant in favor of omaveloxolone (P = .038).
In a 3-year, post hoc, propensity-matched analysis, patients assigned to omaveloxolone had lower mFARS scores than a matched set of untreated patients in a study of the natural history of FA.7Dimethyl fumarate (marketed as Tecfidera [Biogen]), approved in the United States and other countries for the treatment of patients with relapsing forms of multiple sclerosis, also has Nrf2 as a therapeutic target, although its precise mechanism of action is unclear. Clinical trials of this agent for the treatment of FA are under consideration in Europe, Dr. Lynch said.
Apart from these agents, treatment of patients with FA largely centers on management of metabolic and cardiac complications; physical and occupational therapy; devices such as orthopedic shoes, canes, and wheelchairs; and, when indicated, surgery to correct skeletal problems or for implantation of a cardiac-assist device.
The FA therapeutic pipeline
According to the Friedreich’s Ataxia Research Alliance, other approaches to improving mitochondrial function and reducing oxidative stress in FA are under investigation or awaiting approval, including elamipretide, for which FDA approval is pending for Barth syndrome (a rare, X-linked disorder) and for primary mitochondrial myopathy; nicotinamide adenine dinucleotide (NAD+, a coenzyme for redox reactions) plus exercise; and MIB-626, a crystalline form of nicotinamide mononucleotide, a precursor of NAD+.
Vatiquinone, an investigational inhibitor of 15-lipoxygenase, a regulator of energetic and oxidative stress pathways, failed to meet its primary endpoint of significant improvement on the mFARS score at 72 weeks of follow-up in the MOVE-FA trial, according to the manufacturer, PTC Therapeutics.8Another therapeutic approach under investigation is modulation of frataxin-controlled metabolic pathways with leriglitazone, an orally available selective peroxisome proliferator-activated receptor gamma agonist,9 or with the prodrug precursor of monomethyl fumarate plus dimethyl fumarate.
CTI-1601, a recombinant fusion protein intended to deliver human frataxin into the mitochondria of patients with FA, is in phase 1 trials. This compound has been granted rare pediatric disease designation, fast track designation, and orphan drug status by the FDA, according to the manufacturer, Larimar Therapeutics.10Etravirine, a nonnucleoside reverse transcriptase inhibitor approved for treating HIV infection, has been demonstrated to increase the frataxin protein in cells derived from FA patients and in the heart and skeletal muscle of frataxin-deficient YG8 mice. This agent recently completed a phase 2 trial in patients with FA.11
Gene therapy: Promising
Given the genetic etiology of FA, gene therapy strategies aimed at either increasing FA gene expression or editing the genome to replace defective FXN are under active investigation.
Increasing FA gene expression. DT-216 (Design Therapeutics) is a novel, gene-targeted chimera small molecule designed to target the GAA repeat expansion mutation and restore FXN expression. This agent completed phase 1 dosing studies in 2022.
Oligonucleotides, which are nucleic acid polymers primarily used for gene silencing, are also being explored for increasing the expression of FXN, in research at the University of Texas Southwestern Medical Center, Dallas, and the University of Massachusetts, Worcester.
Gene replacement strategies under investigation to treat FA include LX2006 (Lexeo Therapeutics), a gene replacement therapy using an adeno-associated viral vector to deliver FXN intravenously, with the goal of getting the gene into myocardial cells and increasing the frataxin level in mitochondria.
A similar approach is being taken by Ronald G. Crystal, MD, and colleagues at Weill Cornell Medicine, New York. The group is designing phase 1 studies of AAVrh.10hFXN, a serotype rh.10 adeno-associated virus coding for human frataxin, with the goal of treating cardiac manifestations of FA.12FA researcher Arnulf H. Koeppen, MD, from the Samuel S. Stratton Department of Veterans Affairs Medical Center, Albany, N.Y., and Albany Medical College, said in an interview that gene replacement therapy in FA is focused on the heart “because there is no blood-heart barrier, but there is a blood-brain barrier that makes it more complicated for gene therapy to reach the brain.”
Future directions
Dr. Koeppen, Dr. Lynch, and colleagues Ian H. Harding, PhD, from Monash University, Melbourne, and Massimo Pandolfo, MD, McGill University, Montreal, conducted an extensive review of FA with a focus on challenges that researchers and drug developers face crafting therapies for this complex disorder.13
They noted that FA is “characterized by marked differences in the vulnerability of neuronal systems. In general, the proprioceptive system appears to be affected early, while later in the disease, the dentate nucleus of the cerebellum and, to some degree, the corticospinal tracts degenerate.”
The authors took a deep dive into the evidence, old and new, to evaluate the effects of FA on the central and peripheral nervous systems and to look at the course of neuropathologic changes associated with the disease. They propose a comprehensive approach to identify nervous system locations that are likely to be most successfully targeted at different disease time points.
“The proprioceptive system, usually considered a major target for frataxin-restoring treatments, shows substantial evidence of hypoplasia and/or early developmental loss, with minimal evidence of progression over time,” they wrote. “It seems likely that this system is not an ideal target for therapies given after early childhood. Targeting the [dentate nucleus] of the cerebellum is likely to be most effective early in the course of the disease, when it is functionally affected, but still shows limited atrophy. The corticospinal tract degenerates over time contributing to disease progression throughout its late stages and may be considered a target.”
David Lynch, MD, PhD, and Arnulf Koeppen, MD, disclose support from the Friedreich’s Ataxia Research Alliance. Dr. Lynch also discloses support from the National Institutes of Health, U.S. Food and Drug Administration, Muscular Dystrophy Association, Reata Pharmaceuticals, and Retrotope.
References
1. Williams CT and De Jesus O. Friedreich ataxia. StatPearls. 2023 Jun 27. https://www.ncbi.nlm.nih.gov/books/NBK563199/.
2. National Institute of Neurological Disorders and Stroke. Friedreich ataxia. 2023 Sep 2. https://www.ninds.nih.gov/health-information/disorders/friedreich-ataxia.
3. Adanyeguh IM et al. Brain Commun. 2023;5(4):fcad196. doi: 10.1093/braincomms/fcad196.
4. Camapuzano V et al. Science. 1996;271(5254):1423-7. doi: 10.1126/science.271.5254.1423.
5. RTA 408 capsules in patients with Friedreich’s ataxia–MOXIe. ClinicalTrials. gov Identifier: NCT02255435. 2022 Dec 6. https://clinicaltrials.gov/study/NCT02255435.
6. Food and Drug Administration. FDA approves first treatment for Friedreich’s ataxia. 2023 Feb 28. www.fda.gov/drugs/news-events-human-drugs/fda-approves-first-treatment-friedreichs-ataxia#.
7. Lynch DR et al. Ann Clin Transl Neurol. 2023 Sep 10. doi: 10.1002/acn3.51897
8. PTC Therapeutics. PTC Therapeutics announces topline results from vatiquinone MOVE-FA registration-directed trial. 2023 May 23. https://ir.ptcbio.com/news-releases/news-release-details/ptc-therapeutics-announces-topline-results-vatiquinone-move-fa.
9. Minoryx Therapeutics. The FRAMES Clinical Study in FRDA. https://www.minoryx.com/clinical-studies/clinical-study-frames/.
10. Larimar Therapeutics. CTI-1601 for Friedreich’s ataxia. https://larimartx.com/our-programs/cti-1601/.
11. Safety and efficacy of etravirine in Friedreich ataxia patients (FAEST1). ClinicalTrials.gov Identifier: NCT04273165. 2023 Mar 20. https://clinicaltrials.gov/study/NCT04273165.
12. Phase IA study of AAVrh.10hFXN gene therapy for the cardiomyopathy of Friedreich’s ataxia. ClinicalTrials.gov Identifier: NCT05302271. https://clinicaltrials.gov/study/NCT05302271.
13. Harding IH et al. Hum Gene Ther. 2020;31(23-24):1226-36. doi: 10.1089/hum.2020.264
It took 160 years but, in February 2023, the Food and Drug Administration approved the first drug specifically designed to treat the rare neuromuscular disease Friedreich ataxia (FA). The disease, first described in 1863 by German physician Nikolaus Friedreich, has an estimated incidence of 1 in 50,000 worldwide. It is the most common form of hereditary ataxia, accounting for approximately 50% of all cases of ataxia and approximately 75% of cases among patients younger than 25 years in the United States.1
FA typically presents in childhood or early adolescence; in some patients, symptoms manifest in the middle of the third decade of life. Patients exhibit symptoms such as ataxia that becomes worse over time, gait ataxia, impaired sensation in the extremities that can spread centrally, loss of normal reflexes, especially in the knees, speech disorders (dysarthria), muscle spasticity, scoliosis, and dysphagia.
Severity of disease ranges from relatively mild to completely disabling. Symptoms are progressive; patients almost inevitably require ambulatory support or a wheelchair. They might develop diabetes mellitus and can lose hearing and vision as the disease progresses. Hypertrophic cardiomyopathy is the most common cause of death among FA patients. Some patients who have less severe features might live into their 60s – even beyond that age.2There is no cure for FA. Until recently, no therapy was available other than supportive care to address associated neuromuscular, cardiovascular, and metabolic complications.
Making the diagnosis
Genetic testing can provide a definitive diagnosis of FA. (The genetic etiology of the disease is described later in this article.)
In addition to genetic screening, the workup includes a thorough medical history and physical examination that focuses on problems with balance, proprioception, absence of reflexes, and neurological signs. Tests include electromyography, nerve-conduction studies, electrocardiography, a metabolic profile, and MRI of the brain and spinal cord.
MRI utility in FA. In a paper published in July 2023 in Brain Communications, investigators from the University of Minnesota, Minneapolis, reported that various MRI techniques can be combined to detect early-stage alterations and disease progression in patients with FA.3 The researchers compared images taken at baseline and at 1, 2, and 3 years in 28 FA patients and 20 age- and gender-matched controls.
They observed that, compared with controls, patients with FA had lower cerebellar white matter volume but not lower cerebellar gray matter volume; larger cerebellar peduncle, thalamus, and brain stem structures; and a higher volume of the fourth ventricle. Using diffusion-tensor imaging and fixel-based analysis of diffusion MRI metrics, they also detected microstructural differences in several brain regions – especially in the cerebellum and corticospinal tract.
“Over time, many of these macrostructural and microstructural alterations progressed, especially cerebellar gray- and white-matter volume and microstructures of the superior cerebellar peduncle, the posterior limb of the internal capsule, and the superior corona radiata,” the investigators reported. In addition, “linear regressions showed significant associations between many of those imaging metrics and clinical scales.”
Pathophysiological basis of FA
The underlying genetic pathology of FA was first described in 1996 by investigators from the University of Valencia (Spain). They reported that FA is caused by a mutation in FXN (formerly X25), a gene that encodes for the protein frataxin, which is important for producing mitochondrial adenosine triphosphate and managing iron stores.4
The mutation results in multiple guanine-adenine-adenine repeats in FXN, or, in a few cases, a point mutation or deletion in 1 allele of FXN, with multiple GAA repeats in the other allele. A hallmark of FA is impairment of cellular antioxidative defense mechanisms – a major cause of disease progression.
The GAA repeat leads to methylation of the promoter region of FXN. This results in production and accumulation in cells of an abnormal, ineffective form of frataxin and oxidative damage to cells, particularly those that require larger amounts of energy, such as cells in the brain, heart, and pancreas.
“You would expect that the cells would be revving up all of their endogenous defenses,” David Lynch, MD, PhD, director of the Friedreich ataxia program at Children’s Hospital of Philadelphia, explained in an interview. “These oxidative damage responses are controlled by a DNA response element called the antioxidant response element, and it’s activated by the transcription factor Nrf2 [nuclear factor erythroid 2–related factor 2].”
Treatment options have been limited
Omaveloxolone. Dr. Lynch is principal investigator for the MOXIe trial of the safety, pharmacodynamics, and efficacy of omaveloxolone (marketed as Skyclarys [Reata Pharmaceuticals]),5 which received FDA orphan drug, fast track, priority review, and rare pediatric disease designations for the treatment of FA and, in February 2023, formal FDA approval.6 Development of this drug, which activates Nrf2 and induces antioxidant target genes, arose from basic science investigation into mechanisms by which cells respond to stresses.
“Omaveloxolone works on the Nrf2 pathway, which is, paradoxically, deficient in FA,” Dr. Lynch said. “This pathway should be active all the time. You would expect that, in cells from Friedreich ataxia in a person or an animal model of the disease, you’d see that Nrf2 would be very active but, in fact, what you find is the opposite,” Dr. Lynch explained. “It’s relatively inefficient, it’s localized in the cell, and the antioxidant response element genes – the things we all use to protect ourselves from mitochondrial damage – are all relatively turned off.”
In the first phase of MOXIe, 103 patients with FA were randomly assigned to receive either omaveloxolone, 15 mg orally (51 patients), or placebo (52 patients) for 48 weeks.
The primary endpoint was change in the modified Friedreich’s Ataxia Rating Scale (mFARS) score at 48 weeks. The scale is a clinically validated neurological instrument that evaluates upper- and lower-limb coordination, upright stability, and bulbar function.
Patients assigned to placebo had worsening of function at 48 weeks (mean increase in mFARS score, 0.85). In contrast, patients assigned to omaveloxolone had a mean decrease in the mFARS score of –1.56, indicating improvement. The between-group difference of –2.41 points was statistically significant in favor of omaveloxolone (P = .038).
In a 3-year, post hoc, propensity-matched analysis, patients assigned to omaveloxolone had lower mFARS scores than a matched set of untreated patients in a study of the natural history of FA.7Dimethyl fumarate (marketed as Tecfidera [Biogen]), approved in the United States and other countries for the treatment of patients with relapsing forms of multiple sclerosis, also has Nrf2 as a therapeutic target, although its precise mechanism of action is unclear. Clinical trials of this agent for the treatment of FA are under consideration in Europe, Dr. Lynch said.
Apart from these agents, treatment of patients with FA largely centers on management of metabolic and cardiac complications; physical and occupational therapy; devices such as orthopedic shoes, canes, and wheelchairs; and, when indicated, surgery to correct skeletal problems or for implantation of a cardiac-assist device.
The FA therapeutic pipeline
According to the Friedreich’s Ataxia Research Alliance, other approaches to improving mitochondrial function and reducing oxidative stress in FA are under investigation or awaiting approval, including elamipretide, for which FDA approval is pending for Barth syndrome (a rare, X-linked disorder) and for primary mitochondrial myopathy; nicotinamide adenine dinucleotide (NAD+, a coenzyme for redox reactions) plus exercise; and MIB-626, a crystalline form of nicotinamide mononucleotide, a precursor of NAD+.
Vatiquinone, an investigational inhibitor of 15-lipoxygenase, a regulator of energetic and oxidative stress pathways, failed to meet its primary endpoint of significant improvement on the mFARS score at 72 weeks of follow-up in the MOVE-FA trial, according to the manufacturer, PTC Therapeutics.8Another therapeutic approach under investigation is modulation of frataxin-controlled metabolic pathways with leriglitazone, an orally available selective peroxisome proliferator-activated receptor gamma agonist,9 or with the prodrug precursor of monomethyl fumarate plus dimethyl fumarate.
CTI-1601, a recombinant fusion protein intended to deliver human frataxin into the mitochondria of patients with FA, is in phase 1 trials. This compound has been granted rare pediatric disease designation, fast track designation, and orphan drug status by the FDA, according to the manufacturer, Larimar Therapeutics.10Etravirine, a nonnucleoside reverse transcriptase inhibitor approved for treating HIV infection, has been demonstrated to increase the frataxin protein in cells derived from FA patients and in the heart and skeletal muscle of frataxin-deficient YG8 mice. This agent recently completed a phase 2 trial in patients with FA.11
Gene therapy: Promising
Given the genetic etiology of FA, gene therapy strategies aimed at either increasing FA gene expression or editing the genome to replace defective FXN are under active investigation.
Increasing FA gene expression. DT-216 (Design Therapeutics) is a novel, gene-targeted chimera small molecule designed to target the GAA repeat expansion mutation and restore FXN expression. This agent completed phase 1 dosing studies in 2022.
Oligonucleotides, which are nucleic acid polymers primarily used for gene silencing, are also being explored for increasing the expression of FXN, in research at the University of Texas Southwestern Medical Center, Dallas, and the University of Massachusetts, Worcester.
Gene replacement strategies under investigation to treat FA include LX2006 (Lexeo Therapeutics), a gene replacement therapy using an adeno-associated viral vector to deliver FXN intravenously, with the goal of getting the gene into myocardial cells and increasing the frataxin level in mitochondria.
A similar approach is being taken by Ronald G. Crystal, MD, and colleagues at Weill Cornell Medicine, New York. The group is designing phase 1 studies of AAVrh.10hFXN, a serotype rh.10 adeno-associated virus coding for human frataxin, with the goal of treating cardiac manifestations of FA.12FA researcher Arnulf H. Koeppen, MD, from the Samuel S. Stratton Department of Veterans Affairs Medical Center, Albany, N.Y., and Albany Medical College, said in an interview that gene replacement therapy in FA is focused on the heart “because there is no blood-heart barrier, but there is a blood-brain barrier that makes it more complicated for gene therapy to reach the brain.”
Future directions
Dr. Koeppen, Dr. Lynch, and colleagues Ian H. Harding, PhD, from Monash University, Melbourne, and Massimo Pandolfo, MD, McGill University, Montreal, conducted an extensive review of FA with a focus on challenges that researchers and drug developers face crafting therapies for this complex disorder.13
They noted that FA is “characterized by marked differences in the vulnerability of neuronal systems. In general, the proprioceptive system appears to be affected early, while later in the disease, the dentate nucleus of the cerebellum and, to some degree, the corticospinal tracts degenerate.”
The authors took a deep dive into the evidence, old and new, to evaluate the effects of FA on the central and peripheral nervous systems and to look at the course of neuropathologic changes associated with the disease. They propose a comprehensive approach to identify nervous system locations that are likely to be most successfully targeted at different disease time points.
“The proprioceptive system, usually considered a major target for frataxin-restoring treatments, shows substantial evidence of hypoplasia and/or early developmental loss, with minimal evidence of progression over time,” they wrote. “It seems likely that this system is not an ideal target for therapies given after early childhood. Targeting the [dentate nucleus] of the cerebellum is likely to be most effective early in the course of the disease, when it is functionally affected, but still shows limited atrophy. The corticospinal tract degenerates over time contributing to disease progression throughout its late stages and may be considered a target.”
David Lynch, MD, PhD, and Arnulf Koeppen, MD, disclose support from the Friedreich’s Ataxia Research Alliance. Dr. Lynch also discloses support from the National Institutes of Health, U.S. Food and Drug Administration, Muscular Dystrophy Association, Reata Pharmaceuticals, and Retrotope.
References
1. Williams CT and De Jesus O. Friedreich ataxia. StatPearls. 2023 Jun 27. https://www.ncbi.nlm.nih.gov/books/NBK563199/.
2. National Institute of Neurological Disorders and Stroke. Friedreich ataxia. 2023 Sep 2. https://www.ninds.nih.gov/health-information/disorders/friedreich-ataxia.
3. Adanyeguh IM et al. Brain Commun. 2023;5(4):fcad196. doi: 10.1093/braincomms/fcad196.
4. Camapuzano V et al. Science. 1996;271(5254):1423-7. doi: 10.1126/science.271.5254.1423.
5. RTA 408 capsules in patients with Friedreich’s ataxia–MOXIe. ClinicalTrials. gov Identifier: NCT02255435. 2022 Dec 6. https://clinicaltrials.gov/study/NCT02255435.
6. Food and Drug Administration. FDA approves first treatment for Friedreich’s ataxia. 2023 Feb 28. www.fda.gov/drugs/news-events-human-drugs/fda-approves-first-treatment-friedreichs-ataxia#.
7. Lynch DR et al. Ann Clin Transl Neurol. 2023 Sep 10. doi: 10.1002/acn3.51897
8. PTC Therapeutics. PTC Therapeutics announces topline results from vatiquinone MOVE-FA registration-directed trial. 2023 May 23. https://ir.ptcbio.com/news-releases/news-release-details/ptc-therapeutics-announces-topline-results-vatiquinone-move-fa.
9. Minoryx Therapeutics. The FRAMES Clinical Study in FRDA. https://www.minoryx.com/clinical-studies/clinical-study-frames/.
10. Larimar Therapeutics. CTI-1601 for Friedreich’s ataxia. https://larimartx.com/our-programs/cti-1601/.
11. Safety and efficacy of etravirine in Friedreich ataxia patients (FAEST1). ClinicalTrials.gov Identifier: NCT04273165. 2023 Mar 20. https://clinicaltrials.gov/study/NCT04273165.
12. Phase IA study of AAVrh.10hFXN gene therapy for the cardiomyopathy of Friedreich’s ataxia. ClinicalTrials.gov Identifier: NCT05302271. https://clinicaltrials.gov/study/NCT05302271.
13. Harding IH et al. Hum Gene Ther. 2020;31(23-24):1226-36. doi: 10.1089/hum.2020.264
It took 160 years but, in February 2023, the Food and Drug Administration approved the first drug specifically designed to treat the rare neuromuscular disease Friedreich ataxia (FA). The disease, first described in 1863 by German physician Nikolaus Friedreich, has an estimated incidence of 1 in 50,000 worldwide. It is the most common form of hereditary ataxia, accounting for approximately 50% of all cases of ataxia and approximately 75% of cases among patients younger than 25 years in the United States.1
FA typically presents in childhood or early adolescence; in some patients, symptoms manifest in the middle of the third decade of life. Patients exhibit symptoms such as ataxia that becomes worse over time, gait ataxia, impaired sensation in the extremities that can spread centrally, loss of normal reflexes, especially in the knees, speech disorders (dysarthria), muscle spasticity, scoliosis, and dysphagia.
