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Spinal muscular atrophy: Patient care in the age of genetically targeted therapy
In 2016, the U.S. Food and Drug Administration approved nusinersen, the first treatment for spinal muscular atrophy (SMA). Until then, SMA had a mortality rate nearly double that of the general population.1 Two-thirds of patients were symptomatic within 6 months of birth and, in the absence of mechanical ventilation and other support, had a nearly 100% mortality rate by age 2.2
Five years later, there are three approved treatments for SMA, all of which have been shown to slow or even halt disease progression in many patients. Neurologists, whose SMA patient population once consisted almost entirely of children, are now treating more adults with the disease. Indeed, more than half of all people alive with SMA in the United States today are adults, according to Cure SMA.
“Managing SMA used to be clinic follow-ups where we were doing our best supportive care and watching people fall apart before our eyes,” said John Brandsema, MD, a physician and neuromuscular section head at the Children’s Hospital of Philadelphia. “Today, what we see in the vast majority of people is that they are either the same as they were before – which is completely against the natural history of this disease and something to be celebrated – or that people are really better with their function. It totally changes everything in the clinic.”
Among those changes are a more proactive approach to rehabilitation and an even greater emphasis on personalized medicine and multidisciplinary care. But there is also a need for updated treatment guidelines, a new classification system to measure disease severity, specific biomarkers to guide therapy choices, more data on long-term efficacy of existing therapeutics, new medications to complement those therapies, and a deeper understanding of a disease that may have treatment options but still has no cure.
Advances in early diagnosis
Patients with SMA lack a working copy of the survival motor neuron 1 (SMN1) gene, which provides instructions for producing a protein called SMN that is critical for the maintenance and function of motor neurons. Without this protein, motor neurons eventually die, causing debilitating and progressive muscle weakness that affects the ability to walk, eat, and breathe. SMA is rare, affecting about 1 in 10,000 newborns.
In approximately 96% of patients, SMA is caused by homozygous loss of the SMN1 gene. People with SMA have at least one copy of the SMN2 gene, sometimes called a “backup” gene, that also produces SMN protein. However, a single nucleotide difference between SMN2 and SMN1 causes about 90% of the protein produced by SMN2 to be truncated and less stable. Even with multiple copies of SMN2 present, as is the case with many infants with SMA, the amount of functional protein produced isn’t enough to compensate for the loss of SMN1.3
All three approved medications are SMN up-regulators and work to increase the amount of functional SMN protein. Starting these medications early, even before symptoms present, is critical to preserve motor function. Early treatment depends on early diagnosis, which became more widespread after 2018 when SMA was added to the federally Recommended Uniform Screening Panel for newborns. As of July 1, 2022, 47 states have incorporated SMA newborn screening into their state panel, ensuring that 97% of all infants born in the United States undergo SMA screening shortly after birth. Screening in the remaining states – Hawaii, Nevada, and South Carolina – and Washington, D.C. is expected by mid-2023.
SMA newborn screening is a PCR-based assay that detects homozygous SMN1 gene deletion found in about 95% of all people with SMA. The remaining 5% of cases are caused by various genetic mutations that can only be detected with gene sequencing. In these cases, and in children who don’t undergo SMA newborn screening, the disease is usually identified when symptoms are noticed by a parent, pediatrician, or primary care provider. But a study found that in 2018 only 52.7% of pediatricians correctly identified genetic testing as a requirement for a definitive diagnosis of SMA; in 2019, with a larger sample size, that number decreased to 45%.4 The lack of awareness of diagnostic requirements for SMA could contribute to delays in diagnosis, said Mary Schroth, MD, chief medical officer for Cure SMA and a coauthor of the study.
“In our world, suspicion of SMA in an infant is an emergency situation,” Dr. Schroth said. “These babies need to be referred immediately and have genetic testing so that treatment can begin as soon as possible.”
Based on the study findings, Dr. Schroth and others with Cure SMA launched a new tool in 2021 designed to help pediatricians, primary care physicians, and parents identify early signs of SMA, so that a referral to a pediatric neurologist happens quickly. Called SMArt Moves, the educational resource features videos and a checklist to help increase early detection in infants who had a negative SMA newborn screening result or did not receive SMA screening at birth.5
Who to treat, when, and with which treatment
For many patients, having multiple effective treatment options means that SMA is no longer a fatal disease in early childhood, but one that can be managed into adolescence and adulthood. The question for clinicians is, who do they treat, when, and with which treatment?
Studies have long shown that the number of copies of the backup gene that a patient has is inversely associated with disease severity.6 In 2018, a group of SMA experts published a treatment algorithm to help guide decision-making following a positive SMA newborn screening.7 The treatment guidelines were updated in 2020 based on clinical trial data for presymptomatic infants, and current recommendations include immediate treatment for infants with two to four copies of the SMN2 gene.8 For patients with only one copy of SMN2, most of whom will likely be symptomatic at birth, the guidelines recommend that treatment decisions be made jointly between the clinician and the family.7,8
Some suggest that the number of SMN2 copies a patient has should also be a factor in determining phenotype, which has started a conversation on the development of a new classification system.9 The original classification system for disease severity – Types 0-4 – was based on age of onset and degree of motor function achieved, with Type 0 developing prenatally and being the most severe and Type 4 developing in adulthood. Type 1 is the most common, affecting more than half of all people with SMA, followed by Types 2-4. In 2018, updated consensus care guidelines offered a revised classification system that better reflected disease progression in the age of therapy. The functional motor outcomes include nonsitters (historically Type I), sitters (historically Type 2/3), and walkers (historically Type 3/4).10,11 These guidelines are a start, but clinicians say more revision is needed.
“Types 1, 2, 3, 4 were based on function – getting to a certain point and then losing it, but now that we can treat this disease, people will shift categories based on therapeutic response or based on normal development that is possible now that the neurologic piece has been stabilized,” Dr. Brandsema said. “We need to completely change our thinking around all these different aspects of SMA management.”
While discussions of a new classification system for SMA are underway, another effort to update treatment recommendations is closer to completion. Led by Cure SMA, a group of about 50 physician experts in the United States and Europe who specialize in SMA are revising guidelines for diagnosis and treatment, the first time the recommendations have been updated since 2018. The updated recommendations, which should be published later this year, will focus on diagnosis and treatment considerations.
“We have three treatments that are available, and there are specific FDA indications for each of those, but it’s not totally clear just how those medications should be used or applied to different clinical situations,” said Dr. Schroth. “We’re in a rapid phase of learning right now in the SMA community, trying to understand how these treatments alter physiology and disease outcomes and how to best use the tools that we now have available to us. In parallel with clinical treatments, we have to be doing the best care we can to optimize the outcomes for those treatments.”
Research advances in 2021
Although all three drugs approved to treat SMA – nusinersen (Spinraza; Biogen), onasemnogene abeparvovec-xioi gene replacement therapy (Zolgensma; Novartis Gene Therapies), and risdiplam (Evrysdi, Genentech/Roche) – are highly effective, there are still unanswered questions and unmet needs. New research findings from 2021 focused on higher dosing, different drug-delivery methods, combination therapy, and complementary therapeutics to address SMA comorbidities.
Higher-dose nusinersen. The first drug approved to treat SMA, nusinersen is an antisense oligonucleotide approved for all ages and all SMA types. It works by altering splicing of the SMN2 gene pre-mRNA to make more complete SMN protein. Given as an intrathecal (IT) injection, four “loading doses” are administered within the first 2 months of treatment, followed by a maintenance dose every 4 months for the duration of the individual’s life.
Reports from patients of waning effects of nusinersen just prior to follow-up treatment have led some clinicians to ask if a higher dose may be needed. A study underway seeks to address that issue.
DEVOTE is a phase 2/3 trial to study the safety and efficacy of high-dose nusinersen in patients with SMA. Preliminary findings reported in 2021 found no adverse events among patients treated with 28 mg of nusinersen for 161-257 days.12 Another analysis from this trial found that higher doses are associated with greater decrease of plasma phosphorylated neurofilament heavy chain (pNF-H) levels in patients with SMA and may lead to clinically meaningful improvement in motor function beyond that observed with the approved 12 mg dose.13 The trial is ongoing.
Another trial, ASCEND, is a phase 3B study assessing higher dose nusinersen in patients previously treated with risdiplam. Recruitment for that trial began in October 2021.
Long-term efficacy and IT administration of SMA therapy. Several studies are looking at the long-term efficacy and alternate routes of administration of onasemnogene abeparvovec and other SMA therapies.
A one-time gene replacement therapy delivered via an IV infusion replaces the function of the missing or nonworking SMN1 gene with a new, working copy of the SMN1 gene. FDA approved in 2019, it is authorized for use in patients with SMA up to 2 years of age.
The latest data from an ongoing, long-term follow-up safety study of onasemnogene abeparvovec, published in May 2021, suggest that the treatment’s effects persist more than 5 years after treatment. Researchers followed 13 infants with symptomatic SMA type 1 since the beginning of the phase 1 clinical trial of the gene transfer therapy. All patients who received the therapeutic dose maintained their baseline motor function, and two of the patients actually improved without other SMN-targeted treatment. At a median 6.2 years after they received treatment, all were alive and none needed permanent ventilation.14
After a 2-year hold by the FDA, a study of IT administration of onasemnogene abeparvovec is now enrolling patients. Citing concerns from animal studies that IT administration might result in dorsal root ganglia injury, the FDA issued a partial hold on the STRONG trial in 2019. Following positive study results in nonhuman primates, the FDA announced the trial can continue. Novartis is launching a new phase 3 STEER trial to test the drug delivered intrathecally in patients aged 2-18 years with Type 2 SMA. IT administration could allow the gene therapy to be used safely and effectively in more patients with SMA.