Severity of disease ranges from relatively mild to completely disabling. Symptoms are progressive; patients almost inevitably require ambulatory support or a wheelchair. They might develop diabetes mellitus and can lose hearing and vision as the disease progresses. Hypertrophic cardiomyopathy is the most common cause of death among FA patients. Some patients who have less severe features might live into their 60s – even beyond that age.2There is no cure for FA. Until recently, no therapy was available other than supportive care to address associated neuromuscular, cardiovascular, and metabolic complications.
Making the diagnosis
Genetic testing can provide a definitive diagnosis of FA. (The genetic etiology of the disease is described later in this article.)
In addition to genetic screening, the workup includes a thorough medical history and physical examination that focuses on problems with balance, proprioception, absence of reflexes, and neurological signs. Tests include electromyography, nerve-conduction studies, electrocardiography, a metabolic profile, and MRI of the brain and spinal cord.
MRI utility in FA. In a paper published in July 2023 in Brain Communications, investigators from the University of Minnesota, Minneapolis, reported that various MRI techniques can be combined to detect early-stage alterations and disease progression in patients with FA.3 The researchers compared images taken at baseline and at 1, 2, and 3 years in 28 FA patients and 20 age- and gender-matched controls.
They observed that, compared with controls, patients with FA had lower cerebellar white matter volume but not lower cerebellar gray matter volume; larger cerebellar peduncle, thalamus, and brain stem structures; and a higher volume of the fourth ventricle. Using diffusion-tensor imaging and fixel-based analysis of diffusion MRI metrics, they also detected microstructural differences in several brain regions – especially in the cerebellum and corticospinal tract.
“Over time, many of these macrostructural and microstructural alterations progressed, especially cerebellar gray- and white-matter volume and microstructures of the superior cerebellar peduncle, the posterior limb of the internal capsule, and the superior corona radiata,” the investigators reported. In addition, “linear regressions showed significant associations between many of those imaging metrics and clinical scales.”
Pathophysiological basis of FA
The underlying genetic pathology of FA was first described in 1996 by investigators from the University of Valencia (Spain). They reported that FA is caused by a mutation in FXN (formerly X25), a gene that encodes for the protein frataxin, which is important for producing mitochondrial adenosine triphosphate and managing iron stores.4
The mutation results in multiple guanine-adenine-adenine repeats in FXN, or, in a few cases, a point mutation or deletion in 1 allele of FXN, with multiple GAA repeats in the other allele. A hallmark of FA is impairment of cellular antioxidative defense mechanisms – a major cause of disease progression.
The GAA repeat leads to methylation of the promoter region of FXN. This results in production and accumulation in cells of an abnormal, ineffective form of frataxin and oxidative damage to cells, particularly those that require larger amounts of energy, such as cells in the brain, heart, and pancreas.
“You would expect that the cells would be revving up all of their endogenous defenses,” David Lynch, MD, PhD, director of the Friedreich ataxia program at Children’s Hospital of Philadelphia, explained in an interview. “These oxidative damage responses are controlled by a DNA response element called the antioxidant response element, and it’s activated by the transcription factor Nrf2 [nuclear factor erythroid 2–related factor 2].”
Treatment options have been limited
Omaveloxolone. Dr. Lynch is principal investigator for the MOXIe trial of the safety, pharmacodynamics, and efficacy of omaveloxolone (marketed as Skyclarys [Reata Pharmaceuticals]),5 which received FDA orphan drug, fast track, priority review, and rare pediatric disease designations for the treatment of FA and, in February 2023, formal FDA approval.6 Development of this drug, which activates Nrf2 and induces antioxidant target genes, arose from basic science investigation into mechanisms by which cells respond to stresses.
“Omaveloxolone works on the Nrf2 pathway, which is, paradoxically, deficient in FA,” Dr. Lynch said. “This pathway should be active all the time. You would expect that, in cells from Friedreich ataxia in a person or an animal model of the disease, you’d see that Nrf2 would be very active but, in fact, what you find is the opposite,” Dr. Lynch explained. “It’s relatively inefficient, it’s localized in the cell, and the antioxidant response element genes – the things we all use to protect ourselves from mitochondrial damage – are all relatively turned off.”
In the first phase of MOXIe, 103 patients with FA were randomly assigned to receive either omaveloxolone, 15 mg orally (51 patients), or placebo (52 patients) for 48 weeks.
The primary endpoint was change in the modified Friedreich’s Ataxia Rating Scale (mFARS) score at 48 weeks. The scale is a clinically validated neurological instrument that evaluates upper- and lower-limb coordination, upright stability, and bulbar function.
Patients assigned to placebo had worsening of function at 48 weeks (mean increase in mFARS score, 0.85). In contrast, patients assigned to omaveloxolone had a mean decrease in the mFARS score of –1.56, indicating improvement. The between-group difference of –2.41 points was statistically significant in favor of omaveloxolone (P = .038).
In a 3-year, post hoc, propensity-matched analysis, patients assigned to omaveloxolone had lower mFARS scores than a matched set of untreated patients in a study of the natural history of FA.7Dimethyl fumarate (marketed as Tecfidera [Biogen]), approved in the United States and other countries for the treatment of patients with relapsing forms of multiple sclerosis, also has Nrf2 as a therapeutic target, although its precise mechanism of action is unclear. Clinical trials of this agent for the treatment of FA are under consideration in Europe, Dr. Lynch said.
Apart from these agents, treatment of patients with FA largely centers on management of metabolic and cardiac complications; physical and occupational therapy; devices such as orthopedic shoes, canes, and wheelchairs; and, when indicated, surgery to correct skeletal problems or for implantation of a cardiac-assist device.
The FA therapeutic pipeline
According to the Friedreich’s Ataxia Research Alliance, other approaches to improving mitochondrial function and reducing oxidative stress in FA are under investigation or awaiting approval, including elamipretide, for which FDA approval is pending for Barth syndrome (a rare, X-linked disorder) and for primary mitochondrial myopathy; nicotinamide adenine dinucleotide (NAD+, a coenzyme for redox reactions) plus exercise; and MIB-626, a crystalline form of nicotinamide mononucleotide, a precursor of NAD+.
Vatiquinone, an investigational inhibitor of 15-lipoxygenase, a regulator of energetic and oxidative stress pathways, failed to meet its primary endpoint of significant improvement on the mFARS score at 72 weeks of follow-up in the MOVE-FA trial, according to the manufacturer, PTC Therapeutics.8Another therapeutic approach under investigation is modulation of frataxin-controlled metabolic pathways with leriglitazone, an orally available selective peroxisome proliferator-activated receptor gamma agonist,9 or with the prodrug precursor of monomethyl fumarate plus dimethyl fumarate.
CTI-1601, a recombinant fusion protein intended to deliver human frataxin into the mitochondria of patients with FA, is in phase 1 trials. This compound has been granted rare pediatric disease designation, fast track designation, and orphan drug status by the FDA, according to the manufacturer, Larimar Therapeutics.10Etravirine, a nonnucleoside reverse transcriptase inhibitor approved for treating HIV infection, has been demonstrated to increase the frataxin protein in cells derived from FA patients and in the heart and skeletal muscle of frataxin-deficient YG8 mice. This agent recently completed a phase 2 trial in patients with FA.11
Gene therapy: Promising
Given the genetic etiology of FA, gene therapy strategies aimed at either increasing FA gene expression or editing the genome to replace defective FXN are under active investigation.
Increasing FA gene expression. DT-216 (Design Therapeutics) is a novel, gene-targeted chimera small molecule designed to target the GAA repeat expansion mutation and restore FXN expression. This agent completed phase 1 dosing studies in 2022.
Oligonucleotides, which are nucleic acid polymers primarily used for gene silencing, are also being explored for increasing the expression of FXN, in research at the University of Texas Southwestern Medical Center, Dallas, and the University of Massachusetts, Worcester.
Gene replacement strategies under investigation to treat FA include LX2006 (Lexeo Therapeutics), a gene replacement therapy using an adeno-associated viral vector to deliver FXN intravenously, with the goal of getting the gene into myocardial cells and increasing the frataxin level in mitochondria.
A similar approach is being taken by Ronald G. Crystal, MD, and colleagues at Weill Cornell Medicine, New York. The group is designing phase 1 studies of AAVrh.10hFXN, a serotype rh.10 adeno-associated virus coding for human frataxin, with the goal of treating cardiac manifestations of FA.12FA researcher Arnulf H. Koeppen, MD, from the Samuel S. Stratton Department of Veterans Affairs Medical Center, Albany, N.Y., and Albany Medical College, said in an interview that gene replacement therapy in FA is focused on the heart “because there is no blood-heart barrier, but there is a blood-brain barrier that makes it more complicated for gene therapy to reach the brain.”
Future directions
Dr. Koeppen, Dr. Lynch, and colleagues Ian H. Harding, PhD, from Monash University, Melbourne, and Massimo Pandolfo, MD, McGill University, Montreal, conducted an extensive review of FA with a focus on challenges that researchers and drug developers face crafting therapies for this complex disorder.13
They noted that FA is “characterized by marked differences in the vulnerability of neuronal systems. In general, the proprioceptive system appears to be affected early, while later in the disease, the dentate nucleus of the cerebellum and, to some degree, the corticospinal tracts degenerate.”
The authors took a deep dive into the evidence, old and new, to evaluate the effects of FA on the central and peripheral nervous systems and to look at the course of neuropathologic changes associated with the disease. They propose a comprehensive approach to identify nervous system locations that are likely to be most successfully targeted at different disease time points.
“The proprioceptive system, usually considered a major target for frataxin-restoring treatments, shows substantial evidence of hypoplasia and/or early developmental loss, with minimal evidence of progression over time,” they wrote. “It seems likely that this system is not an ideal target for therapies given after early childhood. Targeting the [dentate nucleus] of the cerebellum is likely to be most effective early in the course of the disease, when it is functionally affected, but still shows limited atrophy. The corticospinal tract degenerates over time contributing to disease progression throughout its late stages and may be considered a target.”
David Lynch, MD, PhD, and Arnulf Koeppen, MD, disclose support from the Friedreich’s Ataxia Research Alliance. Dr. Lynch also discloses support from the National Institutes of Health, U.S. Food and Drug Administration, Muscular Dystrophy Association, Reata Pharmaceuticals, and Retrotope.
References
1. Williams CT and De Jesus O. Friedreich ataxia. StatPearls. 2023 Jun 27. https://www.ncbi.nlm.nih.gov/books/NBK563199/.
2. National Institute of Neurological Disorders and Stroke. Friedreich ataxia. 2023 Sep 2. https://www.ninds.nih.gov/health-information/disorders/friedreich-ataxia.
3. Adanyeguh IM et al. Brain Commun. 2023;5(4):fcad196. doi: 10.1093/braincomms/fcad196.
4. Camapuzano V et al. Science. 1996;271(5254):1423-7. doi: 10.1126/science.271.5254.1423.
5. RTA 408 capsules in patients with Friedreich’s ataxia–MOXIe. ClinicalTrials. gov Identifier: NCT02255435. 2022 Dec 6. https://clinicaltrials.gov/study/NCT02255435.
6. Food and Drug Administration. FDA approves first treatment for Friedreich’s ataxia. 2023 Feb 28. www.fda.gov/drugs/news-events-human-drugs/fda-approves-first-treatment-friedreichs-ataxia#.
7. Lynch DR et al. Ann Clin Transl Neurol. 2023 Sep 10. doi: 10.1002/acn3.51897
8. PTC Therapeutics. PTC Therapeutics announces topline results from vatiquinone MOVE-FA registration-directed trial. 2023 May 23. https://ir.ptcbio.com/news-releases/news-release-details/ptc-therapeutics-announces-topline-results-vatiquinone-move-fa.
9. Minoryx Therapeutics. The FRAMES Clinical Study in FRDA. https://www.minoryx.com/clinical-studies/clinical-study-frames/.
10. Larimar Therapeutics. CTI-1601 for Friedreich’s ataxia. https://larimartx.com/our-programs/cti-1601/.
11. Safety and efficacy of etravirine in Friedreich ataxia patients (FAEST1). ClinicalTrials.gov Identifier: NCT04273165. 2023 Mar 20. https://clinicaltrials.gov/study/NCT04273165.
12. Phase IA study of AAVrh.10hFXN gene therapy for the cardiomyopathy of Friedreich’s ataxia. ClinicalTrials.gov Identifier: NCT05302271. https://clinicaltrials.gov/study/NCT05302271.
13. Harding IH et al. Hum Gene Ther. 2020;31(23-24):1226-36. doi: 10.1089/hum.2020.264
Has prompt diagnosis of amyotrophic lateral sclerosis become urgent?
Amyotrophic lateral sclerosis (ALS) falls easily into the Food and Drug Administration definition of “rare disease.” With an estimated prevalence in the United States of fewer than 20,000 cases,1 ALS sits comfortably below the cutoff of 200,000 cases that serves to define a disease as “rare.”
After a recent steep climb, there are something on the order of 50 therapies, across more than 10 drug classes, in clinical trials for the treatment of ALS.2 This bounty represents exciting progress toward the development of targeted therapies for a characteristically fatal disease.
That headway is coupled with a sobering limitation, however: Relatively few ALS patients are being enrolled.
The knotty problem with therapeutic trials for ALS
“Trials are generally designed for patients with adequate functional reserve and predicted survival, to ensure that a signal of benefit can be seen,” said Nicholas John Maragakis, MD, director of the ALS Clinical Trials Unit at Johns Hopkins University, Baltimore. “Many of my patients are too severely affected at presentation.”
Dr. Maragakis hasn’t calculated the precise percentage of patients he is enrolling in one of the many available trials available at the Johns Hopkins center. He estimates that it is less than 20%, however.
That percentage is comparable to what is reported by Stephen Scelsa, MD, and Daniel J. Macgowan, MD, who share much of the ALS caseload in a dedicated, comprehensive ALS center at Mount Sinai Beth Israel, New York. Both are on the faculty at the Icahn School of Medicine at Mount Sinai.
“The considerable delay in the diagnosis of ALS remains a challenge,” Dr. Scelsa acknowledges. Like Dr. Maragakis, he reports that, by the time patients develop symptoms that make referral to a comprehensive ALS center like Mount Sinai Beth Israel appropriate, many no longer meet eligibility criteria for most experimental treatments.
Some therapeutic targets in clinical trials, such as neuroinflammation, offer potential benefit even in advancing disease, but it is prevention that is usually the goal of experimental ALS therapies. This approach is associated with far more promise than attempting to reverse existing neurologic damage, which might not be possible, according to both Dr. Scelsa and Dr. Macgowan.
“The clinical trials are typically looking for patients with less than 2 years since the onset of symptoms and at least 60% of predicted respiratory function,” Dr. Macgowan said.
Because of these or other similarly restrictive criteria, coupled with common delays before patients arrive at a center where trials are available, “the window for clinical research closes very quickly,” Dr. Macgowan added, and “the band of patients who are eligible is relatively narrow.”
At Hennepin Healthcare in Minneapolis, which, like Johns Hopkins and Mount Sinai, offers an advanced multidisciplinary approach to ALS care in a dedicated clinic, the problem of late referrals is no different. Samuel Maiser, MD, chair of neurology, does attempt to counter this delay by moving quickly.
“I almost always offer a therapeutic trial to a patient with early-stage ALS,” he said. He does so earlier, rather than later, and explains: “I do not want to delay that conversation, because any delay might reduce the chance for getting into a trial.”
The generalist can make a difference in therapeutic success
The proliferation of clinical trials has made early diagnosis of ALS urgent. However, the experts interviewed for this article agreed: Accelerating the time to diagnosis is more dependent on the general neurologist or primary care physician than on the ALS specialist. ALS is a diagnosis of exclusion, but there is now very little delay in reaching a probable diagnosis at a dedicated center.
Yet neurodegenerative complaints in early-stage ALS are often nonspecific and mild; confidence in making a potential diagnosis of ALS is limited among primary care clinicians and general neurologists, who almost always see these patients first. Usually, the problem is not failure to include ALS in the differential diagnosis but hesitation in being candid when there is still doubt.
General neurologists, in particular, Dr. Maragakis said, “are often highly suspicious of a diagnosis of ALS very early on but are concerned about using this term until the clinical signs are more compelling.”
This is understandable. There is reluctance to deliver bad news when confidence in the diagnosis is limited. But the experts agreed: Delayed diagnosis is not in the patient’s interest now that there is at least the potential for entering a trial supported by a scientific rationale for benefit.
“Waiting for 100% certainty – this could actually harm our patients,” Dr. Maiser said. The tendency to avoid delivering bad news, he said, “is human nature, and it is not easy to tell people that ALS is the potential cause, but it’s important for early treatment.”
Some evidence suggests that the incidence of ALS is increasing3 but this is not necessarily evident at the clinical level. “It is not my impression that the incidence of ALS is increasing,” Dr. Macgowan said, “so much as I think we are getting better at making the diagnosis.”
Where we stand: Pathophysiology, diagnosis, treatment
Pathophysiology. ALS is characterized by muscle denervation.4 In the great majority of cases, the disease represents a proteinopathy involving loss of the TDP-43 protein from nuclei. However, pathological heterogeneity means that other pathophysiological mechanisms – mediated by oxidative stress, mitochondrial dysfunction, and neurotoxicity related to excessive stimulation of postsynaptic glutamate receptors – can participate.2,5,6
Approximately 10% of patients have a known gene associated with ALS.7 The rest have what is considered sporadic ALS, although some experts estimate that heritability will eventually be confirmed in 50% or more of cases that have been given the “sporadic” label.8,9 More than 30 genes have been linked to ALS in genomewide association studies. Among patients whose disease carries a known familial link, four genes – SOD1, TARDBP, FUS, and C9orf72 – account for approximately 70% of cases.2
Diagnosis. Genetic testing in patients with suspected or confirmed ALS is the standard of care at most, if not all, comprehensive ALS treatment centers, according to the four experts interviewed by Neurology Reviews 2023 Rare Neurological Disease Special Report for this article. Such testing was routine for years because of its potential for helping researchers to understand subtypes of disease; today, testing has assumed even greater practical value with recent approval of the first ALS gene therapy: Tofersen (Qalsody, Biogen), licensed in 2023, is an antisense oligonucleotide therapy that targets SOD1 mRNA to reduce production of the SOD1 protein, a mediator of disease progression.
“Genetic testing has been useful for telling us something about the disease and its prognosis,” Dr. Maragakis said, “but an approved gene therapy means it can have a direct effect on treatment.”
ALS therapeutics. Other gene therapies are in development. Gene signatures are likely to provide even more opportunities for clinical trials in the future.
Following three loading doses of tofersen at 14-day intervals, the maintenance regimen, administered intrathecally by lumbar puncture, is every 28 days. In the phase 3 trial, tofersen reduced levels of SOD1 protein and neurofilament light chain, a biomarker of axonal injury.10 Tofersen is appropriate only in patients with SOD1-associated ALS; the drug’s favorable clinical impact, including a positive effect, if any, on survival has not been demonstrated. Extension studies are underway.
Tofersen joins three other FDA-approved ALS therapies:
• Riluzole, an oral drug available since 1995 that slows disease progression by blocking glutamate.
• Edaravone, an antioxidant approved in 2017, administered orally or intravenously.
• An orally administered combination of sodium phenylbutyrate and taurursodiol marketed as Relyvrio and formerly known as AMX0035, that was introduced in 2022.
“We offer riluzole, which is safe in combination with other therapies, to most patients,” said Dr. Scelsa, who noted that treatment trials often test experimental drugs on top of riluzole. He moves to edaravone or Relyvrio, which are far more expensive, selectively. Tofersen, which is also expensive, is reserved for patients with SOD1-associated disease; however, not all eligible patients opt for this therapy after reviewing its benefits and risks.
“There is not yet a guarantee that tofersen will improve outcomes, and it requires intrathecal injections for life,”
Dr. Maiser said. “Some patients, particularly my older patients, have said, ‘No thank you,’ based on the available data.”
Dr. Macgowan pointed out that lumbar puncture repeated indefinitely can be “challenging.” He, too, discusses all available treatment options with every patient, including riluzole, which he agreed is associated with a meaningful benefit, particularly when started early.
Because of the safety of riluzole, Dr. Maragakis takes early treatment a step further. For neurologists who have a high level of suspicion of ALS in a given patient, “my advice would be to treat aggressively from the get-go. Even if not 100% certain of the diagnosis, I would start them on riluzole while waiting for confirmation.” Like the other experts interviewed here, he acknowledged that referral to a busy comprehensive ALS center often takes time, making it reasonable to initiate treatment when suspicion is high.
On the front lines, “the neurologist can tell the patient that ALS is just one of several potential explanations for symptoms but there is concern,” said Dr. Maragakis, proposing a strategy to introduce the possibility of ALS and start treatment that might slow disease while waiting for confirmation of the diagnosis. “My biggest concern is that no one is making that call,” he said, trying to address at least one reason for the current delay in making referrals.
Comprehensive care at specialty centers
Whenever possible, ALS is a disease best managed at a center that offers comprehensive management, including multidisciplinary care. On this point, the four experts agreed.
“Tertiary-care centers for ALS serve a critical purpose,”
Dr. Maiser said. For a disease that affects nearly every aspect of life, the skills of a multidisciplinary support staff offer an “opportunity to stay in front of the disease” for as long as possible. Teamwork often leads to “outside-of-the-box thinking” for helping patients and families cope with the range of disabilities that undermine the patient’s quality of life.
Details of ALS management matter. At Mount Sinai and Hennepin Healthcare, and at Johns Hopkins, where demand recently led to the opening of a second ALS clinic, the ALS center is set up to address the full spectrum of needs. Staff members have multiple skills so that they can work together to make patients comfortable and prepare them for what is inevitably progression – even if the rate of that progression varies.