Efficacy of risdiplam in more patients. The first oral treatment for SMA was approved by the FDA in 2020. It’s given once per day in patients with SMA of all ages and disease types. The drug increases functional SMN protein production by the SMN2 gene.
A July 2021 publication of the results of the FIREFISH study found that infants with Type I SMA treated with risdiplam for 12 months were significantly more likely to achieve motor milestones, such as sitting without support, compared with untreated infants with Type 1 SMA.15 Risdiplam is also effective in older patients with Type 2 or 3 SMA, according to results published in December from the SUNFISH clinical trial.16 Another study, RAINBOWFISH, is studying safety and efficacy at 24 months in presymptomatic infants started on treatment at up to 6 weeks of age.
The efficacy of risdiplam in previously treated patients is the subject of JEWELFISH, an ongoing study in patients 6 months to 60 years with SMA. Preliminary data presented at the 2020 Virtual SMA Research and Clinical Care Meeting suggest treatment with risdiplam led to a median two-fold increase in the amount of blood SMN protein levels after 4 weeks, which was sustained for at least 24 months.17
Combination therapy. Among the more eagerly awaited results are those from studies of combination therapies, including those that combine approved SMN up-regulators with new non–SMN-targeted therapeutics.
“We’re seeing that while these three approved therapies have dramatic results, especially for infants who are treated presymptomatically, there are still unmet medical needs in those patients, particularly for older teens and adults whose disease may have progressed before they were able to start therapy,” said Jackie Glascock, PhD, vice president of research for Cure SMA.
Of particular interest are studies of myostatin inhibitors, therapeutics that block the production of the protein myostatin. Myostatin acts on muscle cells to reduce muscle growth. Animal studies suggest that inhibiting myostatin increases muscle mass, which could be important in patients with muscle loss due to SMA.
Three experimental myostatin inhibitors are currently in clinical trials. MANATEE is a global phase 2-3 trial that aims to evaluate the safety and efficacy of the antimyostatin antibody GYM329 (RO7204239) in combination with risdiplam. SAPPHIRE is a phase 3 trial of apitegromab (SRK-015) in combination with nusinersen or risdiplam. RESILIANT is a phase 3 trial of tadefgrobep alfa in combination with other treatments.
A trial is underway to study the efficacy and safety of nusinersen in patients with persistent symptoms of SMA after treatment with the gene therapy. The phase 4 study, RESPOND, is enrolling children aged 2-36 months.
What’s needed next
Despite the advances in treatment and patient care, Dr. Brandsema, Dr. Schroth, and Dr. Glascock note that there remain unmet needs in the SMA community in a variety of areas.
Increased focus on adults with SMA. Before nusinersen, treatment of SMA mainly involved treating its symptoms. Many patients stopped seeing their neurologist, relying more heavily on pulmonary care specialists and/or primary care providers to address breathing, nutrition, and mobility problems. “Now with the approval of these treatments, they’re coming back to see their neurologists and are becoming more visible in the SMA community,” Dr. Schroth said.
Despite this re-emergence, a 2020 meta-analysis of studies on adults with SMA found a paucity of data on physical and occupational therapy, respiratory management, mental health care, and palliative care.18
“There is just so much work we need to do in the area of adult clinical care of SMA.”
Treatment algorithms. While the development of the newborn screening algorithm and revised patient care guidelines are helpful resources, clinicians still face uncertainty when choosing which therapy will work best for their patients. Treatment algorithms that help clinicians figure out what therapy or combination of therapies will offer the best outcomes for individual patients are desperately needed, Dr. Brandsema said.
“Each person’s experience of this disease is so unique to the individual based partly on their genetics and partly on the factors about what got them into care and how compliant they are with everything we’re trying to do to help them,” he said. “Biomarkers would help clinicians create personalized treatment plans for each patient.”
More basic science. While scientists have a good understanding of the SMN gene, there are many unanswered questions about the function of the SMN protein and its relationship to motor neuron loss. SMN is a ubiquitously expressed protein, and its function in other cell types is largely unknown. Despite all of the research advances, there is much basic science left to be done.
“We are strongly advocating to regulatory authorities that these aren’t cures and we need to continue to invest in the basic research,” Dr. Glascock said. “These biological questions that pertain to SMN and its function and expression really drive drug development. I really think that understanding those pathways better will lead us to more druggable targets.”
Two deaths from liver failure linked to spinal muscular atrophy drug
Two children taking the gene therapy drug onasemnogene abeparvovec (Zolgensma, Novartis) for spinal muscular atrophy (SMA) have died from acute liver failure, according to a statement issued by the drug’s manufacturer.
The patients were 4 months and 28 months of age and lived in Russia and Kazakhstan. They died 5-6 weeks after infusion with Zolgensma and approximately 1-10 days after the initiation of a corticosteroid taper.
These are the first known fatal cases of acute liver failure associated with the drug, which the company notes was a known side effect included in the product label and in a boxed warning in the United States.
“Following two recent patient fatalities, and in alignment with health authorities, we will be updating the labeling to specify that fatal acute liver failure has been reported,” the statement reads.
“While this is important safety information, it is not a new safety signal,” it adds.
Rare genetic disorder
SMA is a rare genetic disorder that affects about 1 in 10,000 newborns. Patients with SMA lack a working copy of the survival motor neuron 1 (SMN1) gene, which encodes a protein called SMN that is critical for the maintenance and function of motor neurons.
Without this protein, motor neurons eventually die, causing debilitating and progressive muscle weakness that affects the ability to walk, eat, and breathe.
Zolgensma, a one-time gene replacement therapy delivered via intravenous infusion, replaces the function of the missing or nonworking SMN1 gene with a new, working copy of the SMN1 gene.
The first gene therapy treatment for SMA, it was approved by the U.S. Food and Drug Administration in 2019 for patients with SMA up to 2 years of age. It is also the most expensive drug in the world, costing about $2.1 million for a one-time treatment.
“We have notified health authorities in all markets where Zolgensma is used, including the FDA, and are communicating to relevant healthcare professionals as an additional step in markets where this action is supported by health authorities,” the manufacturer’s statement says.
Studies have suggested that the treatment’s effects persist more than 5 years after infusion.
Clinical trials currently underway by Novartis are studying the drug’s long-term efficacy and safety and its potential use in older patients.
The company is also leading the phase 3 clinical trial STEER to test intrathecal (IT) administration of the drug in patients ages 2-18 years who have type 2 SMA.
That trial began late last year after the FDA lifted a 2-year partial hold on an earlier study. The FDA halted the STRONG trial in 2019, citing concerns from animal studies that IT administration may result in dorsal root ganglia injury. The partial hold was released last fall following positive study results in nonhuman primates.
None of the current trials will be affected by the two deaths reported, according to a Novartis spokesperson.
Kelli Whitlock Burton is a staff writer/reporter for Medscape Neurology and MDedge Neurology.
References
1. Viscidi E et al. Comparative all-cause mortality among a large population of patients with spinal muscular atrophy versus matched controls. Neurol Ther. 2022 Mar;11(1):449-457. doi: 10.1007/s40120-021-00307-7.
2. Finkel RS et al. Observational study of spinal muscular atrophy type I and implications for clinical trials. Neurology. 2014 Aug 26;83(9):810-817. doi: 10.1212/WNL.0000000000000741.
3. Klotz J et al. Advances in the therapy of spinal muscular atrophy. J Pediatr. 2021 Sep;236:13-20.e1. doi: 10.1016/j.jpeds.2021.06.033.
4. Curry M et al. Awareness screening and referral patterns among pediatricians in the United States related to early clinical features of spinal muscular atrophy (SMA). BMC Pediatr. 2021 May;21(1):236. doi: 10.1186/s12887-021-02692-2.
5. SMArt Moves. https://smartmoves.curesma.org/
6. Swoboda KJ et al. Natural history of denervation in SMA: Relation to age, SMN2 copy number, and function. Ann Neurol. 2005 May;57(5):704-12. doi: 10.1002/ana.20473.
7. Glascock J et al. Treatment algorithm for infants diagnosed with spinal muscular atrophy through newborn screening. J Neuromuscul Dis. 2018;5(2):145-158. doi: 10.3233/JND-180304.
8. Glascock J et al. Revised recommendations for the treatment of infants diagnosed with spinal muscular atrophy via newborn screening who have 4 copies of SMN2. J Neuromuscul Dis. 2020;7(2):97-100. doi: 10.3233/JND-190468.
9. Talbot K, Tizzano EF. The clinical landscape for SMA in a new therapeutic era. Gene Ther. 2017 Sep;24(9):529-533. doi: 10.1038/gt.2017.52.
10. Mercuri E et al. Diagnosis and management of spinal muscular atrophy: Part 1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscul Disord. 2018 Feb;28(2):103-115. doi: 10.1016/j.nmd.2017.11.005.
11. Finkel RS et al. Diagnosis and management of spinal muscular atrophy: Part 2: Pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics. Neuromuscul Disord. 2018 Mar;28(3):197-207. doi: 10.1016/j.nmd.2017.11.004.
12. Pascual SI et al. Ongoing phase 2/3 DEVOTE (232SM203) randomized, controlled study to explore high-dose nusinersen in SMA: Part A interim results and Part B enrollment update. Presented at MDA Clinical and Scientific Conference 2021, Mar 15-18.
13. Finkel RS et al. Scientific rationale for a higher dose of nusinersen. Presented at 2021 Cure SMA Annual Meeting, Jun 9-11. Abstract P46.
14. Mendell JR et al. Five-year extension results of the phase 1 START trial of onasemnogene abeparvovec in spinal muscular atrophy. JAMA Neurol. 2021 Jul;78(7):834-841. doi: 10.1001/jamaneurol.2021.1272.
15. Darras BT et al. Risdiplam-treated infants with type 1 spinal muscular atrophy versus historical controls. N Engl J Med. 2021 Jul 29;385(5):427-435. doi: 10.1056/NEJMoa2102047.
16. Mercuri E et al. Safety and efficacy of once-daily risdiplam in type 2 and non-ambulant type 3 spinal muscular atrophy (SUNFISH part 2): A phase 3, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2022 Jan;21(1):42-52. doi: 10.1016/S1474-4422(21)00367-7. Erratum in: Lancet Neurol. 2022 Feb;21(2):e2. doi: 10.1016/S1474-4422(22)00006-0. Correction in: Lancet Neurol. 2022 Mar;21(3):e3. doi: 10.1016/S1474-4422(22)00038-2.
17. Genentech announces 2-year risdiplam data from SUNFISH and new data from JEWELFISH in infants, children and adults with SMA. https://www.curesma.org/genentech-risdiplam-data-conference-2020/
18. Wan HWY et al. Health, wellbeing and lived experiences of adults with SMA: a scoping systematic review. Orphanet J Rare Dis. 2020;15(1):70. doi: 10.1186/s13023-020-1339-3.
In 2016, the U.S. Food and Drug Administration approved nusinersen, the first treatment for spinal muscular atrophy (SMA). Until then, SMA had a mortality rate nearly double that of the general population.1 Two-thirds of patients were symptomatic within 6 months of birth and, in the absence of mechanical ventilation and other support, had a nearly 100% mortality rate by age 2.2
Five years later, there are three approved treatments for SMA, all of which have been shown to slow or even halt disease progression in many patients. Neurologists, whose SMA patient population once consisted almost entirely of children, are now treating more adults with the disease. Indeed, more than half of all people alive with SMA in the United States today are adults, according to Cure SMA.
“Managing SMA used to be clinic follow-ups where we were doing our best supportive care and watching people fall apart before our eyes,” said John Brandsema, MD, a physician and neuromuscular section head at the Children’s Hospital of Philadelphia. “Today, what we see in the vast majority of people is that they are either the same as they were before – which is completely against the natural history of this disease and something to be celebrated – or that people are really better with their function. It totally changes everything in the clinic.”
Among those changes are a more proactive approach to rehabilitation and an even greater emphasis on personalized medicine and multidisciplinary care. But there is also a need for updated treatment guidelines, a new classification system to measure disease severity, specific biomarkers to guide therapy choices, more data on long-term efficacy of existing therapeutics, new medications to complement those therapies, and a deeper understanding of a disease that may have treatment options but still has no cure.
Advances in early diagnosis
Patients with SMA lack a working copy of the survival motor neuron 1 (SMN1) gene, which provides instructions for producing a protein called SMN that is critical for the maintenance and function of motor neurons. Without this protein, motor neurons eventually die, causing debilitating and progressive muscle weakness that affects the ability to walk, eat, and breathe. SMA is rare, affecting about 1 in 10,000 newborns.
In approximately 96% of patients, SMA is caused by homozygous loss of the SMN1 gene. People with SMA have at least one copy of the SMN2 gene, sometimes called a “backup” gene, that also produces SMN protein. However, a single nucleotide difference between SMN2 and SMN1 causes about 90% of the protein produced by SMN2 to be truncated and less stable. Even with multiple copies of SMN2 present, as is the case with many infants with SMA, the amount of functional protein produced isn’t enough to compensate for the loss of SMN1.3
All three approved medications are SMN up-regulators and work to increase the amount of functional SMN protein. Starting these medications early, even before symptoms present, is critical to preserve motor function. Early treatment depends on early diagnosis, which became more widespread after 2018 when SMA was added to the federally Recommended Uniform Screening Panel for newborns. As of July 1, 2022, 47 states have incorporated SMA newborn screening into their state panel, ensuring that 97% of all infants born in the United States undergo SMA screening shortly after birth. Screening in the remaining states – Hawaii, Nevada, and South Carolina – and Washington, D.C. is expected by mid-2023.
SMA newborn screening is a PCR-based assay that detects homozygous SMN1 gene deletion found in about 95% of all people with SMA. The remaining 5% of cases are caused by various genetic mutations that can only be detected with gene sequencing. In these cases, and in children who don’t undergo SMA newborn screening, the disease is usually identified when symptoms are noticed by a parent, pediatrician, or primary care provider. But a study found that in 2018 only 52.7% of pediatricians correctly identified genetic testing as a requirement for a definitive diagnosis of SMA; in 2019, with a larger sample size, that number decreased to 45%.4 The lack of awareness of diagnostic requirements for SMA could contribute to delays in diagnosis, said Mary Schroth, MD, chief medical officer for Cure SMA and a coauthor of the study.
“In our world, suspicion of SMA in an infant is an emergency situation,” Dr. Schroth said. “These babies need to be referred immediately and have genetic testing so that treatment can begin as soon as possible.”
Based on the study findings, Dr. Schroth and others with Cure SMA launched a new tool in 2021 designed to help pediatricians, primary care physicians, and parents identify early signs of SMA, so that a referral to a pediatric neurologist happens quickly. Called SMArt Moves, the educational resource features videos and a checklist to help increase early detection in infants who had a negative SMA newborn screening result or did not receive SMA screening at birth.5
Who to treat, when, and with which treatment
For many patients, having multiple effective treatment options means that SMA is no longer a fatal disease in early childhood, but one that can be managed into adolescence and adulthood. The question for clinicians is, who do they treat, when, and with which treatment?
Studies have long shown that the number of copies of the backup gene that a patient has is inversely associated with disease severity.6 In 2018, a group of SMA experts published a treatment algorithm to help guide decision-making following a positive SMA newborn screening.7 The treatment guidelines were updated in 2020 based on clinical trial data for presymptomatic infants, and current recommendations include immediate treatment for infants with two to four copies of the SMN2 gene.8 For patients with only one copy of SMN2, most of whom will likely be symptomatic at birth, the guidelines recommend that treatment decisions be made jointly between the clinician and the family.7,8
Some suggest that the number of SMN2 copies a patient has should also be a factor in determining phenotype, which has started a conversation on the development of a new classification system.9 The original classification system for disease severity – Types 0-4 – was based on age of onset and degree of motor function achieved, with Type 0 developing prenatally and being the most severe and Type 4 developing in adulthood. Type 1 is the most common, affecting more than half of all people with SMA, followed by Types 2-4. In 2018, updated consensus care guidelines offered a revised classification system that better reflected disease progression in the age of therapy. The functional motor outcomes include nonsitters (historically Type I), sitters (historically Type 2/3), and walkers (historically Type 3/4).10,11 These guidelines are a start, but clinicians say more revision is needed.
“Types 1, 2, 3, 4 were based on function – getting to a certain point and then losing it, but now that we can treat this disease, people will shift categories based on therapeutic response or based on normal development that is possible now that the neurologic piece has been stabilized,” Dr. Brandsema said. “We need to completely change our thinking around all these different aspects of SMA management.”
While discussions of a new classification system for SMA are underway, another effort to update treatment recommendations is closer to completion. Led by Cure SMA, a group of about 50 physician experts in the United States and Europe who specialize in SMA are revising guidelines for diagnosis and treatment, the first time the recommendations have been updated since 2018. The updated recommendations, which should be published later this year, will focus on diagnosis and treatment considerations.
“We have three treatments that are available, and there are specific FDA indications for each of those, but it’s not totally clear just how those medications should be used or applied to different clinical situations,” said Dr. Schroth. “We’re in a rapid phase of learning right now in the SMA community, trying to understand how these treatments alter physiology and disease outcomes and how to best use the tools that we now have available to us. In parallel with clinical treatments, we have to be doing the best care we can to optimize the outcomes for those treatments.”
Research advances in 2021
Although all three drugs approved to treat SMA – nusinersen (Spinraza; Biogen), onasemnogene abeparvovec-xioi gene replacement therapy (Zolgensma; Novartis Gene Therapies), and risdiplam (Evrysdi, Genentech/Roche) – are highly effective, there are still unanswered questions and unmet needs. New research findings from 2021 focused on higher dosing, different drug-delivery methods, combination therapy, and complementary therapeutics to address SMA comorbidities.
Higher-dose nusinersen. The first drug approved to treat SMA, nusinersen is an antisense oligonucleotide approved for all ages and all SMA types. It works by altering splicing of the SMN2 gene pre-mRNA to make more complete SMN protein. Given as an intrathecal (IT) injection, four “loading doses” are administered within the first 2 months of treatment, followed by a maintenance dose every 4 months for the duration of the individual’s life.
Reports from patients of waning effects of nusinersen just prior to follow-up treatment have led some clinicians to ask if a higher dose may be needed. A study underway seeks to address that issue.
DEVOTE is a phase 2/3 trial to study the safety and efficacy of high-dose nusinersen in patients with SMA. Preliminary findings reported in 2021 found no adverse events among patients treated with 28 mg of nusinersen for 161-257 days.12 Another analysis from this trial found that higher doses are associated with greater decrease of plasma phosphorylated neurofilament heavy chain (pNF-H) levels in patients with SMA and may lead to clinically meaningful improvement in motor function beyond that observed with the approved 12 mg dose.13 The trial is ongoing.
Another trial, ASCEND, is a phase 3B study assessing higher dose nusinersen in patients previously treated with risdiplam. Recruitment for that trial began in October 2021.
Long-term efficacy and IT administration of SMA therapy. Several studies are looking at the long-term efficacy and alternate routes of administration of onasemnogene abeparvovec and other SMA therapies.