All these centers incorporate a rational, thorough discussion of end-of-life options in a palliative care approach that targets optimized quality of life. One goal is to prepare patients to consider and be prepared to make decisions when it is time for tracheostomy, percutaneous endoscopic gastrostomy, and other life support options that are not always well tolerated. The goal? Avoiding unnecessary anguish during end-stage disease when impaired respiratory function – the primary cause of ALS-related death – no longer sustains unassisted survival.
“I am concerned for the many ALS patients without access to this type of comprehensive care,” Dr. Macgowan said.
Like the other experts here, he emphasized that the demands of ALS care can be “overwhelming” outside a comprehensive care setting – for the patient, their family, and individual providers.
Looking ahead
There are many reasons to be optimistic about improving the survival and care of patients with ALS. Besides therapies in clinical trials, Dr. Scelsa explained, there is the potential role for monitoring neurofilament light changes, a biomarker of neurodegeneration, in patients who are at risk of ALS.
Dr. Maragakis offered an analogy to the gene therapy onasemnogene abeparvovec, which can prevent the associated neurodegeneration of spinal muscular atrophy if initiated before symptoms appear. He said that, in ALS, neurofilament light changes or other biomarkers might offer an opportunity to halt the progression of disease before it starts – if one or more therapies in development prove workable.
In the meantime, neurologists who do not specialize in ALS should be thinking about how they can participate in speedier diagnostic pathways.
“There are a number of therapies that look promising,” Dr. Maiser told Rare Neurological Disease Special Report. He singled out strategies to degrade TDP-43 or prevent it from forming. If these treatments are found effective, it’s expected that they would be of value in sporadic ALS, the most common form. Again, though, “the challenge is getting patients on this therapy at the earliest stages of disease.”
Dr. Maragakis discloses equity ownership/stock options with Braintrust Bio and Akava; he is a patent holder with Johns Hopkins [ALS] and has received grant/research/clinical trial support from Apellis Pharma, Biogen Idec, Cytokinetics, Helixmith, Calico, Sanofi, Department of Defense ALSRP, Maryland Stem Cell Research Fund, Massachusetts General Hospital, Medicinova, and NINDS. He serves as consultant or advisory board member for Amylyx; Cytokinetics, Roche, Healey Center, Nura Bio, Northeast ALS Consortium, Akava, Inflammx, and Secretome. Dr. Scelsa did not report any conflicts of interest. Dr. Macgowan and Dr. Maiser have no relevant conflicts of interest to disclose.
References
1. Mehta P et al. Prevalence of amyotrophic lateral sclerosis in the United States using established and novel methodologies, 2017. Amyotroph Lateral Scler Frontotemporal Degener. 2023;24(1-2):108-16. doi: 10.1080/21678421.2022.2059380.
2. Mead RJ et al. Amyotrophic lateral sclerosis: A neurodegenerative disorder poised for successful therapeutic translation. Nat Rev Drug Discov. 2023;22(3):185-212. doi: 10.1038/s41573-022-00612-2.
3. Longinetti E and Fang F. Epidemiology of amyotrophic lateral sclerosis: An update of recent literature. Curr Opin Neurol. 2019;32(5):771-6. doi: 10.1097/WCO.0000000000000730.
4. van den Bos MAJ et al. Pathophysiology and diagnosis of ALS: Insights from advances in neurophysiological techniques. Int J Mol Sci. 2019;20(11):2818. doi: 10.3390/ijms20112818.
5. Neumann M et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006;314(5796):130-3. doi: 10.1126/science.1134108.
6. Ling S-C et al. Converging mechanisms in ALS and FTD: Disrupted RNA and protein homeostasis. Neuron. 2013;79(3):416-38. doi: 10.1016/j.neuron.2013.07.033.
7. Ranganathan R et al. Multifaceted genes in amyotrophic lateral sclerosis-frontotemporal dementia. Front Neurosci. 2020;14:684. doi: 10.3389/fnins.2020.00684.
8. Ryan M et al. Lifetime risk and heritability of amyotrophic lateral sclerosis. JAMA Neurol. 2019;76(11):1367-74. doi: 10.1001/jamaneurol.2019.2044.
9. van Rheenen W et al. Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology. Nat Genet. 2021;53(12):1636-48. doi: 10.1038/s41588-021-00973-1.
10. Miller TM et al; VALOR and OLE Working Group. Trial of antisense oligonucleotide tofersen for SOD1 ALS. N Engl J Med. 2022;387(12):1099-110. doi: 10.1056/NEJMoa2204705.
Amyotrophic lateral sclerosis (ALS) falls easily into the Food and Drug Administration definition of “rare disease.” With an estimated prevalence in the United States of fewer than 20,000 cases,1 ALS sits comfortably below the cutoff of 200,000 cases that serves to define a disease as “rare.”
After a recent steep climb, there are something on the order of 50 therapies, across more than 10 drug classes, in clinical trials for the treatment of ALS.2 This bounty represents exciting progress toward the development of targeted therapies for a characteristically fatal disease.
That headway is coupled with a sobering limitation, however: Relatively few ALS patients are being enrolled.
The knotty problem with therapeutic trials for ALS
“Trials are generally designed for patients with adequate functional reserve and predicted survival, to ensure that a signal of benefit can be seen,” said Nicholas John Maragakis, MD, director of the ALS Clinical Trials Unit at Johns Hopkins University, Baltimore. “Many of my patients are too severely affected at presentation.”
Dr. Maragakis hasn’t calculated the precise percentage of patients he is enrolling in one of the many available trials available at the Johns Hopkins center. He estimates that it is less than 20%, however.
That percentage is comparable to what is reported by Stephen Scelsa, MD, and Daniel J. Macgowan, MD, who share much of the ALS caseload in a dedicated, comprehensive ALS center at Mount Sinai Beth Israel, New York. Both are on the faculty at the Icahn School of Medicine at Mount Sinai.
“The considerable delay in the diagnosis of ALS remains a challenge,” Dr. Scelsa acknowledges. Like Dr. Maragakis, he reports that, by the time patients develop symptoms that make referral to a comprehensive ALS center like Mount Sinai Beth Israel appropriate, many no longer meet eligibility criteria for most experimental treatments.
Some therapeutic targets in clinical trials, such as neuroinflammation, offer potential benefit even in advancing disease, but it is prevention that is usually the goal of experimental ALS therapies. This approach is associated with far more promise than attempting to reverse existing neurologic damage, which might not be possible, according to both Dr. Scelsa and Dr. Macgowan.
“The clinical trials are typically looking for patients with less than 2 years since the onset of symptoms and at least 60% of predicted respiratory function,” Dr. Macgowan said.
Because of these or other similarly restrictive criteria, coupled with common delays before patients arrive at a center where trials are available, “the window for clinical research closes very quickly,” Dr. Macgowan added, and “the band of patients who are eligible is relatively narrow.”
At Hennepin Healthcare in Minneapolis, which, like Johns Hopkins and Mount Sinai, offers an advanced multidisciplinary approach to ALS care in a dedicated clinic, the problem of late referrals is no different. Samuel Maiser, MD, chair of neurology, does attempt to counter this delay by moving quickly.
“I almost always offer a therapeutic trial to a patient with early-stage ALS,” he said. He does so earlier, rather than later, and explains: “I do not want to delay that conversation, because any delay might reduce the chance for getting into a trial.”
The generalist can make a difference in therapeutic success
The proliferation of clinical trials has made early diagnosis of ALS urgent. However, the experts interviewed for this article agreed: Accelerating the time to diagnosis is more dependent on the general neurologist or primary care physician than on the ALS specialist. ALS is a diagnosis of exclusion, but there is now very little delay in reaching a probable diagnosis at a dedicated center.
Yet neurodegenerative complaints in early-stage ALS are often nonspecific and mild; confidence in making a potential diagnosis of ALS is limited among primary care clinicians and general neurologists, who almost always see these patients first. Usually, the problem is not failure to include ALS in the differential diagnosis but hesitation in being candid when there is still doubt.
General neurologists, in particular, Dr. Maragakis said, “are often highly suspicious of a diagnosis of ALS very early on but are concerned about using this term until the clinical signs are more compelling.”
This is understandable. There is reluctance to deliver bad news when confidence in the diagnosis is limited. But the experts agreed: Delayed diagnosis is not in the patient’s interest now that there is at least the potential for entering a trial supported by a scientific rationale for benefit.
“Waiting for 100% certainty – this could actually harm our patients,” Dr. Maiser said. The tendency to avoid delivering bad news, he said, “is human nature, and it is not easy to tell people that ALS is the potential cause, but it’s important for early treatment.”
Some evidence suggests that the incidence of ALS is increasing3 but this is not necessarily evident at the clinical level. “It is not my impression that the incidence of ALS is increasing,” Dr. Macgowan said, “so much as I think we are getting better at making the diagnosis.”
Where we stand: Pathophysiology, diagnosis, treatment
Pathophysiology. ALS is characterized by muscle denervation.4 In the great majority of cases, the disease represents a proteinopathy involving loss of the TDP-43 protein from nuclei. However, pathological heterogeneity means that other pathophysiological mechanisms – mediated by oxidative stress, mitochondrial dysfunction, and neurotoxicity related to excessive stimulation of postsynaptic glutamate receptors – can participate.2,5,6
Approximately 10% of patients have a known gene associated with ALS.7 The rest have what is considered sporadic ALS, although some experts estimate that heritability will eventually be confirmed in 50% or more of cases that have been given the “sporadic” label.8,9 More than 30 genes have been linked to ALS in genomewide association studies. Among patients whose disease carries a known familial link, four genes – SOD1, TARDBP, FUS, and C9orf72 – account for approximately 70% of cases.2
Diagnosis. Genetic testing in patients with suspected or confirmed ALS is the standard of care at most, if not all, comprehensive ALS treatment centers, according to the four experts interviewed by Neurology Reviews 2023 Rare Neurological Disease Special Report for this article. Such testing was routine for years because of its potential for helping researchers to understand subtypes of disease; today, testing has assumed even greater practical value with recent approval of the first ALS gene therapy: Tofersen (Qalsody, Biogen), licensed in 2023, is an antisense oligonucleotide therapy that targets SOD1 mRNA to reduce production of the SOD1 protein, a mediator of disease progression.
“Genetic testing has been useful for telling us something about the disease and its prognosis,” Dr. Maragakis said, “but an approved gene therapy means it can have a direct effect on treatment.”
ALS therapeutics. Other gene therapies are in development. Gene signatures are likely to provide even more opportunities for clinical trials in the future.
Following three loading doses of tofersen at 14-day intervals, the maintenance regimen, administered intrathecally by lumbar puncture, is every 28 days. In the phase 3 trial, tofersen reduced levels of SOD1 protein and neurofilament light chain, a biomarker of axonal injury.10 Tofersen is appropriate only in patients with SOD1-associated ALS; the drug’s favorable clinical impact, including a positive effect, if any, on survival has not been demonstrated. Extension studies are underway.
Tofersen joins three other FDA-approved ALS therapies:
• Riluzole, an oral drug available since 1995 that slows disease progression by blocking glutamate.
• Edaravone, an antioxidant approved in 2017, administered orally or intravenously.
• An orally administered combination of sodium phenylbutyrate and taurursodiol marketed as Relyvrio and formerly known as AMX0035, that was introduced in 2022.
“We offer riluzole, which is safe in combination with other therapies, to most patients,” said Dr. Scelsa, who noted that treatment trials often test experimental drugs on top of riluzole. He moves to edaravone or Relyvrio, which are far more expensive, selectively. Tofersen, which is also expensive, is reserved for patients with SOD1-associated disease; however, not all eligible patients opt for this therapy after reviewing its benefits and risks.
“There is not yet a guarantee that tofersen will improve outcomes, and it requires intrathecal injections for life,”
Dr. Maiser said. “Some patients, particularly my older patients, have said, ‘No thank you,’ based on the available data.”
Dr. Macgowan pointed out that lumbar puncture repeated indefinitely can be “challenging.” He, too, discusses all available treatment options with every patient, including riluzole, which he agreed is associated with a meaningful benefit, particularly when started early.
Because of the safety of riluzole, Dr. Maragakis takes early treatment a step further. For neurologists who have a high level of suspicion of ALS in a given patient, “my advice would be to treat aggressively from the get-go. Even if not 100% certain of the diagnosis, I would start them on riluzole while waiting for confirmation.” Like the other experts interviewed here, he acknowledged that referral to a busy comprehensive ALS center often takes time, making it reasonable to initiate treatment when suspicion is high.
On the front lines, “the neurologist can tell the patient that ALS is just one of several potential explanations for symptoms but there is concern,” said Dr. Maragakis, proposing a strategy to introduce the possibility of ALS and start treatment that might slow disease while waiting for confirmation of the diagnosis. “My biggest concern is that no one is making that call,” he said, trying to address at least one reason for the current delay in making referrals.
Comprehensive care at specialty centers
Whenever possible, ALS is a disease best managed at a center that offers comprehensive management, including multidisciplinary care. On this point, the four experts agreed.
“Tertiary-care centers for ALS serve a critical purpose,”
Dr. Maiser said. For a disease that affects nearly every aspect of life, the skills of a multidisciplinary support staff offer an “opportunity to stay in front of the disease” for as long as possible. Teamwork often leads to “outside-of-the-box thinking” for helping patients and families cope with the range of disabilities that undermine the patient’s quality of life.
Details of ALS management matter. At Mount Sinai and Hennepin Healthcare, and at Johns Hopkins, where demand recently led to the opening of a second ALS clinic, the ALS center is set up to address the full spectrum of needs. Staff members have multiple skills so that they can work together to make patients comfortable and prepare them for what is inevitably progression – even if the rate of that progression varies.
All these centers incorporate a rational, thorough discussion of end-of-life options in a palliative care approach that targets optimized quality of life. One goal is to prepare patients to consider and be prepared to make decisions when it is time for tracheostomy, percutaneous endoscopic gastrostomy, and other life support options that are not always well tolerated. The goal? Avoiding unnecessary anguish during end-stage disease when impaired respiratory function – the primary cause of ALS-related death – no longer sustains unassisted survival.
“I am concerned for the many ALS patients without access to this type of comprehensive care,” Dr. Macgowan said.
Like the other experts here, he emphasized that the demands of ALS care can be “overwhelming” outside a comprehensive care setting – for the patient, their family, and individual providers.
Looking ahead
There are many reasons to be optimistic about improving the survival and care of patients with ALS. Besides therapies in clinical trials, Dr. Scelsa explained, there is the potential role for monitoring neurofilament light changes, a biomarker of neurodegeneration, in patients who are at risk of ALS.
Dr. Maragakis offered an analogy to the gene therapy onasemnogene abeparvovec, which can prevent the associated neurodegeneration of spinal muscular atrophy if initiated before symptoms appear. He said that, in ALS, neurofilament light changes or other biomarkers might offer an opportunity to halt the progression of disease before it starts – if one or more therapies in development prove workable.
In the meantime, neurologists who do not specialize in ALS should be thinking about how they can participate in speedier diagnostic pathways.
“There are a number of therapies that look promising,” Dr. Maiser told Rare Neurological Disease Special Report. He singled out strategies to degrade TDP-43 or prevent it from forming. If these treatments are found effective, it’s expected that they would be of value in sporadic ALS, the most common form. Again, though, “the challenge is getting patients on this therapy at the earliest stages of disease.”
Dr. Maragakis discloses equity ownership/stock options with Braintrust Bio and Akava; he is a patent holder with Johns Hopkins [ALS] and has received grant/research/clinical trial support from Apellis Pharma, Biogen Idec, Cytokinetics, Helixmith, Calico, Sanofi, Department of Defense ALSRP, Maryland Stem Cell Research Fund, Massachusetts General Hospital, Medicinova, and NINDS. He serves as consultant or advisory board member for Amylyx; Cytokinetics, Roche, Healey Center, Nura Bio, Northeast ALS Consortium, Akava, Inflammx, and Secretome. Dr. Scelsa did not report any conflicts of interest. Dr. Macgowan and Dr. Maiser have no relevant conflicts of interest to disclose.
References
1. Mehta P et al. Prevalence of amyotrophic lateral sclerosis in the United States using established and novel methodologies, 2017. Amyotroph Lateral Scler Frontotemporal Degener. 2023;24(1-2):108-16. doi: 10.1080/21678421.2022.2059380.
2. Mead RJ et al. Amyotrophic lateral sclerosis: A neurodegenerative disorder poised for successful therapeutic translation. Nat Rev Drug Discov. 2023;22(3):185-212. doi: 10.1038/s41573-022-00612-2.
3. Longinetti E and Fang F. Epidemiology of amyotrophic lateral sclerosis: An update of recent literature. Curr Opin Neurol. 2019;32(5):771-6. doi: 10.1097/WCO.0000000000000730.
4. van den Bos MAJ et al. Pathophysiology and diagnosis of ALS: Insights from advances in neurophysiological techniques. Int J Mol Sci. 2019;20(11):2818. doi: 10.3390/ijms20112818.
5. Neumann M et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006;314(5796):130-3. doi: 10.1126/science.1134108.
6. Ling S-C et al. Converging mechanisms in ALS and FTD: Disrupted RNA and protein homeostasis. Neuron. 2013;79(3):416-38. doi: 10.1016/j.neuron.2013.07.033.
7. Ranganathan R et al. Multifaceted genes in amyotrophic lateral sclerosis-frontotemporal dementia. Front Neurosci. 2020;14:684. doi: 10.3389/fnins.2020.00684.
8. Ryan M et al. Lifetime risk and heritability of amyotrophic lateral sclerosis. JAMA Neurol. 2019;76(11):1367-74. doi: 10.1001/jamaneurol.2019.2044.
9. van Rheenen W et al. Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology. Nat Genet. 2021;53(12):1636-48. doi: 10.1038/s41588-021-00973-1.
10. Miller TM et al; VALOR and OLE Working Group. Trial of antisense oligonucleotide tofersen for SOD1 ALS. N Engl J Med. 2022;387(12):1099-110. doi: 10.1056/NEJMoa2204705.
Amyotrophic lateral sclerosis (ALS) falls easily into the Food and Drug Administration definition of “rare disease.” With an estimated prevalence in the United States of fewer than 20,000 cases,1 ALS sits comfortably below the cutoff of 200,000 cases that serves to define a disease as “rare.”
After a recent steep climb, there are something on the order of 50 therapies, across more than 10 drug classes, in clinical trials for the treatment of ALS.2 This bounty represents exciting progress toward the development of targeted therapies for a characteristically fatal disease.
That headway is coupled with a sobering limitation, however: Relatively few ALS patients are being enrolled.
The knotty problem with therapeutic trials for ALS
“Trials are generally designed for patients with adequate functional reserve and predicted survival, to ensure that a signal of benefit can be seen,” said Nicholas John Maragakis, MD, director of the ALS Clinical Trials Unit at Johns Hopkins University, Baltimore. “Many of my patients are too severely affected at presentation.”
Dr. Maragakis hasn’t calculated the precise percentage of patients he is enrolling in one of the many available trials available at the Johns Hopkins center. He estimates that it is less than 20%, however.
That percentage is comparable to what is reported by Stephen Scelsa, MD, and Daniel J. Macgowan, MD, who share much of the ALS caseload in a dedicated, comprehensive ALS center at Mount Sinai Beth Israel, New York. Both are on the faculty at the Icahn School of Medicine at Mount Sinai.
“The considerable delay in the diagnosis of ALS remains a challenge,” Dr. Scelsa acknowledges. Like Dr. Maragakis, he reports that, by the time patients develop symptoms that make referral to a comprehensive ALS center like Mount Sinai Beth Israel appropriate, many no longer meet eligibility criteria for most experimental treatments.
Some therapeutic targets in clinical trials, such as neuroinflammation, offer potential benefit even in advancing disease, but it is prevention that is usually the goal of experimental ALS therapies. This approach is associated with far more promise than attempting to reverse existing neurologic damage, which might not be possible, according to both Dr. Scelsa and Dr. Macgowan.
“The clinical trials are typically looking for patients with less than 2 years since the onset of symptoms and at least 60% of predicted respiratory function,” Dr. Macgowan said.
Because of these or other similarly restrictive criteria, coupled with common delays before patients arrive at a center where trials are available, “the window for clinical research closes very quickly,” Dr. Macgowan added, and “the band of patients who are eligible is relatively narrow.”
At Hennepin Healthcare in Minneapolis, which, like Johns Hopkins and Mount Sinai, offers an advanced multidisciplinary approach to ALS care in a dedicated clinic, the problem of late referrals is no different. Samuel Maiser, MD, chair of neurology, does attempt to counter this delay by moving quickly.
“I almost always offer a therapeutic trial to a patient with early-stage ALS,” he said. He does so earlier, rather than later, and explains: “I do not want to delay that conversation, because any delay might reduce the chance for getting into a trial.”
The generalist can make a difference in therapeutic success
The proliferation of clinical trials has made early diagnosis of ALS urgent. However, the experts interviewed for this article agreed: Accelerating the time to diagnosis is more dependent on the general neurologist or primary care physician than on the ALS specialist. ALS is a diagnosis of exclusion, but there is now very little delay in reaching a probable diagnosis at a dedicated center.
Yet neurodegenerative complaints in early-stage ALS are often nonspecific and mild; confidence in making a potential diagnosis of ALS is limited among primary care clinicians and general neurologists, who almost always see these patients first. Usually, the problem is not failure to include ALS in the differential diagnosis but hesitation in being candid when there is still doubt.
General neurologists, in particular, Dr. Maragakis said, “are often highly suspicious of a diagnosis of ALS very early on but are concerned about using this term until the clinical signs are more compelling.”
This is understandable. There is reluctance to deliver bad news when confidence in the diagnosis is limited. But the experts agreed: Delayed diagnosis is not in the patient’s interest now that there is at least the potential for entering a trial supported by a scientific rationale for benefit.