A one-time gene replacement therapy delivered via an IV infusion replaces the function of the missing or nonworking SMN1 gene with a new, working copy of the SMN1 gene. FDA approved in 2019, it is authorized for use in patients with SMA up to 2 years of age.
The latest data from an ongoing, long-term follow-up safety study of onasemnogene abeparvovec, published in May 2021, suggest that the treatment’s effects persist more than 5 years after treatment. Researchers followed 13 infants with symptomatic SMA type 1 since the beginning of the phase 1 clinical trial of the gene transfer therapy. All patients who received the therapeutic dose maintained their baseline motor function, and two of the patients actually improved without other SMN-targeted treatment. At a median 6.2 years after they received treatment, all were alive and none needed permanent ventilation.14
After a 2-year hold by the FDA, a study of IT administration of onasemnogene abeparvovec is now enrolling patients. Citing concerns from animal studies that IT administration might result in dorsal root ganglia injury, the FDA issued a partial hold on the STRONG trial in 2019. Following positive study results in nonhuman primates, the FDA announced the trial can continue. Novartis is launching a new phase 3 STEER trial to test the drug delivered intrathecally in patients aged 2-18 years with Type 2 SMA. IT administration could allow the gene therapy to be used safely and effectively in more patients with SMA.
Efficacy of risdiplam in more patients. The first oral treatment for SMA was approved by the FDA in 2020. It’s given once per day in patients with SMA of all ages and disease types. The drug increases functional SMN protein production by the SMN2 gene.
A July 2021 publication of the results of the FIREFISH study found that infants with Type I SMA treated with risdiplam for 12 months were significantly more likely to achieve motor milestones, such as sitting without support, compared with untreated infants with Type 1 SMA.15 Risdiplam is also effective in older patients with Type 2 or 3 SMA, according to results published in December from the SUNFISH clinical trial.16 Another study, RAINBOWFISH, is studying safety and efficacy at 24 months in presymptomatic infants started on treatment at up to 6 weeks of age.
The efficacy of risdiplam in previously treated patients is the subject of JEWELFISH, an ongoing study in patients 6 months to 60 years with SMA. Preliminary data presented at the 2020 Virtual SMA Research and Clinical Care Meeting suggest treatment with risdiplam led to a median two-fold increase in the amount of blood SMN protein levels after 4 weeks, which was sustained for at least 24 months.17
Combination therapy. Among the more eagerly awaited results are those from studies of combination therapies, including those that combine approved SMN up-regulators with new non–SMN-targeted therapeutics.
“We’re seeing that while these three approved therapies have dramatic results, especially for infants who are treated presymptomatically, there are still unmet medical needs in those patients, particularly for older teens and adults whose disease may have progressed before they were able to start therapy,” said Jackie Glascock, PhD, vice president of research for Cure SMA.
Of particular interest are studies of myostatin inhibitors, therapeutics that block the production of the protein myostatin. Myostatin acts on muscle cells to reduce muscle growth. Animal studies suggest that inhibiting myostatin increases muscle mass, which could be important in patients with muscle loss due to SMA.
Three experimental myostatin inhibitors are currently in clinical trials. MANATEE is a global phase 2-3 trial that aims to evaluate the safety and efficacy of the antimyostatin antibody GYM329 (RO7204239) in combination with risdiplam. SAPPHIRE is a phase 3 trial of apitegromab (SRK-015) in combination with nusinersen or risdiplam. RESILIANT is a phase 3 trial of tadefgrobep alfa in combination with other treatments.
A trial is underway to study the efficacy and safety of nusinersen in patients with persistent symptoms of SMA after treatment with the gene therapy. The phase 4 study, RESPOND, is enrolling children aged 2-36 months.
What’s needed next
Despite the advances in treatment and patient care, Dr. Brandsema, Dr. Schroth, and Dr. Glascock note that there remain unmet needs in the SMA community in a variety of areas.
Increased focus on adults with SMA. Before nusinersen, treatment of SMA mainly involved treating its symptoms. Many patients stopped seeing their neurologist, relying more heavily on pulmonary care specialists and/or primary care providers to address breathing, nutrition, and mobility problems. “Now with the approval of these treatments, they’re coming back to see their neurologists and are becoming more visible in the SMA community,” Dr. Schroth said.
Despite this re-emergence, a 2020 meta-analysis of studies on adults with SMA found a paucity of data on physical and occupational therapy, respiratory management, mental health care, and palliative care.18
“There is just so much work we need to do in the area of adult clinical care of SMA.”
Treatment algorithms. While the development of the newborn screening algorithm and revised patient care guidelines are helpful resources, clinicians still face uncertainty when choosing which therapy will work best for their patients. Treatment algorithms that help clinicians figure out what therapy or combination of therapies will offer the best outcomes for individual patients are desperately needed, Dr. Brandsema said.
“Each person’s experience of this disease is so unique to the individual based partly on their genetics and partly on the factors about what got them into care and how compliant they are with everything we’re trying to do to help them,” he said. “Biomarkers would help clinicians create personalized treatment plans for each patient.”
More basic science. While scientists have a good understanding of the SMN gene, there are many unanswered questions about the function of the SMN protein and its relationship to motor neuron loss. SMN is a ubiquitously expressed protein, and its function in other cell types is largely unknown. Despite all of the research advances, there is much basic science left to be done.
“We are strongly advocating to regulatory authorities that these aren’t cures and we need to continue to invest in the basic research,” Dr. Glascock said. “These biological questions that pertain to SMN and its function and expression really drive drug development. I really think that understanding those pathways better will lead us to more druggable targets.”
Two deaths from liver failure linked to spinal muscular atrophy drug
Two children taking the gene therapy drug onasemnogene abeparvovec (Zolgensma, Novartis) for spinal muscular atrophy (SMA) have died from acute liver failure, according to a statement issued by the drug’s manufacturer.
The patients were 4 months and 28 months of age and lived in Russia and Kazakhstan. They died 5-6 weeks after infusion with Zolgensma and approximately 1-10 days after the initiation of a corticosteroid taper.
These are the first known fatal cases of acute liver failure associated with the drug, which the company notes was a known side effect included in the product label and in a boxed warning in the United States.
“Following two recent patient fatalities, and in alignment with health authorities, we will be updating the labeling to specify that fatal acute liver failure has been reported,” the statement reads.
“While this is important safety information, it is not a new safety signal,” it adds.
Rare genetic disorder
SMA is a rare genetic disorder that affects about 1 in 10,000 newborns. Patients with SMA lack a working copy of the survival motor neuron 1 (SMN1) gene, which encodes a protein called SMN that is critical for the maintenance and function of motor neurons.
Without this protein, motor neurons eventually die, causing debilitating and progressive muscle weakness that affects the ability to walk, eat, and breathe.
Zolgensma, a one-time gene replacement therapy delivered via intravenous infusion, replaces the function of the missing or nonworking SMN1 gene with a new, working copy of the SMN1 gene.
The first gene therapy treatment for SMA, it was approved by the U.S. Food and Drug Administration in 2019 for patients with SMA up to 2 years of age. It is also the most expensive drug in the world, costing about $2.1 million for a one-time treatment.
“We have notified health authorities in all markets where Zolgensma is used, including the FDA, and are communicating to relevant healthcare professionals as an additional step in markets where this action is supported by health authorities,” the manufacturer’s statement says.
Studies have suggested that the treatment’s effects persist more than 5 years after infusion.
Clinical trials currently underway by Novartis are studying the drug’s long-term efficacy and safety and its potential use in older patients.
The company is also leading the phase 3 clinical trial STEER to test intrathecal (IT) administration of the drug in patients ages 2-18 years who have type 2 SMA.
That trial began late last year after the FDA lifted a 2-year partial hold on an earlier study. The FDA halted the STRONG trial in 2019, citing concerns from animal studies that IT administration may result in dorsal root ganglia injury. The partial hold was released last fall following positive study results in nonhuman primates.
None of the current trials will be affected by the two deaths reported, according to a Novartis spokesperson.
Kelli Whitlock Burton is a staff writer/reporter for Medscape Neurology and MDedge Neurology.
References
1. Viscidi E et al. Comparative all-cause mortality among a large population of patients with spinal muscular atrophy versus matched controls. Neurol Ther. 2022 Mar;11(1):449-457. doi: 10.1007/s40120-021-00307-7.
2. Finkel RS et al. Observational study of spinal muscular atrophy type I and implications for clinical trials. Neurology. 2014 Aug 26;83(9):810-817. doi: 10.1212/WNL.0000000000000741.
3. Klotz J et al. Advances in the therapy of spinal muscular atrophy. J Pediatr. 2021 Sep;236:13-20.e1. doi: 10.1016/j.jpeds.2021.06.033.
4. Curry M et al. Awareness screening and referral patterns among pediatricians in the United States related to early clinical features of spinal muscular atrophy (SMA). BMC Pediatr. 2021 May;21(1):236. doi: 10.1186/s12887-021-02692-2.
5. SMArt Moves. https://smartmoves.curesma.org/
6. Swoboda KJ et al. Natural history of denervation in SMA: Relation to age, SMN2 copy number, and function. Ann Neurol. 2005 May;57(5):704-12. doi: 10.1002/ana.20473.
7. Glascock J et al. Treatment algorithm for infants diagnosed with spinal muscular atrophy through newborn screening. J Neuromuscul Dis. 2018;5(2):145-158. doi: 10.3233/JND-180304.
8. Glascock J et al. Revised recommendations for the treatment of infants diagnosed with spinal muscular atrophy via newborn screening who have 4 copies of SMN2. J Neuromuscul Dis. 2020;7(2):97-100. doi: 10.3233/JND-190468.