“Waiting for 100% certainty – this could actually harm our patients,” Dr. Maiser said. The tendency to avoid delivering bad news, he said, “is human nature, and it is not easy to tell people that ALS is the potential cause, but it’s important for early treatment.”
Some evidence suggests that the incidence of ALS is increasing3 but this is not necessarily evident at the clinical level. “It is not my impression that the incidence of ALS is increasing,” Dr. Macgowan said, “so much as I think we are getting better at making the diagnosis.”
Where we stand: Pathophysiology, diagnosis, treatment
Pathophysiology. ALS is characterized by muscle denervation.4 In the great majority of cases, the disease represents a proteinopathy involving loss of the TDP-43 protein from nuclei. However, pathological heterogeneity means that other pathophysiological mechanisms – mediated by oxidative stress, mitochondrial dysfunction, and neurotoxicity related to excessive stimulation of postsynaptic glutamate receptors – can participate.2,5,6
Approximately 10% of patients have a known gene associated with ALS.7 The rest have what is considered sporadic ALS, although some experts estimate that heritability will eventually be confirmed in 50% or more of cases that have been given the “sporadic” label.8,9 More than 30 genes have been linked to ALS in genomewide association studies. Among patients whose disease carries a known familial link, four genes – SOD1, TARDBP, FUS, and C9orf72 – account for approximately 70% of cases.2
Diagnosis. Genetic testing in patients with suspected or confirmed ALS is the standard of care at most, if not all, comprehensive ALS treatment centers, according to the four experts interviewed by Neurology Reviews 2023 Rare Neurological Disease Special Report for this article. Such testing was routine for years because of its potential for helping researchers to understand subtypes of disease; today, testing has assumed even greater practical value with recent approval of the first ALS gene therapy: Tofersen (Qalsody, Biogen), licensed in 2023, is an antisense oligonucleotide therapy that targets SOD1 mRNA to reduce production of the SOD1 protein, a mediator of disease progression.
“Genetic testing has been useful for telling us something about the disease and its prognosis,” Dr. Maragakis said, “but an approved gene therapy means it can have a direct effect on treatment.”
ALS therapeutics. Other gene therapies are in development. Gene signatures are likely to provide even more opportunities for clinical trials in the future.
Following three loading doses of tofersen at 14-day intervals, the maintenance regimen, administered intrathecally by lumbar puncture, is every 28 days. In the phase 3 trial, tofersen reduced levels of SOD1 protein and neurofilament light chain, a biomarker of axonal injury.10 Tofersen is appropriate only in patients with SOD1-associated ALS; the drug’s favorable clinical impact, including a positive effect, if any, on survival has not been demonstrated. Extension studies are underway.
Tofersen joins three other FDA-approved ALS therapies:
• Riluzole, an oral drug available since 1995 that slows disease progression by blocking glutamate.
• Edaravone, an antioxidant approved in 2017, administered orally or intravenously.
• An orally administered combination of sodium phenylbutyrate and taurursodiol marketed as Relyvrio and formerly known as AMX0035, that was introduced in 2022.
“We offer riluzole, which is safe in combination with other therapies, to most patients,” said Dr. Scelsa, who noted that treatment trials often test experimental drugs on top of riluzole. He moves to edaravone or Relyvrio, which are far more expensive, selectively. Tofersen, which is also expensive, is reserved for patients with SOD1-associated disease; however, not all eligible patients opt for this therapy after reviewing its benefits and risks.
“There is not yet a guarantee that tofersen will improve outcomes, and it requires intrathecal injections for life,”
Dr. Maiser said. “Some patients, particularly my older patients, have said, ‘No thank you,’ based on the available data.”
Dr. Macgowan pointed out that lumbar puncture repeated indefinitely can be “challenging.” He, too, discusses all available treatment options with every patient, including riluzole, which he agreed is associated with a meaningful benefit, particularly when started early.
Because of the safety of riluzole, Dr. Maragakis takes early treatment a step further. For neurologists who have a high level of suspicion of ALS in a given patient, “my advice would be to treat aggressively from the get-go. Even if not 100% certain of the diagnosis, I would start them on riluzole while waiting for confirmation.” Like the other experts interviewed here, he acknowledged that referral to a busy comprehensive ALS center often takes time, making it reasonable to initiate treatment when suspicion is high.
On the front lines, “the neurologist can tell the patient that ALS is just one of several potential explanations for symptoms but there is concern,” said Dr. Maragakis, proposing a strategy to introduce the possibility of ALS and start treatment that might slow disease while waiting for confirmation of the diagnosis. “My biggest concern is that no one is making that call,” he said, trying to address at least one reason for the current delay in making referrals.
Comprehensive care at specialty centers
Whenever possible, ALS is a disease best managed at a center that offers comprehensive management, including multidisciplinary care. On this point, the four experts agreed.
“Tertiary-care centers for ALS serve a critical purpose,”
Dr. Maiser said. For a disease that affects nearly every aspect of life, the skills of a multidisciplinary support staff offer an “opportunity to stay in front of the disease” for as long as possible. Teamwork often leads to “outside-of-the-box thinking” for helping patients and families cope with the range of disabilities that undermine the patient’s quality of life.
Details of ALS management matter. At Mount Sinai and Hennepin Healthcare, and at Johns Hopkins, where demand recently led to the opening of a second ALS clinic, the ALS center is set up to address the full spectrum of needs. Staff members have multiple skills so that they can work together to make patients comfortable and prepare them for what is inevitably progression – even if the rate of that progression varies.
All these centers incorporate a rational, thorough discussion of end-of-life options in a palliative care approach that targets optimized quality of life. One goal is to prepare patients to consider and be prepared to make decisions when it is time for tracheostomy, percutaneous endoscopic gastrostomy, and other life support options that are not always well tolerated. The goal? Avoiding unnecessary anguish during end-stage disease when impaired respiratory function – the primary cause of ALS-related death – no longer sustains unassisted survival.
“I am concerned for the many ALS patients without access to this type of comprehensive care,” Dr. Macgowan said.
Like the other experts here, he emphasized that the demands of ALS care can be “overwhelming” outside a comprehensive care setting – for the patient, their family, and individual providers.
Looking ahead
There are many reasons to be optimistic about improving the survival and care of patients with ALS. Besides therapies in clinical trials, Dr. Scelsa explained, there is the potential role for monitoring neurofilament light changes, a biomarker of neurodegeneration, in patients who are at risk of ALS.
Dr. Maragakis offered an analogy to the gene therapy onasemnogene abeparvovec, which can prevent the associated neurodegeneration of spinal muscular atrophy if initiated before symptoms appear. He said that, in ALS, neurofilament light changes or other biomarkers might offer an opportunity to halt the progression of disease before it starts – if one or more therapies in development prove workable.
In the meantime, neurologists who do not specialize in ALS should be thinking about how they can participate in speedier diagnostic pathways.
“There are a number of therapies that look promising,” Dr. Maiser told Rare Neurological Disease Special Report. He singled out strategies to degrade TDP-43 or prevent it from forming. If these treatments are found effective, it’s expected that they would be of value in sporadic ALS, the most common form. Again, though, “the challenge is getting patients on this therapy at the earliest stages of disease.”
Dr. Maragakis discloses equity ownership/stock options with Braintrust Bio and Akava; he is a patent holder with Johns Hopkins [ALS] and has received grant/research/clinical trial support from Apellis Pharma, Biogen Idec, Cytokinetics, Helixmith, Calico, Sanofi, Department of Defense ALSRP, Maryland Stem Cell Research Fund, Massachusetts General Hospital, Medicinova, and NINDS. He serves as consultant or advisory board member for Amylyx; Cytokinetics, Roche, Healey Center, Nura Bio, Northeast ALS Consortium, Akava, Inflammx, and Secretome. Dr. Scelsa did not report any conflicts of interest. Dr. Macgowan and Dr. Maiser have no relevant conflicts of interest to disclose.
References
1. Mehta P et al. Prevalence of amyotrophic lateral sclerosis in the United States using established and novel methodologies, 2017. Amyotroph Lateral Scler Frontotemporal Degener. 2023;24(1-2):108-16. doi: 10.1080/21678421.2022.2059380.
2. Mead RJ et al. Amyotrophic lateral sclerosis: A neurodegenerative disorder poised for successful therapeutic translation. Nat Rev Drug Discov. 2023;22(3):185-212. doi: 10.1038/s41573-022-00612-2.
3. Longinetti E and Fang F. Epidemiology of amyotrophic lateral sclerosis: An update of recent literature. Curr Opin Neurol. 2019;32(5):771-6. doi: 10.1097/WCO.0000000000000730.
4. van den Bos MAJ et al. Pathophysiology and diagnosis of ALS: Insights from advances in neurophysiological techniques. Int J Mol Sci. 2019;20(11):2818. doi: 10.3390/ijms20112818.
5. Neumann M et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006;314(5796):130-3. doi: 10.1126/science.1134108.
6. Ling S-C et al. Converging mechanisms in ALS and FTD: Disrupted RNA and protein homeostasis. Neuron. 2013;79(3):416-38. doi: 10.1016/j.neuron.2013.07.033.
7. Ranganathan R et al. Multifaceted genes in amyotrophic lateral sclerosis-frontotemporal dementia. Front Neurosci. 2020;14:684. doi: 10.3389/fnins.2020.00684.
8. Ryan M et al. Lifetime risk and heritability of amyotrophic lateral sclerosis. JAMA Neurol. 2019;76(11):1367-74. doi: 10.1001/jamaneurol.2019.2044.
9. van Rheenen W et al. Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology. Nat Genet. 2021;53(12):1636-48. doi: 10.1038/s41588-021-00973-1.
10. Miller TM et al; VALOR and OLE Working Group. Trial of antisense oligonucleotide tofersen for SOD1 ALS. N Engl J Med. 2022;387(12):1099-110. doi: 10.1056/NEJMoa2204705.
Emerging therapies in Duchenne and facioscapulohumeral muscular dystrophy
“There have been so many breakthroughs recently on the side of genetically targeted treatment [for muscular dystrophy] that supports muscle better,” said John F. Brandsema, MD, a child neurologist and section head at Children’s Hospital of Philadelphia, in an interview with Neurology Reviews 2023 Rare Neurological Disease Special Report. “We’re starting to see clinical response to some things that have been in trials – after decades of banging our heads on the wall trying new therapies, only to see them fail. I think it’s about reframing Duchenne muscular dystrophy [DMD] and facioscapulohumeral muscular dystrophy [FSHD] as treatable by target therapy because previously, they were treated with supportive care.”
DMD: Current and emerging therapies
DMD is caused by a mutation in the dystrophin gene on the X chromosome that inhibits production of dystrophin, a protein that shields muscles from injury during contraction. Dystrophin deficiency prevents muscle recovery, resulting in muscle-cell death and, ultimately, loss of function due to muscle degeneration.
FDA-approved exon-skipping therapies. Treatment modalities for what has historically been an incurable, lifespan-shortening disease involved supportive care that addresses symptoms, not the underlying cause. Consequently, many patients with DMD live only into their 20s and 30s. The tide began to turn in 2016, however, when the U.S. Food and Drug Administration granted accelerated approval for eteplirsen, an exon 51–skipping treatment that was the first RNA-based therapy for DMD to target the underlying cause. Additional exon-skipping therapies followed, including casimersen, which skips exon 45, and golodirsen and viltolarsen, which skip exon 53.
AOC 1044: Novel exon-skipping. In April 2023, the FDA granted orphan-drug designation to the experimental drug antibody oligonucleotide conjugate (AOC) 1044 that skips exon 44. A small interfering RNA (siRNA), AOC 1044 works in patients who have a mutation amenable to exon 44 skipping (a disease type known as DMD44) by delivering phosphorodiamidate morpholino to skeletal muscle and heart tissue that skips exon 44. The process allows for dystrophin production, thereby preventing degradation of muscle tissue.
The orphan drug status of AOC 1044 made it available to the population of patients enrolled in the EXPLORE44 Phase 1/2 trial. However, studies demonstrating effectiveness of the drug – with the hope of, ultimately, providing widespread access to AOC 1044 – are still underway. In one of those studies, investigators expect to enroll approximately 40 healthy volunteers and 24 DMD44 patients 7-27 years of age.3 The study will evaluate the effects of exon skipping and dystrophin protein levels in participants who have DMD44.
Delandistrogene moxeparvovec. Oct. 27, 2021, marked the inception of the phase 3 Multinational, Randomized, Double-Blind, Placebo-Controlled Systemic Gene Delivery Study to Evaluate the Safety and Efficacy of SRP-9001 in Subjects With Duchenne Muscular Dystrophy (EMBARK). The trial is evaluating the safety and efficacy of the gene-therapy agent delandistrogene moxeparvovec in ambulatory boys who were 4 to less than 8 years of age at randomization. The 126 boys enrolled in the trial met the criteria of (1) a diagnosis of DMD confirmed by documented clinical findings and previous genetic testing and (2) a pathogenic frameshift mutation stop codon located between exons 18 and 79 (inclusive), except for a mutation fully contained within exon 45.
Additional inclusion criteria were (1) the ability to cooperate with motor-assessment testing and (2) receiving a steady daily dose of oral corticosteroid for 12 weeks or longer prior to screening, and (3) the expectation of maintaining the study dosage throughout screening. Boys who had previously received gene therapy, investigational medication, or any treatment that could have amplified dystrophin expression within the time limit specified by the protocol were ineligible to participate. Boys were excluded from the study if they presented with any other illness, medical condition, or need for chronic drug treatment.
Exon-skipping therapies in trials. Various biotech and pharmaceutical companies have initiated clinical trials to explore the potential of additional exon-skipping therapies for the DMD population:
ENTR-601-44 is another exon 44–skipping therapy in the pipeline.
On Aug. 22, 2023, the FDA approved delandistrogene moxeparvovec-rokl, a recombinant gene therapy utilizing an adenovirus vector. The product is indicated for ambulatory patients with DMD 4-5 years of age who have a confirmed mutation of the dystrophin gene.
Dyne Therapeutics is actively recruiting participants to investigate Dyne 251, its exon 51–skipping therapy.
Trials are in the works by BioMarin Pharmaceutical for its next-generation peptide-conjugated phosphorodiamidate morpholino oligomers (PPMO) for skipping exon 51.
Despite the prospects of such therapy, therapeutic targeting of exon 44 addresses only patients with DMD44, who account for approximately 10% of the DMD population. Disease involving the most prevalent site of a dystrophin gene mutation, exon 51, affects 13% of the DMD population. This leaves the majority of patients with DMD without gene therapy. Yet Dr. Brandsema is optimistic nevertheless.
“We were just failing over and over again with DMD treatment, but there is some hope now,” Dr. Brandsema said. “Also, FSHD is right on the cusp of having new therapies approaching.”
FSHD: Emerging therapies
The third more common type of muscular dystrophy is not a life-threatening condition. FSHD affects approximately 4 of every 100,000 people.1 An autosomal-dominant condition, FSHD is ultimately caused by inappropriate expression of the DUX4 protein product – a consequence of a complex genetic activity involving DUX4, its chromosomal locus, and the number of repeats of a microsatellite called D4Z4.4 The disease usually starts in proximal regions of the face (that is, surrounding the eyes and mouth), before spreading to muscular groups of the limbs – most prominently, muscles of the scapulae and humeri. Symptoms usually appear in these places initially, but the condition can affect any part of the body. Fifty percent of FSHD patients experience loss of high-frequency hearing and present with retinovasculopathy. Like DMD, FSHD varies in severity, with some forms presenting at birth.
AOC 1020-CS1 is an example of a new FSHD treatment under investigation. The phase 1/2 FORTITUDE trial is a randomized, double-blind, placebo-controlled study exploring the safety, tolerability, pharmacokinetics, pharmacodynamics, and potential efficacy of single- and multiple-dose AOC 1020-CS1 therapy in FSHD.5 The trial began in April 2023; estimated completion date is September 2025.
As with many rare diseases, however, following patients and capturing data that fully narrate their story remains challenging in both DMD and FSHD. Although clinical trials undoubtedly offer hope of expanding treatment options and additional insights into disease-state management, the often insidious, complex nature of some rare diseases, such as DMD and FSHD, presents some limitations.
“Patients are hard to measure,” Dr. Brandsema explained, “because they’re so variable at baseline in history and progress in a different [slower] way than timelines are set up in our system to study drugs.”
Neonatal screening and early diagnosis: Imperative for improving outcomes
Neonatal screening helps with early detection and treatment. Prompt diagnosis does not necessarily prolong a DMD patient’s life, but it can enhance their quality of life.
DNA diagnostics. A critical component of the path to treatment is DNA diagnostics. According to Barry J. Byrne, MD, PhD, chief medical advisor of the Muscular Dystrophy Association, the Human Genome Project conducted by the National Institutes of Health helped make DNA tests affordable; such tests run about $800 today. However, given continuous advancements in sequencing, Dr. Byrne said that whole-exome sequencing for $100 is within reach.
In terms of accessibility, some nations – Canada is an example – include testing as part of national health care services. In the United States, coverage for testing varies by health insurance plan. In addition, some plans have favored rapid diagnostic testing, and the overall cost is often individualized to the patient.
Early diagnosis and supportive care. Early diagnosis can certainly help improve DMD patients’ quality of life; supportive care provides some benefit. Dr. Byrne stressed the importance of managing extraskeletal clinical manifestations in this patient population. A critical area is initiating cardiovascular treatment immediately following diagnosis, even if the patient does not exhibit cardiovascular symptoms.
“Cardiac manifestations are actually the cause of mortality in DMD, and most boys with DMD should begin cardiovascular treatment shortly after diagnosis,” Dr. Byrne told Neurology Reviews 2023 Rare Neurological Disease Special Report. “The message to neurologists is that these patients can benefit from early cardiovascular treatment because we can prevent the complications of DMD-related heart failure until much later in life.”
Historically, clinicians used echocardiography as the mainstay tool to assess cardiovascular function; however, more and more clinicians are turning to magnetic resonance imaging for such investigation. Dr. Byrne, a cardiologist, explained that magnetic resonance imaging identifies cardiovascular dysfunction at earlier stages than echocardiography can. In addition, although DMD patients frequently experience fatigue, Dr. Byrne cautions neurologists that fatigue is usually related to muscle weakness, not necessarily heart failure.
DMD therapies carry a hefty price
Right now, the projected price range of AOC 1044 is $3.2 million to $3.4 million. Akin to the case with onasemnogene abeparvovec-xioi (Zolgensma) for spinal muscular atrophy, the world’s first gene therapy and first seven-figure drug, the manufacturer of AOC 1044 based pricing on the anticipated cost of treating a DMD44 patient throughout the lifespan, according to Dr. Byrne.
Delandistrogene moxeparvovec might come with an even higher price tag. A cost-effectiveness analysis study priced the therapy at $5 million. In a presentation to investors, the manufacturer projected the price in the range of $5 million to $13 million.6,7
‘It takes a village’: Comprehensive care requires a multidisciplinary team
Dr. Brandsema and Dr. Byrne agree: Optimizing outcomes requires ongoing coordinated and collaborative efforts of an interdisciplinary team of health care providers for the duration of DMD and FSHD patients’ lifespan.
A neurologist by training, Dr. Brandsema recognizes the importance of interdisciplinary collaboration in caring for patients with DMD, given the multiorgan manifestations of the disease.
“We have some hope with DMD, and FSHD is right on the cusp of having new therapies approaching ... It is important to recognize that interdisciplinary follow-up and optimized standard of care are important after dosing.”
“I think many patients living with neurological disorders have multiple providers they rely on for care,” Dr. Byrne said, “but cardiovascular and pulmonary care are important because both are affected in the case of DMD – not so much in FSHD.”
Ultimately, advancements in therapy and care give patients living with these disorders, and their caregivers, a renewed sense of hope – hope that their life will be improved by breakthrough therapies that have been approved or will arrive soon.
Dr. Brandsema discloses he is a consultant for Alexion, Audentes, AveXis/Novartis, Biogen, Cytokinetics, Dyne, Edgewise, Fibrogen, Genentech/Roche, Janssen, Marathon, Momenta, NS Pharma, PTC Therapeutics, Sarepta, Scholar Rock, Takeda, and WaVe. He is a speaker for AveXis and Biogen, a medical advisory council member for Cure SMA, and a site investigator for clinical trials with Alexion, Astellas, AveXis/Novartis, Biogen, Catabasis, CSL Behring, Cytokinetics, Fibrogen, Genentech/Roche, Ionis, Lilly, Janssen, Pfizer, PTC Therapeutics, Sarepta, Scholar Rock, Summit, and WaVe. Dr. Byrne has no relevant financial disclosures.
References
1. Centers for Disease Control and Prevention. What is muscular dystrophy? Updated Nov. 21, 2022. Accessed Sept. 3, 2023. https://www.cdc.gov/ncbddd/musculardystrophy/facts.html.
2. FDA approves first gene therapy for treatment of certain patients with Duchenne muscular dystrophy. U.S. Food and Drug Administration. Press release. June 22, 2023. Accessed Sept. 3, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-treatment-certain-patients-duchenne-muscular-dystrophy.
3. Study of AOC 1044 in healthy adult volunteers and participants with Duchenne muscular dystrophy (DMD) mutations amenable to exon 44 skipping (EXPLORE44). ClinicalTrials.gov Identifier: NCT05670730. Updated April 4, 2023. Accessed Sep. 3, 2023. https://www.clinicaltrials.gov/study/NCT05670730?cond=DMD&intr=AOC%201044&rank=1.
4. Statland JM, Tawil R. Facioscapulohumeral muscular dystrophy. Continuum (Minneap. Minn). 2016;22(6, Muscle and Neuromuscular Junction Disorders):1916-31. doi: 10.1212/CON.0000000000000399.