9. Talbot K, Tizzano EF. The clinical landscape for SMA in a new therapeutic era. Gene Ther. 2017 Sep;24(9):529-533. doi: 10.1038/gt.2017.52.
10. Mercuri E et al. Diagnosis and management of spinal muscular atrophy: Part 1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscul Disord. 2018 Feb;28(2):103-115. doi: 10.1016/j.nmd.2017.11.005.
11. Finkel RS et al. Diagnosis and management of spinal muscular atrophy: Part 2: Pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics. Neuromuscul Disord. 2018 Mar;28(3):197-207. doi: 10.1016/j.nmd.2017.11.004.
12. Pascual SI et al. Ongoing phase 2/3 DEVOTE (232SM203) randomized, controlled study to explore high-dose nusinersen in SMA: Part A interim results and Part B enrollment update. Presented at MDA Clinical and Scientific Conference 2021, Mar 15-18.
13. Finkel RS et al. Scientific rationale for a higher dose of nusinersen. Presented at 2021 Cure SMA Annual Meeting, Jun 9-11. Abstract P46.
14. Mendell JR et al. Five-year extension results of the phase 1 START trial of onasemnogene abeparvovec in spinal muscular atrophy. JAMA Neurol. 2021 Jul;78(7):834-841. doi: 10.1001/jamaneurol.2021.1272.
15. Darras BT et al. Risdiplam-treated infants with type 1 spinal muscular atrophy versus historical controls. N Engl J Med. 2021 Jul 29;385(5):427-435. doi: 10.1056/NEJMoa2102047.
16. Mercuri E et al. Safety and efficacy of once-daily risdiplam in type 2 and non-ambulant type 3 spinal muscular atrophy (SUNFISH part 2): A phase 3, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2022 Jan;21(1):42-52. doi: 10.1016/S1474-4422(21)00367-7. Erratum in: Lancet Neurol. 2022 Feb;21(2):e2. doi: 10.1016/S1474-4422(22)00006-0. Correction in: Lancet Neurol. 2022 Mar;21(3):e3. doi: 10.1016/S1474-4422(22)00038-2.
17. Genentech announces 2-year risdiplam data from SUNFISH and new data from JEWELFISH in infants, children and adults with SMA. https://www.curesma.org/genentech-risdiplam-data-conference-2020/
18. Wan HWY et al. Health, wellbeing and lived experiences of adults with SMA: a scoping systematic review. Orphanet J Rare Dis. 2020;15(1):70. doi: 10.1186/s13023-020-1339-3.
In 2016, the U.S. Food and Drug Administration approved nusinersen, the first treatment for spinal muscular atrophy (SMA). Until then, SMA had a mortality rate nearly double that of the general population.1 Two-thirds of patients were symptomatic within 6 months of birth and, in the absence of mechanical ventilation and other support, had a nearly 100% mortality rate by age 2.2
Five years later, there are three approved treatments for SMA, all of which have been shown to slow or even halt disease progression in many patients. Neurologists, whose SMA patient population once consisted almost entirely of children, are now treating more adults with the disease. Indeed, more than half of all people alive with SMA in the United States today are adults, according to Cure SMA.
“Managing SMA used to be clinic follow-ups where we were doing our best supportive care and watching people fall apart before our eyes,” said John Brandsema, MD, a physician and neuromuscular section head at the Children’s Hospital of Philadelphia. “Today, what we see in the vast majority of people is that they are either the same as they were before – which is completely against the natural history of this disease and something to be celebrated – or that people are really better with their function. It totally changes everything in the clinic.”
Among those changes are a more proactive approach to rehabilitation and an even greater emphasis on personalized medicine and multidisciplinary care. But there is also a need for updated treatment guidelines, a new classification system to measure disease severity, specific biomarkers to guide therapy choices, more data on long-term efficacy of existing therapeutics, new medications to complement those therapies, and a deeper understanding of a disease that may have treatment options but still has no cure.
Advances in early diagnosis
Patients with SMA lack a working copy of the survival motor neuron 1 (SMN1) gene, which provides instructions for producing a protein called SMN that is critical for the maintenance and function of motor neurons. Without this protein, motor neurons eventually die, causing debilitating and progressive muscle weakness that affects the ability to walk, eat, and breathe. SMA is rare, affecting about 1 in 10,000 newborns.
In approximately 96% of patients, SMA is caused by homozygous loss of the SMN1 gene. People with SMA have at least one copy of the SMN2 gene, sometimes called a “backup” gene, that also produces SMN protein. However, a single nucleotide difference between SMN2 and SMN1 causes about 90% of the protein produced by SMN2 to be truncated and less stable. Even with multiple copies of SMN2 present, as is the case with many infants with SMA, the amount of functional protein produced isn’t enough to compensate for the loss of SMN1.3
All three approved medications are SMN up-regulators and work to increase the amount of functional SMN protein. Starting these medications early, even before symptoms present, is critical to preserve motor function. Early treatment depends on early diagnosis, which became more widespread after 2018 when SMA was added to the federally Recommended Uniform Screening Panel for newborns. As of July 1, 2022, 47 states have incorporated SMA newborn screening into their state panel, ensuring that 97% of all infants born in the United States undergo SMA screening shortly after birth. Screening in the remaining states – Hawaii, Nevada, and South Carolina – and Washington, D.C. is expected by mid-2023.
SMA newborn screening is a PCR-based assay that detects homozygous SMN1 gene deletion found in about 95% of all people with SMA. The remaining 5% of cases are caused by various genetic mutations that can only be detected with gene sequencing. In these cases, and in children who don’t undergo SMA newborn screening, the disease is usually identified when symptoms are noticed by a parent, pediatrician, or primary care provider. But a study found that in 2018 only 52.7% of pediatricians correctly identified genetic testing as a requirement for a definitive diagnosis of SMA; in 2019, with a larger sample size, that number decreased to 45%.4 The lack of awareness of diagnostic requirements for SMA could contribute to delays in diagnosis, said Mary Schroth, MD, chief medical officer for Cure SMA and a coauthor of the study.
“In our world, suspicion of SMA in an infant is an emergency situation,” Dr. Schroth said. “These babies need to be referred immediately and have genetic testing so that treatment can begin as soon as possible.”
Based on the study findings, Dr. Schroth and others with Cure SMA launched a new tool in 2021 designed to help pediatricians, primary care physicians, and parents identify early signs of SMA, so that a referral to a pediatric neurologist happens quickly. Called SMArt Moves, the educational resource features videos and a checklist to help increase early detection in infants who had a negative SMA newborn screening result or did not receive SMA screening at birth.5
Who to treat, when, and with which treatment
For many patients, having multiple effective treatment options means that SMA is no longer a fatal disease in early childhood, but one that can be managed into adolescence and adulthood. The question for clinicians is, who do they treat, when, and with which treatment?
Studies have long shown that the number of copies of the backup gene that a patient has is inversely associated with disease severity.6 In 2018, a group of SMA experts published a treatment algorithm to help guide decision-making following a positive SMA newborn screening.7 The treatment guidelines were updated in 2020 based on clinical trial data for presymptomatic infants, and current recommendations include immediate treatment for infants with two to four copies of the SMN2 gene.8 For patients with only one copy of SMN2, most of whom will likely be symptomatic at birth, the guidelines recommend that treatment decisions be made jointly between the clinician and the family.7,8
Some suggest that the number of SMN2 copies a patient has should also be a factor in determining phenotype, which has started a conversation on the development of a new classification system.9 The original classification system for disease severity – Types 0-4 – was based on age of onset and degree of motor function achieved, with Type 0 developing prenatally and being the most severe and Type 4 developing in adulthood. Type 1 is the most common, affecting more than half of all people with SMA, followed by Types 2-4. In 2018, updated consensus care guidelines offered a revised classification system that better reflected disease progression in the age of therapy. The functional motor outcomes include nonsitters (historically Type I), sitters (historically Type 2/3), and walkers (historically Type 3/4).10,11 These guidelines are a start, but clinicians say more revision is needed.
“Types 1, 2, 3, 4 were based on function – getting to a certain point and then losing it, but now that we can treat this disease, people will shift categories based on therapeutic response or based on normal development that is possible now that the neurologic piece has been stabilized,” Dr. Brandsema said. “We need to completely change our thinking around all these different aspects of SMA management.”
While discussions of a new classification system for SMA are underway, another effort to update treatment recommendations is closer to completion. Led by Cure SMA, a group of about 50 physician experts in the United States and Europe who specialize in SMA are revising guidelines for diagnosis and treatment, the first time the recommendations have been updated since 2018. The updated recommendations, which should be published later this year, will focus on diagnosis and treatment considerations.
“We have three treatments that are available, and there are specific FDA indications for each of those, but it’s not totally clear just how those medications should be used or applied to different clinical situations,” said Dr. Schroth. “We’re in a rapid phase of learning right now in the SMA community, trying to understand how these treatments alter physiology and disease outcomes and how to best use the tools that we now have available to us. In parallel with clinical treatments, we have to be doing the best care we can to optimize the outcomes for those treatments.”
Research advances in 2021
Although all three drugs approved to treat SMA – nusinersen (Spinraza; Biogen), onasemnogene abeparvovec-xioi gene replacement therapy (Zolgensma; Novartis Gene Therapies), and risdiplam (Evrysdi, Genentech/Roche) – are highly effective, there are still unanswered questions and unmet needs. New research findings from 2021 focused on higher dosing, different drug-delivery methods, combination therapy, and complementary therapeutics to address SMA comorbidities.
Higher-dose nusinersen. The first drug approved to treat SMA, nusinersen is an antisense oligonucleotide approved for all ages and all SMA types. It works by altering splicing of the SMN2 gene pre-mRNA to make more complete SMN protein. Given as an intrathecal (IT) injection, four “loading doses” are administered within the first 2 months of treatment, followed by a maintenance dose every 4 months for the duration of the individual’s life.
Reports from patients of waning effects of nusinersen just prior to follow-up treatment have led some clinicians to ask if a higher dose may be needed. A study underway seeks to address that issue.
DEVOTE is a phase 2/3 trial to study the safety and efficacy of high-dose nusinersen in patients with SMA. Preliminary findings reported in 2021 found no adverse events among patients treated with 28 mg of nusinersen for 161-257 days.12 Another analysis from this trial found that higher doses are associated with greater decrease of plasma phosphorylated neurofilament heavy chain (pNF-H) levels in patients with SMA and may lead to clinically meaningful improvement in motor function beyond that observed with the approved 12 mg dose.13 The trial is ongoing.
Another trial, ASCEND, is a phase 3B study assessing higher dose nusinersen in patients previously treated with risdiplam. Recruitment for that trial began in October 2021.
Long-term efficacy and IT administration of SMA therapy. Several studies are looking at the long-term efficacy and alternate routes of administration of onasemnogene abeparvovec and other SMA therapies.
A one-time gene replacement therapy delivered via an IV infusion replaces the function of the missing or nonworking SMN1 gene with a new, working copy of the SMN1 gene. FDA approved in 2019, it is authorized for use in patients with SMA up to 2 years of age.
The latest data from an ongoing, long-term follow-up safety study of onasemnogene abeparvovec, published in May 2021, suggest that the treatment’s effects persist more than 5 years after treatment. Researchers followed 13 infants with symptomatic SMA type 1 since the beginning of the phase 1 clinical trial of the gene transfer therapy. All patients who received the therapeutic dose maintained their baseline motor function, and two of the patients actually improved without other SMN-targeted treatment. At a median 6.2 years after they received treatment, all were alive and none needed permanent ventilation.14
After a 2-year hold by the FDA, a study of IT administration of onasemnogene abeparvovec is now enrolling patients. Citing concerns from animal studies that IT administration might result in dorsal root ganglia injury, the FDA issued a partial hold on the STRONG trial in 2019. Following positive study results in nonhuman primates, the FDA announced the trial can continue. Novartis is launching a new phase 3 STEER trial to test the drug delivered intrathecally in patients aged 2-18 years with Type 2 SMA. IT administration could allow the gene therapy to be used safely and effectively in more patients with SMA.
Efficacy of risdiplam in more patients. The first oral treatment for SMA was approved by the FDA in 2020. It’s given once per day in patients with SMA of all ages and disease types. The drug increases functional SMN protein production by the SMN2 gene.
A July 2021 publication of the results of the FIREFISH study found that infants with Type I SMA treated with risdiplam for 12 months were significantly more likely to achieve motor milestones, such as sitting without support, compared with untreated infants with Type 1 SMA.15 Risdiplam is also effective in older patients with Type 2 or 3 SMA, according to results published in December from the SUNFISH clinical trial.16 Another study, RAINBOWFISH, is studying safety and efficacy at 24 months in presymptomatic infants started on treatment at up to 6 weeks of age.
The efficacy of risdiplam in previously treated patients is the subject of JEWELFISH, an ongoing study in patients 6 months to 60 years with SMA. Preliminary data presented at the 2020 Virtual SMA Research and Clinical Care Meeting suggest treatment with risdiplam led to a median two-fold increase in the amount of blood SMN protein levels after 4 weeks, which was sustained for at least 24 months.17
Combination therapy. Among the more eagerly awaited results are those from studies of combination therapies, including those that combine approved SMN up-regulators with new non–SMN-targeted therapeutics.
“We’re seeing that while these three approved therapies have dramatic results, especially for infants who are treated presymptomatically, there are still unmet medical needs in those patients, particularly for older teens and adults whose disease may have progressed before they were able to start therapy,” said Jackie Glascock, PhD, vice president of research for Cure SMA.
Of particular interest are studies of myostatin inhibitors, therapeutics that block the production of the protein myostatin. Myostatin acts on muscle cells to reduce muscle growth. Animal studies suggest that inhibiting myostatin increases muscle mass, which could be important in patients with muscle loss due to SMA.
Three experimental myostatin inhibitors are currently in clinical trials. MANATEE is a global phase 2-3 trial that aims to evaluate the safety and efficacy of the antimyostatin antibody GYM329 (RO7204239) in combination with risdiplam. SAPPHIRE is a phase 3 trial of apitegromab (SRK-015) in combination with nusinersen or risdiplam. RESILIANT is a phase 3 trial of tadefgrobep alfa in combination with other treatments.
A trial is underway to study the efficacy and safety of nusinersen in patients with persistent symptoms of SMA after treatment with the gene therapy. The phase 4 study, RESPOND, is enrolling children aged 2-36 months.
What’s needed next
Despite the advances in treatment and patient care, Dr. Brandsema, Dr. Schroth, and Dr. Glascock note that there remain unmet needs in the SMA community in a variety of areas.
Increased focus on adults with SMA. Before nusinersen, treatment of SMA mainly involved treating its symptoms. Many patients stopped seeing their neurologist, relying more heavily on pulmonary care specialists and/or primary care providers to address breathing, nutrition, and mobility problems. “Now with the approval of these treatments, they’re coming back to see their neurologists and are becoming more visible in the SMA community,” Dr. Schroth said.
Despite this re-emergence, a 2020 meta-analysis of studies on adults with SMA found a paucity of data on physical and occupational therapy, respiratory management, mental health care, and palliative care.18
“There is just so much work we need to do in the area of adult clinical care of SMA.”
Treatment algorithms. While the development of the newborn screening algorithm and revised patient care guidelines are helpful resources, clinicians still face uncertainty when choosing which therapy will work best for their patients. Treatment algorithms that help clinicians figure out what therapy or combination of therapies will offer the best outcomes for individual patients are desperately needed, Dr. Brandsema said.
“Each person’s experience of this disease is so unique to the individual based partly on their genetics and partly on the factors about what got them into care and how compliant they are with everything we’re trying to do to help them,” he said. “Biomarkers would help clinicians create personalized treatment plans for each patient.”
More basic science. While scientists have a good understanding of the SMN gene, there are many unanswered questions about the function of the SMN protein and its relationship to motor neuron loss. SMN is a ubiquitously expressed protein, and its function in other cell types is largely unknown. Despite all of the research advances, there is much basic science left to be done.
“We are strongly advocating to regulatory authorities that these aren’t cures and we need to continue to invest in the basic research,” Dr. Glascock said. “These biological questions that pertain to SMN and its function and expression really drive drug development. I really think that understanding those pathways better will lead us to more druggable targets.”
Two deaths from liver failure linked to spinal muscular atrophy drug
Two children taking the gene therapy drug onasemnogene abeparvovec (Zolgensma, Novartis) for spinal muscular atrophy (SMA) have died from acute liver failure, according to a statement issued by the drug’s manufacturer.
The patients were 4 months and 28 months of age and lived in Russia and Kazakhstan. They died 5-6 weeks after infusion with Zolgensma and approximately 1-10 days after the initiation of a corticosteroid taper.
These are the first known fatal cases of acute liver failure associated with the drug, which the company notes was a known side effect included in the product label and in a boxed warning in the United States.
“Following two recent patient fatalities, and in alignment with health authorities, we will be updating the labeling to specify that fatal acute liver failure has been reported,” the statement reads.
“While this is important safety information, it is not a new safety signal,” it adds.
Rare genetic disorder
SMA is a rare genetic disorder that affects about 1 in 10,000 newborns. Patients with SMA lack a working copy of the survival motor neuron 1 (SMN1) gene, which encodes a protein called SMN that is critical for the maintenance and function of motor neurons.
Without this protein, motor neurons eventually die, causing debilitating and progressive muscle weakness that affects the ability to walk, eat, and breathe.
Zolgensma, a one-time gene replacement therapy delivered via intravenous infusion, replaces the function of the missing or nonworking SMN1 gene with a new, working copy of the SMN1 gene.
The first gene therapy treatment for SMA, it was approved by the U.S. Food and Drug Administration in 2019 for patients with SMA up to 2 years of age. It is also the most expensive drug in the world, costing about $2.1 million for a one-time treatment.
“We have notified health authorities in all markets where Zolgensma is used, including the FDA, and are communicating to relevant healthcare professionals as an additional step in markets where this action is supported by health authorities,” the manufacturer’s statement says.
Studies have suggested that the treatment’s effects persist more than 5 years after infusion.
Clinical trials currently underway by Novartis are studying the drug’s long-term efficacy and safety and its potential use in older patients.
The company is also leading the phase 3 clinical trial STEER to test intrathecal (IT) administration of the drug in patients ages 2-18 years who have type 2 SMA.
That trial began late last year after the FDA lifted a 2-year partial hold on an earlier study. The FDA halted the STRONG trial in 2019, citing concerns from animal studies that IT administration may result in dorsal root ganglia injury. The partial hold was released last fall following positive study results in nonhuman primates.
None of the current trials will be affected by the two deaths reported, according to a Novartis spokesperson.
Kelli Whitlock Burton is a staff writer/reporter for Medscape Neurology and MDedge Neurology.
References
1. Viscidi E et al. Comparative all-cause mortality among a large population of patients with spinal muscular atrophy versus matched controls. Neurol Ther. 2022 Mar;11(1):449-457. doi: 10.1007/s40120-021-00307-7.
2. Finkel RS et al. Observational study of spinal muscular atrophy type I and implications for clinical trials. Neurology. 2014 Aug 26;83(9):810-817. doi: 10.1212/WNL.0000000000000741.