5. Phase 1/2 study of AOC 1020 in adults with facioscapulohumeral muscular dystrophy (FSHD) (FORTITUDE). ClinicalTrials.gov Identifier: NCT05747924. Updated Aug. 9, 2023. Accessed Sept. 3, 2023. https://clinicaltrials.gov/study/NCT05747924?term=fORTITUDE&cond=Facioscapulohumeral%20Muscular%20Dystrophy&rank=1.
6. Klimchak AC, Sedita LE, Rodino-Klapac LR, et al. Assessing the value of delandistrogene moxeparvovec (SRP-9001) gene therapy in patients with Duchenne muscular dystrophy in the United States. J Mark Access Health Policy. 2023;11(1):2216518. doi: 10.1080/20016689.2023.2216518.
7. Ingram D. [Investor relations presentation.] Sarepta Therapeutics website. June 22, 2023. Accessed Sept. 3, 2023. https://investorrelations.sarepta.com/static-files/7216948c-f688-4024-922e-39761bc7a984.
“There have been so many breakthroughs recently on the side of genetically targeted treatment [for muscular dystrophy] that supports muscle better,” said John F. Brandsema, MD, a child neurologist and section head at Children’s Hospital of Philadelphia, in an interview with Neurology Reviews 2023 Rare Neurological Disease Special Report. “We’re starting to see clinical response to some things that have been in trials – after decades of banging our heads on the wall trying new therapies, only to see them fail. I think it’s about reframing Duchenne muscular dystrophy [DMD] and facioscapulohumeral muscular dystrophy [FSHD] as treatable by target therapy because previously, they were treated with supportive care.”
DMD: Current and emerging therapies
DMD is caused by a mutation in the dystrophin gene on the X chromosome that inhibits production of dystrophin, a protein that shields muscles from injury during contraction. Dystrophin deficiency prevents muscle recovery, resulting in muscle-cell death and, ultimately, loss of function due to muscle degeneration.
FDA-approved exon-skipping therapies. Treatment modalities for what has historically been an incurable, lifespan-shortening disease involved supportive care that addresses symptoms, not the underlying cause. Consequently, many patients with DMD live only into their 20s and 30s. The tide began to turn in 2016, however, when the U.S. Food and Drug Administration granted accelerated approval for eteplirsen, an exon 51–skipping treatment that was the first RNA-based therapy for DMD to target the underlying cause. Additional exon-skipping therapies followed, including casimersen, which skips exon 45, and golodirsen and viltolarsen, which skip exon 53.
AOC 1044: Novel exon-skipping. In April 2023, the FDA granted orphan-drug designation to the experimental drug antibody oligonucleotide conjugate (AOC) 1044 that skips exon 44. A small interfering RNA (siRNA), AOC 1044 works in patients who have a mutation amenable to exon 44 skipping (a disease type known as DMD44) by delivering phosphorodiamidate morpholino to skeletal muscle and heart tissue that skips exon 44. The process allows for dystrophin production, thereby preventing degradation of muscle tissue.
The orphan drug status of AOC 1044 made it available to the population of patients enrolled in the EXPLORE44 Phase 1/2 trial. However, studies demonstrating effectiveness of the drug – with the hope of, ultimately, providing widespread access to AOC 1044 – are still underway. In one of those studies, investigators expect to enroll approximately 40 healthy volunteers and 24 DMD44 patients 7-27 years of age.3 The study will evaluate the effects of exon skipping and dystrophin protein levels in participants who have DMD44.
Delandistrogene moxeparvovec. Oct. 27, 2021, marked the inception of the phase 3 Multinational, Randomized, Double-Blind, Placebo-Controlled Systemic Gene Delivery Study to Evaluate the Safety and Efficacy of SRP-9001 in Subjects With Duchenne Muscular Dystrophy (EMBARK). The trial is evaluating the safety and efficacy of the gene-therapy agent delandistrogene moxeparvovec in ambulatory boys who were 4 to less than 8 years of age at randomization. The 126 boys enrolled in the trial met the criteria of (1) a diagnosis of DMD confirmed by documented clinical findings and previous genetic testing and (2) a pathogenic frameshift mutation stop codon located between exons 18 and 79 (inclusive), except for a mutation fully contained within exon 45.
Additional inclusion criteria were (1) the ability to cooperate with motor-assessment testing and (2) receiving a steady daily dose of oral corticosteroid for 12 weeks or longer prior to screening, and (3) the expectation of maintaining the study dosage throughout screening. Boys who had previously received gene therapy, investigational medication, or any treatment that could have amplified dystrophin expression within the time limit specified by the protocol were ineligible to participate. Boys were excluded from the study if they presented with any other illness, medical condition, or need for chronic drug treatment.
Exon-skipping therapies in trials. Various biotech and pharmaceutical companies have initiated clinical trials to explore the potential of additional exon-skipping therapies for the DMD population:
ENTR-601-44 is another exon 44–skipping therapy in the pipeline.
On Aug. 22, 2023, the FDA approved delandistrogene moxeparvovec-rokl, a recombinant gene therapy utilizing an adenovirus vector. The product is indicated for ambulatory patients with DMD 4-5 years of age who have a confirmed mutation of the dystrophin gene.
Dyne Therapeutics is actively recruiting participants to investigate Dyne 251, its exon 51–skipping therapy.
Trials are in the works by BioMarin Pharmaceutical for its next-generation peptide-conjugated phosphorodiamidate morpholino oligomers (PPMO) for skipping exon 51.
Despite the prospects of such therapy, therapeutic targeting of exon 44 addresses only patients with DMD44, who account for approximately 10% of the DMD population. Disease involving the most prevalent site of a dystrophin gene mutation, exon 51, affects 13% of the DMD population. This leaves the majority of patients with DMD without gene therapy. Yet Dr. Brandsema is optimistic nevertheless.
“We were just failing over and over again with DMD treatment, but there is some hope now,” Dr. Brandsema said. “Also, FSHD is right on the cusp of having new therapies approaching.”
FSHD: Emerging therapies
The third more common type of muscular dystrophy is not a life-threatening condition. FSHD affects approximately 4 of every 100,000 people.1 An autosomal-dominant condition, FSHD is ultimately caused by inappropriate expression of the DUX4 protein product – a consequence of a complex genetic activity involving DUX4, its chromosomal locus, and the number of repeats of a microsatellite called D4Z4.4 The disease usually starts in proximal regions of the face (that is, surrounding the eyes and mouth), before spreading to muscular groups of the limbs – most prominently, muscles of the scapulae and humeri. Symptoms usually appear in these places initially, but the condition can affect any part of the body. Fifty percent of FSHD patients experience loss of high-frequency hearing and present with retinovasculopathy. Like DMD, FSHD varies in severity, with some forms presenting at birth.
AOC 1020-CS1 is an example of a new FSHD treatment under investigation. The phase 1/2 FORTITUDE trial is a randomized, double-blind, placebo-controlled study exploring the safety, tolerability, pharmacokinetics, pharmacodynamics, and potential efficacy of single- and multiple-dose AOC 1020-CS1 therapy in FSHD.5 The trial began in April 2023; estimated completion date is September 2025.
As with many rare diseases, however, following patients and capturing data that fully narrate their story remains challenging in both DMD and FSHD. Although clinical trials undoubtedly offer hope of expanding treatment options and additional insights into disease-state management, the often insidious, complex nature of some rare diseases, such as DMD and FSHD, presents some limitations.
“Patients are hard to measure,” Dr. Brandsema explained, “because they’re so variable at baseline in history and progress in a different [slower] way than timelines are set up in our system to study drugs.”
Neonatal screening and early diagnosis: Imperative for improving outcomes
Neonatal screening helps with early detection and treatment. Prompt diagnosis does not necessarily prolong a DMD patient’s life, but it can enhance their quality of life.
DNA diagnostics. A critical component of the path to treatment is DNA diagnostics. According to Barry J. Byrne, MD, PhD, chief medical advisor of the Muscular Dystrophy Association, the Human Genome Project conducted by the National Institutes of Health helped make DNA tests affordable; such tests run about $800 today. However, given continuous advancements in sequencing, Dr. Byrne said that whole-exome sequencing for $100 is within reach.
In terms of accessibility, some nations – Canada is an example – include testing as part of national health care services. In the United States, coverage for testing varies by health insurance plan. In addition, some plans have favored rapid diagnostic testing, and the overall cost is often individualized to the patient.
Early diagnosis and supportive care. Early diagnosis can certainly help improve DMD patients’ quality of life; supportive care provides some benefit. Dr. Byrne stressed the importance of managing extraskeletal clinical manifestations in this patient population. A critical area is initiating cardiovascular treatment immediately following diagnosis, even if the patient does not exhibit cardiovascular symptoms.
“Cardiac manifestations are actually the cause of mortality in DMD, and most boys with DMD should begin cardiovascular treatment shortly after diagnosis,” Dr. Byrne told Neurology Reviews 2023 Rare Neurological Disease Special Report. “The message to neurologists is that these patients can benefit from early cardiovascular treatment because we can prevent the complications of DMD-related heart failure until much later in life.”
Historically, clinicians used echocardiography as the mainstay tool to assess cardiovascular function; however, more and more clinicians are turning to magnetic resonance imaging for such investigation. Dr. Byrne, a cardiologist, explained that magnetic resonance imaging identifies cardiovascular dysfunction at earlier stages than echocardiography can. In addition, although DMD patients frequently experience fatigue, Dr. Byrne cautions neurologists that fatigue is usually related to muscle weakness, not necessarily heart failure.
DMD therapies carry a hefty price
Right now, the projected price range of AOC 1044 is $3.2 million to $3.4 million. Akin to the case with onasemnogene abeparvovec-xioi (Zolgensma) for spinal muscular atrophy, the world’s first gene therapy and first seven-figure drug, the manufacturer of AOC 1044 based pricing on the anticipated cost of treating a DMD44 patient throughout the lifespan, according to Dr. Byrne.
Delandistrogene moxeparvovec might come with an even higher price tag. A cost-effectiveness analysis study priced the therapy at $5 million. In a presentation to investors, the manufacturer projected the price in the range of $5 million to $13 million.6,7
‘It takes a village’: Comprehensive care requires a multidisciplinary team
Dr. Brandsema and Dr. Byrne agree: Optimizing outcomes requires ongoing coordinated and collaborative efforts of an interdisciplinary team of health care providers for the duration of DMD and FSHD patients’ lifespan.
A neurologist by training, Dr. Brandsema recognizes the importance of interdisciplinary collaboration in caring for patients with DMD, given the multiorgan manifestations of the disease.
“We have some hope with DMD, and FSHD is right on the cusp of having new therapies approaching ... It is important to recognize that interdisciplinary follow-up and optimized standard of care are important after dosing.”
“I think many patients living with neurological disorders have multiple providers they rely on for care,” Dr. Byrne said, “but cardiovascular and pulmonary care are important because both are affected in the case of DMD – not so much in FSHD.”
Ultimately, advancements in therapy and care give patients living with these disorders, and their caregivers, a renewed sense of hope – hope that their life will be improved by breakthrough therapies that have been approved or will arrive soon.
Dr. Brandsema discloses he is a consultant for Alexion, Audentes, AveXis/Novartis, Biogen, Cytokinetics, Dyne, Edgewise, Fibrogen, Genentech/Roche, Janssen, Marathon, Momenta, NS Pharma, PTC Therapeutics, Sarepta, Scholar Rock, Takeda, and WaVe. He is a speaker for AveXis and Biogen, a medical advisory council member for Cure SMA, and a site investigator for clinical trials with Alexion, Astellas, AveXis/Novartis, Biogen, Catabasis, CSL Behring, Cytokinetics, Fibrogen, Genentech/Roche, Ionis, Lilly, Janssen, Pfizer, PTC Therapeutics, Sarepta, Scholar Rock, Summit, and WaVe. Dr. Byrne has no relevant financial disclosures.
References
1. Centers for Disease Control and Prevention. What is muscular dystrophy? Updated Nov. 21, 2022. Accessed Sept. 3, 2023. https://www.cdc.gov/ncbddd/musculardystrophy/facts.html.
2. FDA approves first gene therapy for treatment of certain patients with Duchenne muscular dystrophy. U.S. Food and Drug Administration. Press release. June 22, 2023. Accessed Sept. 3, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-treatment-certain-patients-duchenne-muscular-dystrophy.
3. Study of AOC 1044 in healthy adult volunteers and participants with Duchenne muscular dystrophy (DMD) mutations amenable to exon 44 skipping (EXPLORE44). ClinicalTrials.gov Identifier: NCT05670730. Updated April 4, 2023. Accessed Sep. 3, 2023. https://www.clinicaltrials.gov/study/NCT05670730?cond=DMD&intr=AOC%201044&rank=1.
4. Statland JM, Tawil R. Facioscapulohumeral muscular dystrophy. Continuum (Minneap. Minn). 2016;22(6, Muscle and Neuromuscular Junction Disorders):1916-31. doi: 10.1212/CON.0000000000000399.
5. Phase 1/2 study of AOC 1020 in adults with facioscapulohumeral muscular dystrophy (FSHD) (FORTITUDE). ClinicalTrials.gov Identifier: NCT05747924. Updated Aug. 9, 2023. Accessed Sept. 3, 2023. https://clinicaltrials.gov/study/NCT05747924?term=fORTITUDE&cond=Facioscapulohumeral%20Muscular%20Dystrophy&rank=1.
6. Klimchak AC, Sedita LE, Rodino-Klapac LR, et al. Assessing the value of delandistrogene moxeparvovec (SRP-9001) gene therapy in patients with Duchenne muscular dystrophy in the United States. J Mark Access Health Policy. 2023;11(1):2216518. doi: 10.1080/20016689.2023.2216518.
7. Ingram D. [Investor relations presentation.] Sarepta Therapeutics website. June 22, 2023. Accessed Sept. 3, 2023. https://investorrelations.sarepta.com/static-files/7216948c-f688-4024-922e-39761bc7a984.
“There have been so many breakthroughs recently on the side of genetically targeted treatment [for muscular dystrophy] that supports muscle better,” said John F. Brandsema, MD, a child neurologist and section head at Children’s Hospital of Philadelphia, in an interview with Neurology Reviews 2023 Rare Neurological Disease Special Report. “We’re starting to see clinical response to some things that have been in trials – after decades of banging our heads on the wall trying new therapies, only to see them fail. I think it’s about reframing Duchenne muscular dystrophy [DMD] and facioscapulohumeral muscular dystrophy [FSHD] as treatable by target therapy because previously, they were treated with supportive care.”
DMD: Current and emerging therapies
DMD is caused by a mutation in the dystrophin gene on the X chromosome that inhibits production of dystrophin, a protein that shields muscles from injury during contraction. Dystrophin deficiency prevents muscle recovery, resulting in muscle-cell death and, ultimately, loss of function due to muscle degeneration.
FDA-approved exon-skipping therapies. Treatment modalities for what has historically been an incurable, lifespan-shortening disease involved supportive care that addresses symptoms, not the underlying cause. Consequently, many patients with DMD live only into their 20s and 30s. The tide began to turn in 2016, however, when the U.S. Food and Drug Administration granted accelerated approval for eteplirsen, an exon 51–skipping treatment that was the first RNA-based therapy for DMD to target the underlying cause. Additional exon-skipping therapies followed, including casimersen, which skips exon 45, and golodirsen and viltolarsen, which skip exon 53.
AOC 1044: Novel exon-skipping. In April 2023, the FDA granted orphan-drug designation to the experimental drug antibody oligonucleotide conjugate (AOC) 1044 that skips exon 44. A small interfering RNA (siRNA), AOC 1044 works in patients who have a mutation amenable to exon 44 skipping (a disease type known as DMD44) by delivering phosphorodiamidate morpholino to skeletal muscle and heart tissue that skips exon 44. The process allows for dystrophin production, thereby preventing degradation of muscle tissue.
The orphan drug status of AOC 1044 made it available to the population of patients enrolled in the EXPLORE44 Phase 1/2 trial. However, studies demonstrating effectiveness of the drug – with the hope of, ultimately, providing widespread access to AOC 1044 – are still underway. In one of those studies, investigators expect to enroll approximately 40 healthy volunteers and 24 DMD44 patients 7-27 years of age.3 The study will evaluate the effects of exon skipping and dystrophin protein levels in participants who have DMD44.
Delandistrogene moxeparvovec. Oct. 27, 2021, marked the inception of the phase 3 Multinational, Randomized, Double-Blind, Placebo-Controlled Systemic Gene Delivery Study to Evaluate the Safety and Efficacy of SRP-9001 in Subjects With Duchenne Muscular Dystrophy (EMBARK). The trial is evaluating the safety and efficacy of the gene-therapy agent delandistrogene moxeparvovec in ambulatory boys who were 4 to less than 8 years of age at randomization. The 126 boys enrolled in the trial met the criteria of (1) a diagnosis of DMD confirmed by documented clinical findings and previous genetic testing and (2) a pathogenic frameshift mutation stop codon located between exons 18 and 79 (inclusive), except for a mutation fully contained within exon 45.
Additional inclusion criteria were (1) the ability to cooperate with motor-assessment testing and (2) receiving a steady daily dose of oral corticosteroid for 12 weeks or longer prior to screening, and (3) the expectation of maintaining the study dosage throughout screening. Boys who had previously received gene therapy, investigational medication, or any treatment that could have amplified dystrophin expression within the time limit specified by the protocol were ineligible to participate. Boys were excluded from the study if they presented with any other illness, medical condition, or need for chronic drug treatment.
Exon-skipping therapies in trials. Various biotech and pharmaceutical companies have initiated clinical trials to explore the potential of additional exon-skipping therapies for the DMD population:
ENTR-601-44 is another exon 44–skipping therapy in the pipeline.
On Aug. 22, 2023, the FDA approved delandistrogene moxeparvovec-rokl, a recombinant gene therapy utilizing an adenovirus vector. The product is indicated for ambulatory patients with DMD 4-5 years of age who have a confirmed mutation of the dystrophin gene.
Dyne Therapeutics is actively recruiting participants to investigate Dyne 251, its exon 51–skipping therapy.
Trials are in the works by BioMarin Pharmaceutical for its next-generation peptide-conjugated phosphorodiamidate morpholino oligomers (PPMO) for skipping exon 51.
Despite the prospects of such therapy, therapeutic targeting of exon 44 addresses only patients with DMD44, who account for approximately 10% of the DMD population. Disease involving the most prevalent site of a dystrophin gene mutation, exon 51, affects 13% of the DMD population. This leaves the majority of patients with DMD without gene therapy. Yet Dr. Brandsema is optimistic nevertheless.
“We were just failing over and over again with DMD treatment, but there is some hope now,” Dr. Brandsema said. “Also, FSHD is right on the cusp of having new therapies approaching.”
FSHD: Emerging therapies
The third more common type of muscular dystrophy is not a life-threatening condition. FSHD affects approximately 4 of every 100,000 people.1 An autosomal-dominant condition, FSHD is ultimately caused by inappropriate expression of the DUX4 protein product – a consequence of a complex genetic activity involving DUX4, its chromosomal locus, and the number of repeats of a microsatellite called D4Z4.4 The disease usually starts in proximal regions of the face (that is, surrounding the eyes and mouth), before spreading to muscular groups of the limbs – most prominently, muscles of the scapulae and humeri. Symptoms usually appear in these places initially, but the condition can affect any part of the body. Fifty percent of FSHD patients experience loss of high-frequency hearing and present with retinovasculopathy. Like DMD, FSHD varies in severity, with some forms presenting at birth.
AOC 1020-CS1 is an example of a new FSHD treatment under investigation. The phase 1/2 FORTITUDE trial is a randomized, double-blind, placebo-controlled study exploring the safety, tolerability, pharmacokinetics, pharmacodynamics, and potential efficacy of single- and multiple-dose AOC 1020-CS1 therapy in FSHD.5 The trial began in April 2023; estimated completion date is September 2025.
As with many rare diseases, however, following patients and capturing data that fully narrate their story remains challenging in both DMD and FSHD. Although clinical trials undoubtedly offer hope of expanding treatment options and additional insights into disease-state management, the often insidious, complex nature of some rare diseases, such as DMD and FSHD, presents some limitations.
“Patients are hard to measure,” Dr. Brandsema explained, “because they’re so variable at baseline in history and progress in a different [slower] way than timelines are set up in our system to study drugs.”
Neonatal screening and early diagnosis: Imperative for improving outcomes
Neonatal screening helps with early detection and treatment. Prompt diagnosis does not necessarily prolong a DMD patient’s life, but it can enhance their quality of life.
DNA diagnostics. A critical component of the path to treatment is DNA diagnostics. According to Barry J. Byrne, MD, PhD, chief medical advisor of the Muscular Dystrophy Association, the Human Genome Project conducted by the National Institutes of Health helped make DNA tests affordable; such tests run about $800 today. However, given continuous advancements in sequencing, Dr. Byrne said that whole-exome sequencing for $100 is within reach.
In terms of accessibility, some nations – Canada is an example – include testing as part of national health care services. In the United States, coverage for testing varies by health insurance plan. In addition, some plans have favored rapid diagnostic testing, and the overall cost is often individualized to the patient.
Early diagnosis and supportive care. Early diagnosis can certainly help improve DMD patients’ quality of life; supportive care provides some benefit. Dr. Byrne stressed the importance of managing extraskeletal clinical manifestations in this patient population. A critical area is initiating cardiovascular treatment immediately following diagnosis, even if the patient does not exhibit cardiovascular symptoms.
“Cardiac manifestations are actually the cause of mortality in DMD, and most boys with DMD should begin cardiovascular treatment shortly after diagnosis,” Dr. Byrne told Neurology Reviews 2023 Rare Neurological Disease Special Report. “The message to neurologists is that these patients can benefit from early cardiovascular treatment because we can prevent the complications of DMD-related heart failure until much later in life.”
Historically, clinicians used echocardiography as the mainstay tool to assess cardiovascular function; however, more and more clinicians are turning to magnetic resonance imaging for such investigation. Dr. Byrne, a cardiologist, explained that magnetic resonance imaging identifies cardiovascular dysfunction at earlier stages than echocardiography can. In addition, although DMD patients frequently experience fatigue, Dr. Byrne cautions neurologists that fatigue is usually related to muscle weakness, not necessarily heart failure.
DMD therapies carry a hefty price
Right now, the projected price range of AOC 1044 is $3.2 million to $3.4 million. Akin to the case with onasemnogene abeparvovec-xioi (Zolgensma) for spinal muscular atrophy, the world’s first gene therapy and first seven-figure drug, the manufacturer of AOC 1044 based pricing on the anticipated cost of treating a DMD44 patient throughout the lifespan, according to Dr. Byrne.
Delandistrogene moxeparvovec might come with an even higher price tag. A cost-effectiveness analysis study priced the therapy at $5 million. In a presentation to investors, the manufacturer projected the price in the range of $5 million to $13 million.6,7
‘It takes a village’: Comprehensive care requires a multidisciplinary team
Dr. Brandsema and Dr. Byrne agree: Optimizing outcomes requires ongoing coordinated and collaborative efforts of an interdisciplinary team of health care providers for the duration of DMD and FSHD patients’ lifespan.
A neurologist by training, Dr. Brandsema recognizes the importance of interdisciplinary collaboration in caring for patients with DMD, given the multiorgan manifestations of the disease.
“We have some hope with DMD, and FSHD is right on the cusp of having new therapies approaching ... It is important to recognize that interdisciplinary follow-up and optimized standard of care are important after dosing.”
“I think many patients living with neurological disorders have multiple providers they rely on for care,” Dr. Byrne said, “but cardiovascular and pulmonary care are important because both are affected in the case of DMD – not so much in FSHD.”
Ultimately, advancements in therapy and care give patients living with these disorders, and their caregivers, a renewed sense of hope – hope that their life will be improved by breakthrough therapies that have been approved or will arrive soon.
Dr. Brandsema discloses he is a consultant for Alexion, Audentes, AveXis/Novartis, Biogen, Cytokinetics, Dyne, Edgewise, Fibrogen, Genentech/Roche, Janssen, Marathon, Momenta, NS Pharma, PTC Therapeutics, Sarepta, Scholar Rock, Takeda, and WaVe. He is a speaker for AveXis and Biogen, a medical advisory council member for Cure SMA, and a site investigator for clinical trials with Alexion, Astellas, AveXis/Novartis, Biogen, Catabasis, CSL Behring, Cytokinetics, Fibrogen, Genentech/Roche, Ionis, Lilly, Janssen, Pfizer, PTC Therapeutics, Sarepta, Scholar Rock, Summit, and WaVe. Dr. Byrne has no relevant financial disclosures.
References
1. Centers for Disease Control and Prevention. What is muscular dystrophy? Updated Nov. 21, 2022. Accessed Sept. 3, 2023. https://www.cdc.gov/ncbddd/musculardystrophy/facts.html.
2. FDA approves first gene therapy for treatment of certain patients with Duchenne muscular dystrophy. U.S. Food and Drug Administration. Press release. June 22, 2023. Accessed Sept. 3, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-treatment-certain-patients-duchenne-muscular-dystrophy.
3. Study of AOC 1044 in healthy adult volunteers and participants with Duchenne muscular dystrophy (DMD) mutations amenable to exon 44 skipping (EXPLORE44). ClinicalTrials.gov Identifier: NCT05670730. Updated April 4, 2023. Accessed Sep. 3, 2023. https://www.clinicaltrials.gov/study/NCT05670730?cond=DMD&intr=AOC%201044&rank=1.
4. Statland JM, Tawil R. Facioscapulohumeral muscular dystrophy. Continuum (Minneap. Minn). 2016;22(6, Muscle and Neuromuscular Junction Disorders):1916-31. doi: 10.1212/CON.0000000000000399.
5. Phase 1/2 study of AOC 1020 in adults with facioscapulohumeral muscular dystrophy (FSHD) (FORTITUDE). ClinicalTrials.gov Identifier: NCT05747924. Updated Aug. 9, 2023. Accessed Sept. 3, 2023. https://clinicaltrials.gov/study/NCT05747924?term=fORTITUDE&cond=Facioscapulohumeral%20Muscular%20Dystrophy&rank=1.
6. Klimchak AC, Sedita LE, Rodino-Klapac LR, et al. Assessing the value of delandistrogene moxeparvovec (SRP-9001) gene therapy in patients with Duchenne muscular dystrophy in the United States. J Mark Access Health Policy. 2023;11(1):2216518. doi: 10.1080/20016689.2023.2216518.
7. Ingram D. [Investor relations presentation.] Sarepta Therapeutics website. June 22, 2023. Accessed Sept. 3, 2023. https://investorrelations.sarepta.com/static-files/7216948c-f688-4024-922e-39761bc7a984.
Are cellular therapies the future of autoimmune disease?
A revolutionary treatment for cancers may also be able to treat and reset the immune system to provide long-term remission or possibly even cure certain autoimmune diseases.
Chimeric antigen receptor (CAR) T-cell therapy has offered a novel approach to treating hematologic cancers since 2017, but there are early signs that these cellular immunotherapies could be repurposed for B-cell mediated autoimmune diseases.
In September of last year, researchers in Germany reported that five patients with refractory systemic lupus erythematosus (SLE) treated with CAR T-cell therapy all achieved drug-free remission. At the time of publication, no patients had relapsed for up to 17 months after treatment. The authors described seroconversion of antinuclear antibodies in two patients with the longest follow-up, “indicating that abrogation of autoimmune B-cell clones may lead to a more widespread correction of autoimmunity,” the researchers write.
In another case study published in June, researchers used CD-19 targeted CAR-T cells to treat a 41-year-old man with refractory antisynthetase syndrome with progressive myositis and interstitial lung disease. Six months after treatment, there were no signs of myositis on MRI and a chest CT scan showed full regression of alveolitis.
Since then, two biotechnology companies – Cabaletta Bio in Philadelphia and Kyverna Therapeutics in Emeryville, Calif. – have already been granted fast-track designations from the U.S. Food and Drug Administration for CAR T-cell therapy for SLE and lupus nephritis. Bristol-Myers Squibb is also conducting a phase 1 trial in patients with severe, refractory SLE. Several biotechnology companies and hospitals in China are also conducting clinical trials for SLE. But this is only the tip of the iceberg regarding cellular therapies for autoimmune disease, said Max Konig, MD, PhD, an assistant professor of medicine in the division of rheumatology at Johns Hopkins University, Baltimore.
“It’s an incredibly exciting time. It’s unprecedented in the history of autoimmunity,” he noted.
A ‘reboot’ for the immune system
B-cell targeted therapies have been around since the early 2000s with drugs like rituximab, a monoclonal antibody medication that targets CD20, an antigen expressed on the surface of B cells. The CAR T cells currently available target another surface antigen, CD19, and are a much more potent therapy. Both are effective at depleting B cells in blood, but these engineered CD19-targeted T cells can reach B cells sitting in tissues in a way that antibody therapies cannot, Dr. Konig explained.
“If you have a patient with myositis, for example, where autoreactive B cells are sitting in the inflamed muscle, or a patient with rheumatoid arthritis, where you have disease-relevant B cells in hard-to-reach tissues like the synovium, those cells are much harder to deplete with an antibody, compared to a T cell that evolved to surveil and effectively kill in all tissues,” he explained.
In this process, T cells are collected from patients via leukapheresis and then re-engineered to express chimeric antigen receptors. A few days before these modified T cells are infused back into the patient, the patients are given a low-dose chemotherapy (lymphodepletion) regimen to help increase the effectiveness of the therapy. The one-time infusion is generally given on an inpatient basis, and patients are then monitored in hospital for side effects.
Once B cells are depleted, disease symptoms improve. But in the case studies published to date, once B cells re-emerge, they are naïve and no longer producing autoreactive B cells.
“Maybe it’s like a tabula rasa: You wipe [the B cells] out and start with a clean slate. Then, the immune system reboots, and now it’s working, whereas before it was messed up,” said Carl June, MD, who directs the Center for Cellular Immunotherapies at the at the University of Pennsylvania, Philadelphia. Dr. June and his research team led the development of CAR T-cell therapies for blood cancers.
The findings suggest that autoantibodies “might not be hardwired into the immune system,” he said.
But Dr. Konig stressed that we are still in the early days of clinical trials, and more research is necessary to understand the safety and efficacy of these therapies.
“There’s an incredible buzz around CAR T cells at the moment in rheumatology, which is great because I think that’s where the future is,” he said. “But we still need to learn how to appropriately apply these therapies in randomized, controlled trials.”
So far, the evidence behind CD19 CAR T-cell therapies in autoimmune disease is from case studies and phase 1 trials in a very small number of selected patients. (The upcoming Cabaletta and Kyverna trials in lupus will also be small, consisting of 12 patients each.)
Risks of intensive therapy
But while these therapies show promise, the process is very intensive. The lymphodepleting regimen increases the risk for infection and patients are commonly hospitalized for a week or more following infusion for toxicity monitoring. Serious adverse events such as cytokine release syndrome (CRS) can occur days to weeks after CAR T-cell infusion. In the five-patient case series reported in 2022, patients were hospitalized for 10 days following treatment.
The patient with antisynthetase syndrome, as well as three of five patients in the SLE case series study experienced mild CRS following infusion. Patients are also at a high risk for infection, as the engineered T cells target all B cells, not just the autoreactive immune cells.
The inability to differentiate between disease-causing and protective immune cells is an issue for all currently available drugs treating autoimmune disease, Dr. Konig said. But scientists are already working on how to make these potent cellular therapies safer and more precise.
Alternatives to standard CAR T-cell therapies
Engineering T cells with RNA is a new approach to limit the side effects and toxicity of CAR T-cell therapy, said Chris Jewell, PhD, the chief scientific officer at Cartesian Therapeutics, a biotechnology company based in Gaithersburg, Md. The company’s RNA CAR T-cell (rCAR-T) therapy – called DESCARTES-08 – is in phase 2 clinical trials for treatment of myasthenia gravis. Once these rCAR-T cells are infused in patients, as they divide, the RNAnaturally decays, he explained, meaning that after a certain point, the CAR is no longer expressed.
DESCARTES-08 targets B-cell maturation antigen (BCMA), which is primarily expressed on plasma cells, rather than all B cells, Dr. Jewell said.
“Targeting BCMA, we actually have a more selective profile,” he explained. “We are targeting the cells primarily responsible for the pathogenicity; many plasma cells – such as long-lived plasma cells – also take a long time to repopulate.”
This therapy also does not require lymphodepletion prior to infusion and can be done in an outpatient setting. The therapy is given in multiple infusions, once per week.
In the most recent clinical trial, patients with myasthenia gravis received six infusions over 6 weeks and experienced notable decreases in myasthenia gravis severity scale at up to 9 months of follow-up.
While standard CAR T-cell therapies under clinical investigational up to now all use effector T cells, regulatory T cells (Tregs) can also be engineered to target autoimmune disease. Abata Therapeutics, based in Boston, is using this approach for therapies for progressive multiple sclerosis and type 1 diabetes. These engineered Tregs express a T-cell receptor (TCR) that recognizes tissue-specific antigens and suppress inflammation at the site of the disease. “Treg-based cell therapies are really harnessing the natural power of regulatory cells to reset immune tolerance and recalibrate the immune system,” said their chief medical officer, Leonard Dragone, MD, PhD.
These therapies are derived from terminally differentiated cells that have limited capacity to produce pro-inflammatory cytokines including interleukin-2 or interferon gamma, Dr. Dragone explained. “CRS is difficult to envision from engineered Treg products and hasn’t been observed in any clinical experience with polyclonal Tregs,” he said.
This approach also does not require lymphodepletion prior to treatment. The company’s Treg cellular therapy for progressive MS is currently in investigational new drug-enabling studies, and they aim to dose their first patients in 2024.
Precision immunotherapy
For B-cell driven autoimmune diseases where the autoantibody is known, researchers have begun to re-engineer T cells to recognize only autoreactive B cells. While CD19 CAR T cells act more like a sledgehammer, these precision cellular immunotherapies are “like a razor’s strike,” Dr. June said.
“The chimeric autoantibody receptor (CAAR) approach targets autoantibodies that are expressed only on the surface of autoimmune B cells and are not expressed on normal B cells, which ideally should lead to precision targeting of just the cells that cause autoimmune disease,” explained Aimee Payne, MD, PhD, professor of dermatology and director of the Penn Clinical Autoimmunity Center of Excellence at the University of Pennsylvania, Philadelphia.
She and her research team used this approach to develop a treatment for mucosal pemphigus vulgaris, an autoimmune blistering disease of mucous membranes driven by autoantibodies against desmoglein 3.
“The current standard of care for pemphigus is to treat with steroids and rituximab, an infusion therapy that results in global, but temporary, B-cell depletion,” she said. “By expressing desmoglein 3 (DSG3) on the surface of the CAAR T-cell therapy, we target just the anti-DSG3 B cells that cause disease in mucosal pemphigus vulgaris and spare the healthy B cells.”
The therapy – called DSG3-CAART – is being developed by Cabaletta Bio and is now in phase 1 clinical trials. The approach is also being investigated to treat certain types of myasthenia gravis and membranous nephropathy.
Dr. Konig’s lab at Johns Hopkins developed and is now exploring a new precision cellular immunotherapy approach, chimeric autoantigen-T cell receptor (CATCR) T-cell therapy, to treat antiphospholipid syndrome, which is in preclinical stages. In this approach, Dr. Konig and his team are “re-engineering the natural T-cell receptor to selectively kill disease-causing B cells that drive antiphospholipid syndrome,” he explained.
He anticipates the CD19 CAR T-cell therapies currently in clinical trials will help to pave the way for this new generation of precision cellular therapies. The ultimate goal of these therapies, he said, is to uncouple therapeutic potency from infection risk.
“That’s really the holy grail in the treatment of autoimmune diseases. It’s tantalizingly close, but we’re not there yet.”
Dr. June is an inventor on patents and/or patent applications licensed to Novartis Institutes of Biomedical Research and receives license revenue from such licenses. Dr. June is a scientific founder of Tmunity Therapeutics and Capstan Therapeutics and is a member of the scientific advisory boards of AC Immune SA, Alaunos, BlueSphere Bio, Cabaletta, Carisma, Cartography Biosciences, Cellares, Celldex, Decheng Capital, Poseida, Verismo, and WIRB-Copernicus Group. Dr. Konig is a consultant for argenx and Revel and is listed as inventor for patent applications filed by John Hopkins University. Dr. Payne holds equity, grants, payments, and patent licensing from Cabaletta Bio and consults for Janssen.
A version of this article first appeared on Medscape.com.
A revolutionary treatment for cancers may also be able to treat and reset the immune system to provide long-term remission or possibly even cure certain autoimmune diseases.
Chimeric antigen receptor (CAR) T-cell therapy has offered a novel approach to treating hematologic cancers since 2017, but there are early signs that these cellular immunotherapies could be repurposed for B-cell mediated autoimmune diseases.
In September of last year, researchers in Germany reported that five patients with refractory systemic lupus erythematosus (SLE) treated with CAR T-cell therapy all achieved drug-free remission. At the time of publication, no patients had relapsed for up to 17 months after treatment. The authors described seroconversion of antinuclear antibodies in two patients with the longest follow-up, “indicating that abrogation of autoimmune B-cell clones may lead to a more widespread correction of autoimmunity,” the researchers write.
In another case study published in June, researchers used CD-19 targeted CAR-T cells to treat a 41-year-old man with refractory antisynthetase syndrome with progressive myositis and interstitial lung disease. Six months after treatment, there were no signs of myositis on MRI and a chest CT scan showed full regression of alveolitis.
Since then, two biotechnology companies – Cabaletta Bio in Philadelphia and Kyverna Therapeutics in Emeryville, Calif. – have already been granted fast-track designations from the U.S. Food and Drug Administration for CAR T-cell therapy for SLE and lupus nephritis. Bristol-Myers Squibb is also conducting a phase 1 trial in patients with severe, refractory SLE. Several biotechnology companies and hospitals in China are also conducting clinical trials for SLE. But this is only the tip of the iceberg regarding cellular therapies for autoimmune disease, said Max Konig, MD, PhD, an assistant professor of medicine in the division of rheumatology at Johns Hopkins University, Baltimore.
“It’s an incredibly exciting time. It’s unprecedented in the history of autoimmunity,” he noted.
A ‘reboot’ for the immune system
B-cell targeted therapies have been around since the early 2000s with drugs like rituximab, a monoclonal antibody medication that targets CD20, an antigen expressed on the surface of B cells. The CAR T cells currently available target another surface antigen, CD19, and are a much more potent therapy. Both are effective at depleting B cells in blood, but these engineered CD19-targeted T cells can reach B cells sitting in tissues in a way that antibody therapies cannot, Dr. Konig explained.
“If you have a patient with myositis, for example, where autoreactive B cells are sitting in the inflamed muscle, or a patient with rheumatoid arthritis, where you have disease-relevant B cells in hard-to-reach tissues like the synovium, those cells are much harder to deplete with an antibody, compared to a T cell that evolved to surveil and effectively kill in all tissues,” he explained.
In this process, T cells are collected from patients via leukapheresis and then re-engineered to express chimeric antigen receptors. A few days before these modified T cells are infused back into the patient, the patients are given a low-dose chemotherapy (lymphodepletion) regimen to help increase the effectiveness of the therapy. The one-time infusion is generally given on an inpatient basis, and patients are then monitored in hospital for side effects.
Once B cells are depleted, disease symptoms improve. But in the case studies published to date, once B cells re-emerge, they are naïve and no longer producing autoreactive B cells.
“Maybe it’s like a tabula rasa: You wipe [the B cells] out and start with a clean slate. Then, the immune system reboots, and now it’s working, whereas before it was messed up,” said Carl June, MD, who directs the Center for Cellular Immunotherapies at the at the University of Pennsylvania, Philadelphia. Dr. June and his research team led the development of CAR T-cell therapies for blood cancers.
The findings suggest that autoantibodies “might not be hardwired into the immune system,” he said.
But Dr. Konig stressed that we are still in the early days of clinical trials, and more research is necessary to understand the safety and efficacy of these therapies.
“There’s an incredible buzz around CAR T cells at the moment in rheumatology, which is great because I think that’s where the future is,” he said. “But we still need to learn how to appropriately apply these therapies in randomized, controlled trials.”
So far, the evidence behind CD19 CAR T-cell therapies in autoimmune disease is from case studies and phase 1 trials in a very small number of selected patients. (The upcoming Cabaletta and Kyverna trials in lupus will also be small, consisting of 12 patients each.)
Risks of intensive therapy
But while these therapies show promise, the process is very intensive. The lymphodepleting regimen increases the risk for infection and patients are commonly hospitalized for a week or more following infusion for toxicity monitoring. Serious adverse events such as cytokine release syndrome (CRS) can occur days to weeks after CAR T-cell infusion. In the five-patient case series reported in 2022, patients were hospitalized for 10 days following treatment.
The patient with antisynthetase syndrome, as well as three of five patients in the SLE case series study experienced mild CRS following infusion. Patients are also at a high risk for infection, as the engineered T cells target all B cells, not just the autoreactive immune cells.
The inability to differentiate between disease-causing and protective immune cells is an issue for all currently available drugs treating autoimmune disease, Dr. Konig said. But scientists are already working on how to make these potent cellular therapies safer and more precise.
Alternatives to standard CAR T-cell therapies
Engineering T cells with RNA is a new approach to limit the side effects and toxicity of CAR T-cell therapy, said Chris Jewell, PhD, the chief scientific officer at Cartesian Therapeutics, a biotechnology company based in Gaithersburg, Md. The company’s RNA CAR T-cell (rCAR-T) therapy – called DESCARTES-08 – is in phase 2 clinical trials for treatment of myasthenia gravis. Once these rCAR-T cells are infused in patients, as they divide, the RNAnaturally decays, he explained, meaning that after a certain point, the CAR is no longer expressed.
DESCARTES-08 targets B-cell maturation antigen (BCMA), which is primarily expressed on plasma cells, rather than all B cells, Dr. Jewell said.
“Targeting BCMA, we actually have a more selective profile,” he explained. “We are targeting the cells primarily responsible for the pathogenicity; many plasma cells – such as long-lived plasma cells – also take a long time to repopulate.”
This therapy also does not require lymphodepletion prior to infusion and can be done in an outpatient setting. The therapy is given in multiple infusions, once per week.
In the most recent clinical trial, patients with myasthenia gravis received six infusions over 6 weeks and experienced notable decreases in myasthenia gravis severity scale at up to 9 months of follow-up.
While standard CAR T-cell therapies under clinical investigational up to now all use effector T cells, regulatory T cells (Tregs) can also be engineered to target autoimmune disease. Abata Therapeutics, based in Boston, is using this approach for therapies for progressive multiple sclerosis and type 1 diabetes. These engineered Tregs express a T-cell receptor (TCR) that recognizes tissue-specific antigens and suppress inflammation at the site of the disease. “Treg-based cell therapies are really harnessing the natural power of regulatory cells to reset immune tolerance and recalibrate the immune system,” said their chief medical officer, Leonard Dragone, MD, PhD.
These therapies are derived from terminally differentiated cells that have limited capacity to produce pro-inflammatory cytokines including interleukin-2 or interferon gamma, Dr. Dragone explained. “CRS is difficult to envision from engineered Treg products and hasn’t been observed in any clinical experience with polyclonal Tregs,” he said.
This approach also does not require lymphodepletion prior to treatment. The company’s Treg cellular therapy for progressive MS is currently in investigational new drug-enabling studies, and they aim to dose their first patients in 2024.