3. Klotz J et al. Advances in the therapy of spinal muscular atrophy. J Pediatr. 2021 Sep;236:13-20.e1. doi: 10.1016/j.jpeds.2021.06.033.
4. Curry M et al. Awareness screening and referral patterns among pediatricians in the United States related to early clinical features of spinal muscular atrophy (SMA). BMC Pediatr. 2021 May;21(1):236. doi: 10.1186/s12887-021-02692-2.
5. SMArt Moves. https://smartmoves.curesma.org/
6. Swoboda KJ et al. Natural history of denervation in SMA: Relation to age, SMN2 copy number, and function. Ann Neurol. 2005 May;57(5):704-12. doi: 10.1002/ana.20473.
7. Glascock J et al. Treatment algorithm for infants diagnosed with spinal muscular atrophy through newborn screening. J Neuromuscul Dis. 2018;5(2):145-158. doi: 10.3233/JND-180304.
8. Glascock J et al. Revised recommendations for the treatment of infants diagnosed with spinal muscular atrophy via newborn screening who have 4 copies of SMN2. J Neuromuscul Dis. 2020;7(2):97-100. doi: 10.3233/JND-190468.
9. Talbot K, Tizzano EF. The clinical landscape for SMA in a new therapeutic era. Gene Ther. 2017 Sep;24(9):529-533. doi: 10.1038/gt.2017.52.
10. Mercuri E et al. Diagnosis and management of spinal muscular atrophy: Part 1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscul Disord. 2018 Feb;28(2):103-115. doi: 10.1016/j.nmd.2017.11.005.
11. Finkel RS et al. Diagnosis and management of spinal muscular atrophy: Part 2: Pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics. Neuromuscul Disord. 2018 Mar;28(3):197-207. doi: 10.1016/j.nmd.2017.11.004.
12. Pascual SI et al. Ongoing phase 2/3 DEVOTE (232SM203) randomized, controlled study to explore high-dose nusinersen in SMA: Part A interim results and Part B enrollment update. Presented at MDA Clinical and Scientific Conference 2021, Mar 15-18.
13. Finkel RS et al. Scientific rationale for a higher dose of nusinersen. Presented at 2021 Cure SMA Annual Meeting, Jun 9-11. Abstract P46.
14. Mendell JR et al. Five-year extension results of the phase 1 START trial of onasemnogene abeparvovec in spinal muscular atrophy. JAMA Neurol. 2021 Jul;78(7):834-841. doi: 10.1001/jamaneurol.2021.1272.
15. Darras BT et al. Risdiplam-treated infants with type 1 spinal muscular atrophy versus historical controls. N Engl J Med. 2021 Jul 29;385(5):427-435. doi: 10.1056/NEJMoa2102047.
16. Mercuri E et al. Safety and efficacy of once-daily risdiplam in type 2 and non-ambulant type 3 spinal muscular atrophy (SUNFISH part 2): A phase 3, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2022 Jan;21(1):42-52. doi: 10.1016/S1474-4422(21)00367-7. Erratum in: Lancet Neurol. 2022 Feb;21(2):e2. doi: 10.1016/S1474-4422(22)00006-0. Correction in: Lancet Neurol. 2022 Mar;21(3):e3. doi: 10.1016/S1474-4422(22)00038-2.
17. Genentech announces 2-year risdiplam data from SUNFISH and new data from JEWELFISH in infants, children and adults with SMA. https://www.curesma.org/genentech-risdiplam-data-conference-2020/
18. Wan HWY et al. Health, wellbeing and lived experiences of adults with SMA: a scoping systematic review. Orphanet J Rare Dis. 2020;15(1):70. doi: 10.1186/s13023-020-1339-3.
ALS drug gets FDA panel thumbs-up after rare second look
In a rare second review of a new drug application,
By a vote of 7-2, the FDA Peripheral and Central Nervous System Drugs Advisory Committee reversed course on AMX0035 (Amylyx Pharmaceuticals), a combination of sodium phenylbutyrate and taurursodiol.
The panel previously voted 6-4 to reject the drug, ruling that data provided by Amylyx had failed to demonstrate that the survival benefit reported in the only clinical trial of AMX0035 so far was a direct result of the drug.
This time, two panelists who previously voted no were swayed by the drug maker’s new analysis of previously presented research, more than 1,300 public comments in support of the drug, supportive testimony from ALS patients and clinicians, and assurances from company executives that Amylyx would pull the drug from the market if results of an ongoing phase 3 clinical trial show the drug doesn’t work.
“As in March, today we have to have an internal dialogue between our scientific scrutiny and clinical compassion,” said Liana G. Apostolova, MD, from Indiana University, Indianapolis, who originally voted against the application.
“Today I also saw additional confirmatory evidence that was not unequivocally persuasive but was nonetheless reassuring,” Dr. Apostolova said. “Because of that I am voting in support of AMX0035.”
A rare second chance
ALS (Lou Gehrig’s disease) is a progressive, fatal neurodegenerative disease affecting nerve cells in the brain and spinal cord that causes loss of motor control. It is rare, affecting about 30,000 people in the United States with another 5,000 new cases diagnosed each year. Most people with the disease die within 2 years of diagnosis.
The FDA has approved two therapies for ALS, but both have limited efficacy.
Typically, FDA approval requires two large studies or one study with a “very persuasive” effect on survival.
Amylyx’s application is based on a single study, the multicenter, two-phase CENTAUR trial. In that trial, 137 people with ALS received AMX0035 or placebo for 24 weeks.
Researchers found that patients receiving AMX0035 had a 25% slower decline in function, compared with the those taking placebo. A change of 20% or more is considered clinically meaningful.
The investigators also found a statistically significant median difference of 4.8 months in time to death, first hospitalization, or tracheostomy/permanent assisted ventilation in the group originally assigned to receive AMX0035 compared with the group originally assigned to receive placebo (hazard ratio, 0.62; P = .023).
In the panel’s previous vote against the drug application, members cited several issues with the study, concluding that it did not offer persuasive or robust evidence of efficacy. They also cited missing data assumptions in the primary analysis, issues of randomization and imbalances in concomitant use of riluzole and edaravone, the two FDA-approved drugs for ALS.
The FDA later requested additional information from Amylyx, delayed its final ruling on the new drug application to Sept. 29, and called for a second review meeting – a virtually unheard-of move.
An FDA review posted in advance of the meeting Sept. 29 had hinted at a different outcome. In that report, regulators said new data from Amylyx were not “sufficiently independent or persuasive” to establish effectiveness.
However, FDA officials in the meeting stressed the importance of considering unmet medical need in ALS in the panel’s decision-making process.
“Recognizing the substantial unmet medical need in ALS, we feel that it is important that the committee is afforded the opportunity to consider this new information, along with the information presented at the prior meeting, in that context,” Billy Dunn, MD, director of the FDA Office of Neuroscience, said during the meeting.
Panelists heard additional data that Amylyx claims confirms the results of the CENTAUR study, including new analyses of the previously submitted survival data and new data from that study and an open-label extension.
They also provided new information on a biomarker data from a phase 2 study of AMX0035 to treat Alzheimer’s disease.
“I think we note the limitations of the analyses, but we still haven’t taken it off the table that they could be considered as confirmatory evidence and that’s why we’re here today,” said Teresa Buracchio, MD, director of the division of neurology for the FDA.
Two members of the panel who voted no in March stuck with that position at the Sept. 29 meeting.
“Unfortunately, I don’t believe the new evidence we’ve reviewed, while promising, combined with that prior evidence, constitutes substantial evidence of effectiveness,” said panelist Caleb Alexander, MD, a professor of epidemiology and medicine at the Johns Hopkins University Center for Drug Safety and Effectiveness, Baltimore.
Dr. Alexander, who also voted no in March, said that post hoc data presented at the meeting were not enough to assuage concerns that led him and others to reject the drug in March.
A challenging situation
Amylyx is currently leading the 48-week international, phase 3, placebo-controlled PHOENIX clinical trial of AMX0035. The study has enrolled about half of its 600-patient target.
“Undoubtedly, the results of the phase 3 study would be highly informative for a regulatory decision on the current ... review for AMX0035,” said Emily Freilich, MD, of the FDA.
However, results aren’t expected until late 2023 or early 2024, which “places the agency in a challenging situation of potentially making a regulatory decision that may not be subsequently confirmed by the results of the ongoing study.”
In June, Amylyx received conditional approval in Canada for the drug, but final approval depends on the outcome of the PHOENIX trial. The FDA does not offer a conditional approval track.
“If AMX0035 is not approved now, the FDA anticipated decision will likely happen in 2025, underscoring the critical importance of today’s outcome,” said Tammy Sarnelli, MPAHC, global head of Regulatory Affairs for Amylyx Pharmaceuticals.
If the FDA were to approve AMX0035 and results from the PHOENIX trial ultimately fail to prove efficacy, Justin Klee, co-CEO and cofounder of Amylyx Pharmaceuticals, said the company would withdraw the drug.
“To be clear, if PHOENIX is not successful, we will do what is right for patients, which includes voluntarily removing the product from the market,” Mr. Klee said.
Regardless of the company’s decision, FDA officials noted that the agency does have the ability to recall a drug from the market if studies show that it no longer meets requirements for approval.
“The FDA, with all due respect, significantly understates the complexity and likelihood of their pulling a product from the market,” Dr. Alexander said. “Whether or not they can ultimately pull a product from the market is no substitute for the evidentiary thresholds that are required for market access.”
A version of this article first appeared on Medscape.com.