Precision immunotherapy
For B-cell driven autoimmune diseases where the autoantibody is known, researchers have begun to re-engineer T cells to recognize only autoreactive B cells. While CD19 CAR T cells act more like a sledgehammer, these precision cellular immunotherapies are “like a razor’s strike,” Dr. June said.
“The chimeric autoantibody receptor (CAAR) approach targets autoantibodies that are expressed only on the surface of autoimmune B cells and are not expressed on normal B cells, which ideally should lead to precision targeting of just the cells that cause autoimmune disease,” explained Aimee Payne, MD, PhD, professor of dermatology and director of the Penn Clinical Autoimmunity Center of Excellence at the University of Pennsylvania, Philadelphia.
She and her research team used this approach to develop a treatment for mucosal pemphigus vulgaris, an autoimmune blistering disease of mucous membranes driven by autoantibodies against desmoglein 3.
“The current standard of care for pemphigus is to treat with steroids and rituximab, an infusion therapy that results in global, but temporary, B-cell depletion,” she said. “By expressing desmoglein 3 (DSG3) on the surface of the CAAR T-cell therapy, we target just the anti-DSG3 B cells that cause disease in mucosal pemphigus vulgaris and spare the healthy B cells.”
The therapy – called DSG3-CAART – is being developed by Cabaletta Bio and is now in phase 1 clinical trials. The approach is also being investigated to treat certain types of myasthenia gravis and membranous nephropathy.
Dr. Konig’s lab at Johns Hopkins developed and is now exploring a new precision cellular immunotherapy approach, chimeric autoantigen-T cell receptor (CATCR) T-cell therapy, to treat antiphospholipid syndrome, which is in preclinical stages. In this approach, Dr. Konig and his team are “re-engineering the natural T-cell receptor to selectively kill disease-causing B cells that drive antiphospholipid syndrome,” he explained.
He anticipates the CD19 CAR T-cell therapies currently in clinical trials will help to pave the way for this new generation of precision cellular therapies. The ultimate goal of these therapies, he said, is to uncouple therapeutic potency from infection risk.
“That’s really the holy grail in the treatment of autoimmune diseases. It’s tantalizingly close, but we’re not there yet.”
Dr. June is an inventor on patents and/or patent applications licensed to Novartis Institutes of Biomedical Research and receives license revenue from such licenses. Dr. June is a scientific founder of Tmunity Therapeutics and Capstan Therapeutics and is a member of the scientific advisory boards of AC Immune SA, Alaunos, BlueSphere Bio, Cabaletta, Carisma, Cartography Biosciences, Cellares, Celldex, Decheng Capital, Poseida, Verismo, and WIRB-Copernicus Group. Dr. Konig is a consultant for argenx and Revel and is listed as inventor for patent applications filed by John Hopkins University. Dr. Payne holds equity, grants, payments, and patent licensing from Cabaletta Bio and consults for Janssen.
A version of this article first appeared on Medscape.com.
A revolutionary treatment for cancers may also be able to treat and reset the immune system to provide long-term remission or possibly even cure certain autoimmune diseases.
Chimeric antigen receptor (CAR) T-cell therapy has offered a novel approach to treating hematologic cancers since 2017, but there are early signs that these cellular immunotherapies could be repurposed for B-cell mediated autoimmune diseases.
In September of last year, researchers in Germany reported that five patients with refractory systemic lupus erythematosus (SLE) treated with CAR T-cell therapy all achieved drug-free remission. At the time of publication, no patients had relapsed for up to 17 months after treatment. The authors described seroconversion of antinuclear antibodies in two patients with the longest follow-up, “indicating that abrogation of autoimmune B-cell clones may lead to a more widespread correction of autoimmunity,” the researchers write.
In another case study published in June, researchers used CD-19 targeted CAR-T cells to treat a 41-year-old man with refractory antisynthetase syndrome with progressive myositis and interstitial lung disease. Six months after treatment, there were no signs of myositis on MRI and a chest CT scan showed full regression of alveolitis.
Since then, two biotechnology companies – Cabaletta Bio in Philadelphia and Kyverna Therapeutics in Emeryville, Calif. – have already been granted fast-track designations from the U.S. Food and Drug Administration for CAR T-cell therapy for SLE and lupus nephritis. Bristol-Myers Squibb is also conducting a phase 1 trial in patients with severe, refractory SLE. Several biotechnology companies and hospitals in China are also conducting clinical trials for SLE. But this is only the tip of the iceberg regarding cellular therapies for autoimmune disease, said Max Konig, MD, PhD, an assistant professor of medicine in the division of rheumatology at Johns Hopkins University, Baltimore.
“It’s an incredibly exciting time. It’s unprecedented in the history of autoimmunity,” he noted.
A ‘reboot’ for the immune system
B-cell targeted therapies have been around since the early 2000s with drugs like rituximab, a monoclonal antibody medication that targets CD20, an antigen expressed on the surface of B cells. The CAR T cells currently available target another surface antigen, CD19, and are a much more potent therapy. Both are effective at depleting B cells in blood, but these engineered CD19-targeted T cells can reach B cells sitting in tissues in a way that antibody therapies cannot, Dr. Konig explained.
“If you have a patient with myositis, for example, where autoreactive B cells are sitting in the inflamed muscle, or a patient with rheumatoid arthritis, where you have disease-relevant B cells in hard-to-reach tissues like the synovium, those cells are much harder to deplete with an antibody, compared to a T cell that evolved to surveil and effectively kill in all tissues,” he explained.
In this process, T cells are collected from patients via leukapheresis and then re-engineered to express chimeric antigen receptors. A few days before these modified T cells are infused back into the patient, the patients are given a low-dose chemotherapy (lymphodepletion) regimen to help increase the effectiveness of the therapy. The one-time infusion is generally given on an inpatient basis, and patients are then monitored in hospital for side effects.
Once B cells are depleted, disease symptoms improve. But in the case studies published to date, once B cells re-emerge, they are naïve and no longer producing autoreactive B cells.
“Maybe it’s like a tabula rasa: You wipe [the B cells] out and start with a clean slate. Then, the immune system reboots, and now it’s working, whereas before it was messed up,” said Carl June, MD, who directs the Center for Cellular Immunotherapies at the at the University of Pennsylvania, Philadelphia. Dr. June and his research team led the development of CAR T-cell therapies for blood cancers.
The findings suggest that autoantibodies “might not be hardwired into the immune system,” he said.
But Dr. Konig stressed that we are still in the early days of clinical trials, and more research is necessary to understand the safety and efficacy of these therapies.
“There’s an incredible buzz around CAR T cells at the moment in rheumatology, which is great because I think that’s where the future is,” he said. “But we still need to learn how to appropriately apply these therapies in randomized, controlled trials.”
So far, the evidence behind CD19 CAR T-cell therapies in autoimmune disease is from case studies and phase 1 trials in a very small number of selected patients. (The upcoming Cabaletta and Kyverna trials in lupus will also be small, consisting of 12 patients each.)
Risks of intensive therapy
But while these therapies show promise, the process is very intensive. The lymphodepleting regimen increases the risk for infection and patients are commonly hospitalized for a week or more following infusion for toxicity monitoring. Serious adverse events such as cytokine release syndrome (CRS) can occur days to weeks after CAR T-cell infusion. In the five-patient case series reported in 2022, patients were hospitalized for 10 days following treatment.
The patient with antisynthetase syndrome, as well as three of five patients in the SLE case series study experienced mild CRS following infusion. Patients are also at a high risk for infection, as the engineered T cells target all B cells, not just the autoreactive immune cells.
The inability to differentiate between disease-causing and protective immune cells is an issue for all currently available drugs treating autoimmune disease, Dr. Konig said. But scientists are already working on how to make these potent cellular therapies safer and more precise.
Alternatives to standard CAR T-cell therapies
Engineering T cells with RNA is a new approach to limit the side effects and toxicity of CAR T-cell therapy, said Chris Jewell, PhD, the chief scientific officer at Cartesian Therapeutics, a biotechnology company based in Gaithersburg, Md. The company’s RNA CAR T-cell (rCAR-T) therapy – called DESCARTES-08 – is in phase 2 clinical trials for treatment of myasthenia gravis. Once these rCAR-T cells are infused in patients, as they divide, the RNAnaturally decays, he explained, meaning that after a certain point, the CAR is no longer expressed.
DESCARTES-08 targets B-cell maturation antigen (BCMA), which is primarily expressed on plasma cells, rather than all B cells, Dr. Jewell said.
“Targeting BCMA, we actually have a more selective profile,” he explained. “We are targeting the cells primarily responsible for the pathogenicity; many plasma cells – such as long-lived plasma cells – also take a long time to repopulate.”
This therapy also does not require lymphodepletion prior to infusion and can be done in an outpatient setting. The therapy is given in multiple infusions, once per week.
In the most recent clinical trial, patients with myasthenia gravis received six infusions over 6 weeks and experienced notable decreases in myasthenia gravis severity scale at up to 9 months of follow-up.
While standard CAR T-cell therapies under clinical investigational up to now all use effector T cells, regulatory T cells (Tregs) can also be engineered to target autoimmune disease. Abata Therapeutics, based in Boston, is using this approach for therapies for progressive multiple sclerosis and type 1 diabetes. These engineered Tregs express a T-cell receptor (TCR) that recognizes tissue-specific antigens and suppress inflammation at the site of the disease. “Treg-based cell therapies are really harnessing the natural power of regulatory cells to reset immune tolerance and recalibrate the immune system,” said their chief medical officer, Leonard Dragone, MD, PhD.
These therapies are derived from terminally differentiated cells that have limited capacity to produce pro-inflammatory cytokines including interleukin-2 or interferon gamma, Dr. Dragone explained. “CRS is difficult to envision from engineered Treg products and hasn’t been observed in any clinical experience with polyclonal Tregs,” he said.
This approach also does not require lymphodepletion prior to treatment. The company’s Treg cellular therapy for progressive MS is currently in investigational new drug-enabling studies, and they aim to dose their first patients in 2024.
Precision immunotherapy
For B-cell driven autoimmune diseases where the autoantibody is known, researchers have begun to re-engineer T cells to recognize only autoreactive B cells. While CD19 CAR T cells act more like a sledgehammer, these precision cellular immunotherapies are “like a razor’s strike,” Dr. June said.
“The chimeric autoantibody receptor (CAAR) approach targets autoantibodies that are expressed only on the surface of autoimmune B cells and are not expressed on normal B cells, which ideally should lead to precision targeting of just the cells that cause autoimmune disease,” explained Aimee Payne, MD, PhD, professor of dermatology and director of the Penn Clinical Autoimmunity Center of Excellence at the University of Pennsylvania, Philadelphia.
She and her research team used this approach to develop a treatment for mucosal pemphigus vulgaris, an autoimmune blistering disease of mucous membranes driven by autoantibodies against desmoglein 3.
“The current standard of care for pemphigus is to treat with steroids and rituximab, an infusion therapy that results in global, but temporary, B-cell depletion,” she said. “By expressing desmoglein 3 (DSG3) on the surface of the CAAR T-cell therapy, we target just the anti-DSG3 B cells that cause disease in mucosal pemphigus vulgaris and spare the healthy B cells.”
The therapy – called DSG3-CAART – is being developed by Cabaletta Bio and is now in phase 1 clinical trials. The approach is also being investigated to treat certain types of myasthenia gravis and membranous nephropathy.
Dr. Konig’s lab at Johns Hopkins developed and is now exploring a new precision cellular immunotherapy approach, chimeric autoantigen-T cell receptor (CATCR) T-cell therapy, to treat antiphospholipid syndrome, which is in preclinical stages. In this approach, Dr. Konig and his team are “re-engineering the natural T-cell receptor to selectively kill disease-causing B cells that drive antiphospholipid syndrome,” he explained.
He anticipates the CD19 CAR T-cell therapies currently in clinical trials will help to pave the way for this new generation of precision cellular therapies. The ultimate goal of these therapies, he said, is to uncouple therapeutic potency from infection risk.
“That’s really the holy grail in the treatment of autoimmune diseases. It’s tantalizingly close, but we’re not there yet.”
Dr. June is an inventor on patents and/or patent applications licensed to Novartis Institutes of Biomedical Research and receives license revenue from such licenses. Dr. June is a scientific founder of Tmunity Therapeutics and Capstan Therapeutics and is a member of the scientific advisory boards of AC Immune SA, Alaunos, BlueSphere Bio, Cabaletta, Carisma, Cartography Biosciences, Cellares, Celldex, Decheng Capital, Poseida, Verismo, and WIRB-Copernicus Group. Dr. Konig is a consultant for argenx and Revel and is listed as inventor for patent applications filed by John Hopkins University. Dr. Payne holds equity, grants, payments, and patent licensing from Cabaletta Bio and consults for Janssen.
A version of this article first appeared on Medscape.com.
Myasthenia gravis drug gets FDA nod
, the drug’s manufacturer, UCB, has announced.
Rozanolixizumab is a subcutaneous-infused humanized IgG4 monoclonal antibody that binds to the neonatal Fc receptor (FcRn), reducing the concentration of pathogenic IgG autoantibodies.
U.S. approval is based on results of the phase 3 MycarinG study involving 200 patients with AChR or MuSK autoantibody-positive gMG. Patients were randomly assigned to one of two rozanolixizumab groups (7 mg/kg or 10 mg/kg) or placebo for 6 weeks.
As reported last month in Lancet Neurology, rozanolixizumab led to statistically significant improvements in gMG-specific outcomes, including everyday activities such as breathing, talking, swallowing, and being able to rise from a chair.
“There is a significant need for new, innovative treatment options to reduce the day-to-day burden of gMG,” lead investigator Vera Bril, MD, professor of medicine (neurology), University of Toronto, said in a news release.
Rozanolixizumab is “a new treatment option, targeting one of the mechanisms of disease to provide symptom improvement in patient- and physician-reported outcomes at day 43,” Dr. Bril added.
The most common adverse reactions (reported in at least 10% of patients treated with rozanolixizumab) were headache, infections, diarrhea, pyrexia, hypersensitivity reactions, and nausea.
The company expects rozanolixizumab to be available in the United States during the third quarter of 2023.
The FDA granted the application for rozanolixizumab in gMG priority review.
A version of this article first appeared on Medscape.com.
, the drug’s manufacturer, UCB, has announced.
Rozanolixizumab is a subcutaneous-infused humanized IgG4 monoclonal antibody that binds to the neonatal Fc receptor (FcRn), reducing the concentration of pathogenic IgG autoantibodies.
U.S. approval is based on results of the phase 3 MycarinG study involving 200 patients with AChR or MuSK autoantibody-positive gMG. Patients were randomly assigned to one of two rozanolixizumab groups (7 mg/kg or 10 mg/kg) or placebo for 6 weeks.
As reported last month in Lancet Neurology, rozanolixizumab led to statistically significant improvements in gMG-specific outcomes, including everyday activities such as breathing, talking, swallowing, and being able to rise from a chair.
“There is a significant need for new, innovative treatment options to reduce the day-to-day burden of gMG,” lead investigator Vera Bril, MD, professor of medicine (neurology), University of Toronto, said in a news release.
Rozanolixizumab is “a new treatment option, targeting one of the mechanisms of disease to provide symptom improvement in patient- and physician-reported outcomes at day 43,” Dr. Bril added.
The most common adverse reactions (reported in at least 10% of patients treated with rozanolixizumab) were headache, infections, diarrhea, pyrexia, hypersensitivity reactions, and nausea.
The company expects rozanolixizumab to be available in the United States during the third quarter of 2023.
The FDA granted the application for rozanolixizumab in gMG priority review.
A version of this article first appeared on Medscape.com.
, the drug’s manufacturer, UCB, has announced.
Rozanolixizumab is a subcutaneous-infused humanized IgG4 monoclonal antibody that binds to the neonatal Fc receptor (FcRn), reducing the concentration of pathogenic IgG autoantibodies.
U.S. approval is based on results of the phase 3 MycarinG study involving 200 patients with AChR or MuSK autoantibody-positive gMG. Patients were randomly assigned to one of two rozanolixizumab groups (7 mg/kg or 10 mg/kg) or placebo for 6 weeks.
As reported last month in Lancet Neurology, rozanolixizumab led to statistically significant improvements in gMG-specific outcomes, including everyday activities such as breathing, talking, swallowing, and being able to rise from a chair.
“There is a significant need for new, innovative treatment options to reduce the day-to-day burden of gMG,” lead investigator Vera Bril, MD, professor of medicine (neurology), University of Toronto, said in a news release.
Rozanolixizumab is “a new treatment option, targeting one of the mechanisms of disease to provide symptom improvement in patient- and physician-reported outcomes at day 43,” Dr. Bril added.
The most common adverse reactions (reported in at least 10% of patients treated with rozanolixizumab) were headache, infections, diarrhea, pyrexia, hypersensitivity reactions, and nausea.
The company expects rozanolixizumab to be available in the United States during the third quarter of 2023.
The FDA granted the application for rozanolixizumab in gMG priority review.
A version of this article first appeared on Medscape.com.
U.S. incidence, prevalence of myasthenia gravis is rising
, an analysis of new claims data shows. Investigators speculate the rise of this rare disorder may be due to “increased diagnosis and more awareness of the disease over time, which has been shown in several studies,” study investigator Ema Rodrigues, DSc, MPH, with Alexion Pharmaceuticals, Boston.
Dr. Rodrigues presented her research at the 2023 annual meeting of the American Academy of Neurology.
Myasthenia gravis is a rare neuromuscular disease characterized by muscle weakness and fatigue caused by the binding of autoantibodies at the neuromuscular junction. It affects the voluntary muscles of the body, especially those that control the eyes, mouth, throat, and limbs.
In Europe, the incidence and prevalence of myasthenia gravis has increased for the past several decades. In the United States, increasing prevalence has also been observed, but recent estimates are lacking, making it tough to gauge the true burden of disease, Dr. Rodrigues explained.
Claims-based analysis
To investigate, Dr. Rodrigues and colleagues analyzed claims data (commercial, Medicare, and Medicaid) and electronic health records representing over 300 million patients in the United States from 2011 to present.
They calculated sex- and age-specific incidence and prevalence of myasthenia gravis for the year 2021 using U.S. Census data.
Prevalent patients were identified as having one or more myasthenia gravis records in 2021 and two or more myasthenia gravis records, at least 30 days apart, from 2016 to 2021. This cohort had 78,225 patients.
Incident patients were identified as those with a myasthenia gravis record in 2021 and no previous myasthenia gravis record from 2019 to 2020. This cohort had 4,214 patients.
For both the prevalent and incident cohort, the distribution of male and female patients was roughly 50/50, with a slightly higher proportion of females in the incident cohort, Dr. Rodrigues reported.
When looking at age groups, there were “very few pediatric patients,” she noted, with less than 1% of the patients under the age of 12. The highest proportion of patients were 65 years or older. The mean age was 67 in the prevalent cohort and 68 in the incident cohort.
In 2021, the overall incidence of myasthenia gravis was 3.2 per 100,000 with similar estimates for males and females (3.2 vs. 3.1 per 100,000, respectively).
Total prevalence was estimated to be 37.0 per 100,000 with sex-specific estimates being comparable at 37.3 and 36.7 per 100,000 for males and females, respectively.
The incidence and prevalence of myasthenia gravis increased with age, ranging from 0.3 and 0.4 per 100,000, respectively, in children younger than age 2 years, to 10.2 and 116.8 per 100,000, respectively, in people 65 and older.
These estimates are “significantly higher” than those from a prior U.S. analysis from 2003, Dr. Rodrigues told attendees, but they are quite similar to the estimates that were reported in Sweden in 2020.
A limitation of the analysis is that patients who do not seek care regularly may have not been identified due to inclusion criteria, potentially leading to underestimates. Also, no information was available on the myasthenia gravis subtype (ocular vs. generalized).
Underestimated burden
Reached for comment, Richard J. Nowak, MD, MS, director of the Yale Myasthenia Gravis Clinic, Yale School of Medicine, New Haven, Conn., noted that the new report, “albeit limited as a claims-based analysis, presents modern data on incidence and prevalence of myasthenia gravis in the United States.”
“It suggests that the current estimates of myasthenia gravis in the United States are too low and that the true impact/burden of myasthenia gravis is greater. While we are unable to verify the accuracy of the diagnosis, the total myasthenia gravis population is likely to be about 100,000, which is higher than prior estimates.”
“This, in fact, might be driven by greater disease awareness and increased diagnosis along with decreased mortality and longer life expectancy,” Dr. Nowak said.
“Anecdotally, we are most certainly seeing patients with new-onset myasthenia gravis in their 70s, 80s, and even 90s in recent years. The EXPLORE-MG registry published data from a tertiary center on age of onset breakdown showing myasthenia gravis can present at any age,” Dr. Nowak added.
Funding for the study was provided by Alexion, AstraZeneca Rare Disease. Dr. Rodrigues receives compensation and owns stock as an employee of Alexion, AstraZeneca Rare Diseases. Dr. Nowak has no relevant disclosures.
A version of this article originally appeared on Medscape.com.
, an analysis of new claims data shows. Investigators speculate the rise of this rare disorder may be due to “increased diagnosis and more awareness of the disease over time, which has been shown in several studies,” study investigator Ema Rodrigues, DSc, MPH, with Alexion Pharmaceuticals, Boston.
Dr. Rodrigues presented her research at the 2023 annual meeting of the American Academy of Neurology.
Myasthenia gravis is a rare neuromuscular disease characterized by muscle weakness and fatigue caused by the binding of autoantibodies at the neuromuscular junction. It affects the voluntary muscles of the body, especially those that control the eyes, mouth, throat, and limbs.
In Europe, the incidence and prevalence of myasthenia gravis has increased for the past several decades. In the United States, increasing prevalence has also been observed, but recent estimates are lacking, making it tough to gauge the true burden of disease, Dr. Rodrigues explained.
Claims-based analysis
To investigate, Dr. Rodrigues and colleagues analyzed claims data (commercial, Medicare, and Medicaid) and electronic health records representing over 300 million patients in the United States from 2011 to present.
They calculated sex- and age-specific incidence and prevalence of myasthenia gravis for the year 2021 using U.S. Census data.
Prevalent patients were identified as having one or more myasthenia gravis records in 2021 and two or more myasthenia gravis records, at least 30 days apart, from 2016 to 2021. This cohort had 78,225 patients.
Incident patients were identified as those with a myasthenia gravis record in 2021 and no previous myasthenia gravis record from 2019 to 2020. This cohort had 4,214 patients.
For both the prevalent and incident cohort, the distribution of male and female patients was roughly 50/50, with a slightly higher proportion of females in the incident cohort, Dr. Rodrigues reported.
When looking at age groups, there were “very few pediatric patients,” she noted, with less than 1% of the patients under the age of 12. The highest proportion of patients were 65 years or older. The mean age was 67 in the prevalent cohort and 68 in the incident cohort.
In 2021, the overall incidence of myasthenia gravis was 3.2 per 100,000 with similar estimates for males and females (3.2 vs. 3.1 per 100,000, respectively).
Total prevalence was estimated to be 37.0 per 100,000 with sex-specific estimates being comparable at 37.3 and 36.7 per 100,000 for males and females, respectively.
The incidence and prevalence of myasthenia gravis increased with age, ranging from 0.3 and 0.4 per 100,000, respectively, in children younger than age 2 years, to 10.2 and 116.8 per 100,000, respectively, in people 65 and older.
These estimates are “significantly higher” than those from a prior U.S. analysis from 2003, Dr. Rodrigues told attendees, but they are quite similar to the estimates that were reported in Sweden in 2020.
A limitation of the analysis is that patients who do not seek care regularly may have not been identified due to inclusion criteria, potentially leading to underestimates. Also, no information was available on the myasthenia gravis subtype (ocular vs. generalized).
Underestimated burden
Reached for comment, Richard J. Nowak, MD, MS, director of the Yale Myasthenia Gravis Clinic, Yale School of Medicine, New Haven, Conn., noted that the new report, “albeit limited as a claims-based analysis, presents modern data on incidence and prevalence of myasthenia gravis in the United States.”
“It suggests that the current estimates of myasthenia gravis in the United States are too low and that the true impact/burden of myasthenia gravis is greater. While we are unable to verify the accuracy of the diagnosis, the total myasthenia gravis population is likely to be about 100,000, which is higher than prior estimates.”
“This, in fact, might be driven by greater disease awareness and increased diagnosis along with decreased mortality and longer life expectancy,” Dr. Nowak said.
“Anecdotally, we are most certainly seeing patients with new-onset myasthenia gravis in their 70s, 80s, and even 90s in recent years. The EXPLORE-MG registry published data from a tertiary center on age of onset breakdown showing myasthenia gravis can present at any age,” Dr. Nowak added.
Funding for the study was provided by Alexion, AstraZeneca Rare Disease. Dr. Rodrigues receives compensation and owns stock as an employee of Alexion, AstraZeneca Rare Diseases. Dr. Nowak has no relevant disclosures.
A version of this article originally appeared on Medscape.com.
, an analysis of new claims data shows. Investigators speculate the rise of this rare disorder may be due to “increased diagnosis and more awareness of the disease over time, which has been shown in several studies,” study investigator Ema Rodrigues, DSc, MPH, with Alexion Pharmaceuticals, Boston.
Dr. Rodrigues presented her research at the 2023 annual meeting of the American Academy of Neurology.
Myasthenia gravis is a rare neuromuscular disease characterized by muscle weakness and fatigue caused by the binding of autoantibodies at the neuromuscular junction. It affects the voluntary muscles of the body, especially those that control the eyes, mouth, throat, and limbs.
In Europe, the incidence and prevalence of myasthenia gravis has increased for the past several decades. In the United States, increasing prevalence has also been observed, but recent estimates are lacking, making it tough to gauge the true burden of disease, Dr. Rodrigues explained.
Claims-based analysis
To investigate, Dr. Rodrigues and colleagues analyzed claims data (commercial, Medicare, and Medicaid) and electronic health records representing over 300 million patients in the United States from 2011 to present.
They calculated sex- and age-specific incidence and prevalence of myasthenia gravis for the year 2021 using U.S. Census data.
Prevalent patients were identified as having one or more myasthenia gravis records in 2021 and two or more myasthenia gravis records, at least 30 days apart, from 2016 to 2021. This cohort had 78,225 patients.
Incident patients were identified as those with a myasthenia gravis record in 2021 and no previous myasthenia gravis record from 2019 to 2020. This cohort had 4,214 patients.
For both the prevalent and incident cohort, the distribution of male and female patients was roughly 50/50, with a slightly higher proportion of females in the incident cohort, Dr. Rodrigues reported.
When looking at age groups, there were “very few pediatric patients,” she noted, with less than 1% of the patients under the age of 12. The highest proportion of patients were 65 years or older. The mean age was 67 in the prevalent cohort and 68 in the incident cohort.
In 2021, the overall incidence of myasthenia gravis was 3.2 per 100,000 with similar estimates for males and females (3.2 vs. 3.1 per 100,000, respectively).
Total prevalence was estimated to be 37.0 per 100,000 with sex-specific estimates being comparable at 37.3 and 36.7 per 100,000 for males and females, respectively.
The incidence and prevalence of myasthenia gravis increased with age, ranging from 0.3 and 0.4 per 100,000, respectively, in children younger than age 2 years, to 10.2 and 116.8 per 100,000, respectively, in people 65 and older.
These estimates are “significantly higher” than those from a prior U.S. analysis from 2003, Dr. Rodrigues told attendees, but they are quite similar to the estimates that were reported in Sweden in 2020.
A limitation of the analysis is that patients who do not seek care regularly may have not been identified due to inclusion criteria, potentially leading to underestimates. Also, no information was available on the myasthenia gravis subtype (ocular vs. generalized).
Underestimated burden
Reached for comment, Richard J. Nowak, MD, MS, director of the Yale Myasthenia Gravis Clinic, Yale School of Medicine, New Haven, Conn., noted that the new report, “albeit limited as a claims-based analysis, presents modern data on incidence and prevalence of myasthenia gravis in the United States.”
“It suggests that the current estimates of myasthenia gravis in the United States are too low and that the true impact/burden of myasthenia gravis is greater. While we are unable to verify the accuracy of the diagnosis, the total myasthenia gravis population is likely to be about 100,000, which is higher than prior estimates.”
“This, in fact, might be driven by greater disease awareness and increased diagnosis along with decreased mortality and longer life expectancy,” Dr. Nowak said.
“Anecdotally, we are most certainly seeing patients with new-onset myasthenia gravis in their 70s, 80s, and even 90s in recent years. The EXPLORE-MG registry published data from a tertiary center on age of onset breakdown showing myasthenia gravis can present at any age,” Dr. Nowak added.
Funding for the study was provided by Alexion, AstraZeneca Rare Disease. Dr. Rodrigues receives compensation and owns stock as an employee of Alexion, AstraZeneca Rare Diseases. Dr. Nowak has no relevant disclosures.
A version of this article originally appeared on Medscape.com.
From AAN 2023
Therapy to reverse muscle dystrophies shows promise
BOSTON – Becker (BMD) and Duchenne muscle dystrophy (DMD) progress largely from irreversible contraction-induced injury of skeletal muscles, making the very positive interim results of an early-phase trial with a drug that prevents these injuries worth attention.
The phase 1b data in BMD, presented at the 2023 annual meeting of the American Academy of Neurology, were sufficiently promising that controlled phase 2 trials in both BMD and DMD are already enrolling, reported Joanne Donovan, MD, PhD, an adjunct professor at Boston University and chief medical officer of Edgewise Therapeutics, the company developing the drug.
Phase 1 study
Early phase studies are largely focused on safety, but the
Moreover, the evidence of a clinical effect was achieved in adult patients with a North Star Ambulatory Assessment (NSAA) score of 15, signifying advanced disease. Only 12 patients were enrolled and there were no controls, but objective evidence of a favorable effect was generated by highly significant reductions in creatine kinase (CK) and fast skeletal muscle (TNNI2) troponin, which are both biomarkers commonly used to track muscular dystrophy progression.
In patients with BMD or DMD, a lack of dystrophin is a key pathogenic feature, according to Dr. Donovan. She explained that dystrophin in muscles connects contractile proteins to membranes and surrounding matrix. In the presence of dystrophin, muscle fibers support each other, but when this protein is absent, contraction causes injury.
The drug in development, currently identified as EDG-5506, is a selective fast myosin inhibitor. This agent was shown to prevent the muscle injury caused by lack of dystrophin in animal models of muscular dystrophy and is now showing the same effect in humans. Preservation of muscle is critical to preventing BMD and DMD progression according to several sets of data, according to Dr. Donovan.
For one, it has been shown that BMD or DMD patients with relatively preserved function as defined by a NSAA score above 32 have minimal muscle damage. As NSAA scores fall below 32 points, muscle mass diminishes and fat accumulates. In natural history studies of BMD, there is a 1.2-point decline in NSAA score over 5 years, and this tracks with muscle loss and not with other variables, such as patient age.
“Progression depends on the degree of muscle loss,” Dr. Donovan stated, providing the rationale for moving forward with EDG-5506.
Proof of concept
In experimental studies, modulation of fast myelin provided complete protection against muscle injury while preserving its contractile function, and this translated into protection against loss of function. Phase 1 studies in BMD patients and healthy controls have already provided evidence that EDG-5506 is well tolerated and safe, but the new phase 1b provides a proof of concept for its ability to inhibit muscle injury in BMD patients.
In this study, called ARCH, 12 adults 18 years of age or older with a dystrophin mutation and a BMD phenotype who could complete a 100-meter timed test were enrolled. The median age at entry was 32 years. Several patients had participated in a previous phase 1 safety study. The daily starting dose of 10 mg was increased from 10 mg to 15 mg at 2 months. The dose was increased again to 20 mg at 6 months, but the data presented by Dr. Donovan were restricted to the first 6 months.
At the interim 6-month analysis, creatine kinase was reduced by 40% and TINN2 was reduced by 84% (both P < 0.001). The significant reductions in these biomarkers and others, such as myoglobin, were mostly achieved within the first month, although further reductions were observed for some biomarkers subsequently.
The NSAA score at 6 months improved on average by about 1 point on treatment. Natural history studies of BMD predict a 1-point reduction in NSAA score over this period of time. The modest improvements from baseline in pain scores at 1 month were sustained at 6 months.
On the basis of a proteomic analysis, 125 proteins mostly associated with metabolic pathways consistent with muscle injury were found to be altered in BMD patients relative to healthy controls. The majority of these proteins, whether assessed collectively or individually, normalized after 1 to 2 months of treatment with EDG-5506 and have remained stable during follow-up to date, according to Dr. Donovan.
As in previous studies, the drug was well tolerated. The three most common treatment-emergent events were dizziness, somnolence, and headache. Each was reported by about 25% of patients, but no patient discontinued therapy as a result of adverse events.
Findings deemed ‘a big deal’
These data, despite the small number of patients in the study and the limited follow-up, “are a big deal,” according to Nicholas E. Johnson, MD, division chief, neuromuscular disorders, Virginia Commonwealth University, Richmond. He pointed out that there are no effective treatments currently for BMD, and the mechanism of action is plausible.
“I am excited about the potential of this treatment, although we clearly need longer follow-up and more patients evaluated on this treatment,” Dr. Johnson said. He said that clinicians with BMD patients should be aware of the phase 2 trial that is now recruiting adult subjects.
“Becker muscular dystrophy is highly disabling. As disease advances, most patients have very limited function,” said Dr. Johnson, emphasizing the urgent unmet need for an effective therapy.
Dr. Donovan is a full time employee of Edgewise Therapeutics, which funded this study. Dr. Johnson has financial relationships with Acceleron, Arthex, AveXis, Avidity, Biogen, Dyne Therapeutics, Entrada, Juvena, ML Bio, Sarepta Therapeutics, Triplet Therapeutics, and Vertex Pharma.
BOSTON – Becker (BMD) and Duchenne muscle dystrophy (DMD) progress largely from irreversible contraction-induced injury of skeletal muscles, making the very positive interim results of an early-phase trial with a drug that prevents these injuries worth attention.
The phase 1b data in BMD, presented at the 2023 annual meeting of the American Academy of Neurology, were sufficiently promising that controlled phase 2 trials in both BMD and DMD are already enrolling, reported Joanne Donovan, MD, PhD, an adjunct professor at Boston University and chief medical officer of Edgewise Therapeutics, the company developing the drug.
Phase 1 study
Early phase studies are largely focused on safety, but the
Moreover, the evidence of a clinical effect was achieved in adult patients with a North Star Ambulatory Assessment (NSAA) score of 15, signifying advanced disease. Only 12 patients were enrolled and there were no controls, but objective evidence of a favorable effect was generated by highly significant reductions in creatine kinase (CK) and fast skeletal muscle (TNNI2) troponin, which are both biomarkers commonly used to track muscular dystrophy progression.
In patients with BMD or DMD, a lack of dystrophin is a key pathogenic feature, according to Dr. Donovan. She explained that dystrophin in muscles connects contractile proteins to membranes and surrounding matrix. In the presence of dystrophin, muscle fibers support each other, but when this protein is absent, contraction causes injury.
The drug in development, currently identified as EDG-5506, is a selective fast myosin inhibitor. This agent was shown to prevent the muscle injury caused by lack of dystrophin in animal models of muscular dystrophy and is now showing the same effect in humans. Preservation of muscle is critical to preventing BMD and DMD progression according to several sets of data, according to Dr. Donovan.
For one, it has been shown that BMD or DMD patients with relatively preserved function as defined by a NSAA score above 32 have minimal muscle damage. As NSAA scores fall below 32 points, muscle mass diminishes and fat accumulates. In natural history studies of BMD, there is a 1.2-point decline in NSAA score over 5 years, and this tracks with muscle loss and not with other variables, such as patient age.
“Progression depends on the degree of muscle loss,” Dr. Donovan stated, providing the rationale for moving forward with EDG-5506.
Proof of concept
In experimental studies, modulation of fast myelin provided complete protection against muscle injury while preserving its contractile function, and this translated into protection against loss of function. Phase 1 studies in BMD patients and healthy controls have already provided evidence that EDG-5506 is well tolerated and safe, but the new phase 1b provides a proof of concept for its ability to inhibit muscle injury in BMD patients.
In this study, called ARCH, 12 adults 18 years of age or older with a dystrophin mutation and a BMD phenotype who could complete a 100-meter timed test were enrolled. The median age at entry was 32 years. Several patients had participated in a previous phase 1 safety study. The daily starting dose of 10 mg was increased from 10 mg to 15 mg at 2 months. The dose was increased again to 20 mg at 6 months, but the data presented by Dr. Donovan were restricted to the first 6 months.
At the interim 6-month analysis, creatine kinase was reduced by 40% and TINN2 was reduced by 84% (both P < 0.001). The significant reductions in these biomarkers and others, such as myoglobin, were mostly achieved within the first month, although further reductions were observed for some biomarkers subsequently.
The NSAA score at 6 months improved on average by about 1 point on treatment. Natural history studies of BMD predict a 1-point reduction in NSAA score over this period of time. The modest improvements from baseline in pain scores at 1 month were sustained at 6 months.
On the basis of a proteomic analysis, 125 proteins mostly associated with metabolic pathways consistent with muscle injury were found to be altered in BMD patients relative to healthy controls. The majority of these proteins, whether assessed collectively or individually, normalized after 1 to 2 months of treatment with EDG-5506 and have remained stable during follow-up to date, according to Dr. Donovan.
As in previous studies, the drug was well tolerated. The three most common treatment-emergent events were dizziness, somnolence, and headache. Each was reported by about 25% of patients, but no patient discontinued therapy as a result of adverse events.
Findings deemed ‘a big deal’
These data, despite the small number of patients in the study and the limited follow-up, “are a big deal,” according to Nicholas E. Johnson, MD, division chief, neuromuscular disorders, Virginia Commonwealth University, Richmond. He pointed out that there are no effective treatments currently for BMD, and the mechanism of action is plausible.
“I am excited about the potential of this treatment, although we clearly need longer follow-up and more patients evaluated on this treatment,” Dr. Johnson said. He said that clinicians with BMD patients should be aware of the phase 2 trial that is now recruiting adult subjects.
“Becker muscular dystrophy is highly disabling. As disease advances, most patients have very limited function,” said Dr. Johnson, emphasizing the urgent unmet need for an effective therapy.
Dr. Donovan is a full time employee of Edgewise Therapeutics, which funded this study. Dr. Johnson has financial relationships with Acceleron, Arthex, AveXis, Avidity, Biogen, Dyne Therapeutics, Entrada, Juvena, ML Bio, Sarepta Therapeutics, Triplet Therapeutics, and Vertex Pharma.
BOSTON – Becker (BMD) and Duchenne muscle dystrophy (DMD) progress largely from irreversible contraction-induced injury of skeletal muscles, making the very positive interim results of an early-phase trial with a drug that prevents these injuries worth attention.
The phase 1b data in BMD, presented at the 2023 annual meeting of the American Academy of Neurology, were sufficiently promising that controlled phase 2 trials in both BMD and DMD are already enrolling, reported Joanne Donovan, MD, PhD, an adjunct professor at Boston University and chief medical officer of Edgewise Therapeutics, the company developing the drug.
Phase 1 study
Early phase studies are largely focused on safety, but the
Moreover, the evidence of a clinical effect was achieved in adult patients with a North Star Ambulatory Assessment (NSAA) score of 15, signifying advanced disease. Only 12 patients were enrolled and there were no controls, but objective evidence of a favorable effect was generated by highly significant reductions in creatine kinase (CK) and fast skeletal muscle (TNNI2) troponin, which are both biomarkers commonly used to track muscular dystrophy progression.
In patients with BMD or DMD, a lack of dystrophin is a key pathogenic feature, according to Dr. Donovan. She explained that dystrophin in muscles connects contractile proteins to membranes and surrounding matrix. In the presence of dystrophin, muscle fibers support each other, but when this protein is absent, contraction causes injury.
The drug in development, currently identified as EDG-5506, is a selective fast myosin inhibitor. This agent was shown to prevent the muscle injury caused by lack of dystrophin in animal models of muscular dystrophy and is now showing the same effect in humans. Preservation of muscle is critical to preventing BMD and DMD progression according to several sets of data, according to Dr. Donovan.
For one, it has been shown that BMD or DMD patients with relatively preserved function as defined by a NSAA score above 32 have minimal muscle damage. As NSAA scores fall below 32 points, muscle mass diminishes and fat accumulates. In natural history studies of BMD, there is a 1.2-point decline in NSAA score over 5 years, and this tracks with muscle loss and not with other variables, such as patient age.
“Progression depends on the degree of muscle loss,” Dr. Donovan stated, providing the rationale for moving forward with EDG-5506.
Proof of concept
In experimental studies, modulation of fast myelin provided complete protection against muscle injury while preserving its contractile function, and this translated into protection against loss of function. Phase 1 studies in BMD patients and healthy controls have already provided evidence that EDG-5506 is well tolerated and safe, but the new phase 1b provides a proof of concept for its ability to inhibit muscle injury in BMD patients.
In this study, called ARCH, 12 adults 18 years of age or older with a dystrophin mutation and a BMD phenotype who could complete a 100-meter timed test were enrolled. The median age at entry was 32 years. Several patients had participated in a previous phase 1 safety study. The daily starting dose of 10 mg was increased from 10 mg to 15 mg at 2 months. The dose was increased again to 20 mg at 6 months, but the data presented by Dr. Donovan were restricted to the first 6 months.
At the interim 6-month analysis, creatine kinase was reduced by 40% and TINN2 was reduced by 84% (both P < 0.001). The significant reductions in these biomarkers and others, such as myoglobin, were mostly achieved within the first month, although further reductions were observed for some biomarkers subsequently.
The NSAA score at 6 months improved on average by about 1 point on treatment. Natural history studies of BMD predict a 1-point reduction in NSAA score over this period of time. The modest improvements from baseline in pain scores at 1 month were sustained at 6 months.
On the basis of a proteomic analysis, 125 proteins mostly associated with metabolic pathways consistent with muscle injury were found to be altered in BMD patients relative to healthy controls. The majority of these proteins, whether assessed collectively or individually, normalized after 1 to 2 months of treatment with EDG-5506 and have remained stable during follow-up to date, according to Dr. Donovan.
As in previous studies, the drug was well tolerated. The three most common treatment-emergent events were dizziness, somnolence, and headache. Each was reported by about 25% of patients, but no patient discontinued therapy as a result of adverse events.
Findings deemed ‘a big deal’
These data, despite the small number of patients in the study and the limited follow-up, “are a big deal,” according to Nicholas E. Johnson, MD, division chief, neuromuscular disorders, Virginia Commonwealth University, Richmond. He pointed out that there are no effective treatments currently for BMD, and the mechanism of action is plausible.
“I am excited about the potential of this treatment, although we clearly need longer follow-up and more patients evaluated on this treatment,” Dr. Johnson said. He said that clinicians with BMD patients should be aware of the phase 2 trial that is now recruiting adult subjects.
“Becker muscular dystrophy is highly disabling. As disease advances, most patients have very limited function,” said Dr. Johnson, emphasizing the urgent unmet need for an effective therapy.
Dr. Donovan is a full time employee of Edgewise Therapeutics, which funded this study. Dr. Johnson has financial relationships with Acceleron, Arthex, AveXis, Avidity, Biogen, Dyne Therapeutics, Entrada, Juvena, ML Bio, Sarepta Therapeutics, Triplet Therapeutics, and Vertex Pharma.
FROM AAN 2023