In a rare second review of a new drug application,
By a vote of 7-2, the FDA Peripheral and Central Nervous System Drugs Advisory Committee reversed course on AMX0035 (Amylyx Pharmaceuticals), a combination of sodium phenylbutyrate and taurursodiol.
The panel previously voted 6-4 to reject the drug, ruling that data provided by Amylyx had failed to demonstrate that the survival benefit reported in the only clinical trial of AMX0035 so far was a direct result of the drug.
This time, two panelists who previously voted no were swayed by the drug maker’s new analysis of previously presented research, more than 1,300 public comments in support of the drug, supportive testimony from ALS patients and clinicians, and assurances from company executives that Amylyx would pull the drug from the market if results of an ongoing phase 3 clinical trial show the drug doesn’t work.
“As in March, today we have to have an internal dialogue between our scientific scrutiny and clinical compassion,” said Liana G. Apostolova, MD, from Indiana University, Indianapolis, who originally voted against the application.
“Today I also saw additional confirmatory evidence that was not unequivocally persuasive but was nonetheless reassuring,” Dr. Apostolova said. “Because of that I am voting in support of AMX0035.”
A rare second chance
ALS (Lou Gehrig’s disease) is a progressive, fatal neurodegenerative disease affecting nerve cells in the brain and spinal cord that causes loss of motor control. It is rare, affecting about 30,000 people in the United States with another 5,000 new cases diagnosed each year. Most people with the disease die within 2 years of diagnosis.
The FDA has approved two therapies for ALS, but both have limited efficacy.
Typically, FDA approval requires two large studies or one study with a “very persuasive” effect on survival.
Amylyx’s application is based on a single study, the multicenter, two-phase CENTAUR trial. In that trial, 137 people with ALS received AMX0035 or placebo for 24 weeks.
Researchers found that patients receiving AMX0035 had a 25% slower decline in function, compared with the those taking placebo. A change of 20% or more is considered clinically meaningful.
The investigators also found a statistically significant median difference of 4.8 months in time to death, first hospitalization, or tracheostomy/permanent assisted ventilation in the group originally assigned to receive AMX0035 compared with the group originally assigned to receive placebo (hazard ratio, 0.62; P = .023).
In the panel’s previous vote against the drug application, members cited several issues with the study, concluding that it did not offer persuasive or robust evidence of efficacy. They also cited missing data assumptions in the primary analysis, issues of randomization and imbalances in concomitant use of riluzole and edaravone, the two FDA-approved drugs for ALS.
The FDA later requested additional information from Amylyx, delayed its final ruling on the new drug application to Sept. 29, and called for a second review meeting – a virtually unheard-of move.
An FDA review posted in advance of the meeting Sept. 29 had hinted at a different outcome. In that report, regulators said new data from Amylyx were not “sufficiently independent or persuasive” to establish effectiveness.
However, FDA officials in the meeting stressed the importance of considering unmet medical need in ALS in the panel’s decision-making process.
“Recognizing the substantial unmet medical need in ALS, we feel that it is important that the committee is afforded the opportunity to consider this new information, along with the information presented at the prior meeting, in that context,” Billy Dunn, MD, director of the FDA Office of Neuroscience, said during the meeting.
Panelists heard additional data that Amylyx claims confirms the results of the CENTAUR study, including new analyses of the previously submitted survival data and new data from that study and an open-label extension.
They also provided new information on a biomarker data from a phase 2 study of AMX0035 to treat Alzheimer’s disease.
“I think we note the limitations of the analyses, but we still haven’t taken it off the table that they could be considered as confirmatory evidence and that’s why we’re here today,” said Teresa Buracchio, MD, director of the division of neurology for the FDA.
Two members of the panel who voted no in March stuck with that position at the Sept. 29 meeting.
“Unfortunately, I don’t believe the new evidence we’ve reviewed, while promising, combined with that prior evidence, constitutes substantial evidence of effectiveness,” said panelist Caleb Alexander, MD, a professor of epidemiology and medicine at the Johns Hopkins University Center for Drug Safety and Effectiveness, Baltimore.
Dr. Alexander, who also voted no in March, said that post hoc data presented at the meeting were not enough to assuage concerns that led him and others to reject the drug in March.
A challenging situation
Amylyx is currently leading the 48-week international, phase 3, placebo-controlled PHOENIX clinical trial of AMX0035. The study has enrolled about half of its 600-patient target.
“Undoubtedly, the results of the phase 3 study would be highly informative for a regulatory decision on the current ... review for AMX0035,” said Emily Freilich, MD, of the FDA.
However, results aren’t expected until late 2023 or early 2024, which “places the agency in a challenging situation of potentially making a regulatory decision that may not be subsequently confirmed by the results of the ongoing study.”
In June, Amylyx received conditional approval in Canada for the drug, but final approval depends on the outcome of the PHOENIX trial. The FDA does not offer a conditional approval track.
“If AMX0035 is not approved now, the FDA anticipated decision will likely happen in 2025, underscoring the critical importance of today’s outcome,” said Tammy Sarnelli, MPAHC, global head of Regulatory Affairs for Amylyx Pharmaceuticals.
If the FDA were to approve AMX0035 and results from the PHOENIX trial ultimately fail to prove efficacy, Justin Klee, co-CEO and cofounder of Amylyx Pharmaceuticals, said the company would withdraw the drug.
“To be clear, if PHOENIX is not successful, we will do what is right for patients, which includes voluntarily removing the product from the market,” Mr. Klee said.
Regardless of the company’s decision, FDA officials noted that the agency does have the ability to recall a drug from the market if studies show that it no longer meets requirements for approval.
“The FDA, with all due respect, significantly understates the complexity and likelihood of their pulling a product from the market,” Dr. Alexander said. “Whether or not they can ultimately pull a product from the market is no substitute for the evidentiary thresholds that are required for market access.”
A version of this article first appeared on Medscape.com.
In a rare second review of a new drug application,
By a vote of 7-2, the FDA Peripheral and Central Nervous System Drugs Advisory Committee reversed course on AMX0035 (Amylyx Pharmaceuticals), a combination of sodium phenylbutyrate and taurursodiol.
The panel previously voted 6-4 to reject the drug, ruling that data provided by Amylyx had failed to demonstrate that the survival benefit reported in the only clinical trial of AMX0035 so far was a direct result of the drug.
This time, two panelists who previously voted no were swayed by the drug maker’s new analysis of previously presented research, more than 1,300 public comments in support of the drug, supportive testimony from ALS patients and clinicians, and assurances from company executives that Amylyx would pull the drug from the market if results of an ongoing phase 3 clinical trial show the drug doesn’t work.
“As in March, today we have to have an internal dialogue between our scientific scrutiny and clinical compassion,” said Liana G. Apostolova, MD, from Indiana University, Indianapolis, who originally voted against the application.
“Today I also saw additional confirmatory evidence that was not unequivocally persuasive but was nonetheless reassuring,” Dr. Apostolova said. “Because of that I am voting in support of AMX0035.”
A rare second chance
ALS (Lou Gehrig’s disease) is a progressive, fatal neurodegenerative disease affecting nerve cells in the brain and spinal cord that causes loss of motor control. It is rare, affecting about 30,000 people in the United States with another 5,000 new cases diagnosed each year. Most people with the disease die within 2 years of diagnosis.
The FDA has approved two therapies for ALS, but both have limited efficacy.
Typically, FDA approval requires two large studies or one study with a “very persuasive” effect on survival.
Amylyx’s application is based on a single study, the multicenter, two-phase CENTAUR trial. In that trial, 137 people with ALS received AMX0035 or placebo for 24 weeks.
Researchers found that patients receiving AMX0035 had a 25% slower decline in function, compared with the those taking placebo. A change of 20% or more is considered clinically meaningful.
The investigators also found a statistically significant median difference of 4.8 months in time to death, first hospitalization, or tracheostomy/permanent assisted ventilation in the group originally assigned to receive AMX0035 compared with the group originally assigned to receive placebo (hazard ratio, 0.62; P = .023).
In the panel’s previous vote against the drug application, members cited several issues with the study, concluding that it did not offer persuasive or robust evidence of efficacy. They also cited missing data assumptions in the primary analysis, issues of randomization and imbalances in concomitant use of riluzole and edaravone, the two FDA-approved drugs for ALS.
The FDA later requested additional information from Amylyx, delayed its final ruling on the new drug application to Sept. 29, and called for a second review meeting – a virtually unheard-of move.
An FDA review posted in advance of the meeting Sept. 29 had hinted at a different outcome. In that report, regulators said new data from Amylyx were not “sufficiently independent or persuasive” to establish effectiveness.
However, FDA officials in the meeting stressed the importance of considering unmet medical need in ALS in the panel’s decision-making process.
“Recognizing the substantial unmet medical need in ALS, we feel that it is important that the committee is afforded the opportunity to consider this new information, along with the information presented at the prior meeting, in that context,” Billy Dunn, MD, director of the FDA Office of Neuroscience, said during the meeting.
Panelists heard additional data that Amylyx claims confirms the results of the CENTAUR study, including new analyses of the previously submitted survival data and new data from that study and an open-label extension.
They also provided new information on a biomarker data from a phase 2 study of AMX0035 to treat Alzheimer’s disease.
“I think we note the limitations of the analyses, but we still haven’t taken it off the table that they could be considered as confirmatory evidence and that’s why we’re here today,” said Teresa Buracchio, MD, director of the division of neurology for the FDA.
Two members of the panel who voted no in March stuck with that position at the Sept. 29 meeting.
“Unfortunately, I don’t believe the new evidence we’ve reviewed, while promising, combined with that prior evidence, constitutes substantial evidence of effectiveness,” said panelist Caleb Alexander, MD, a professor of epidemiology and medicine at the Johns Hopkins University Center for Drug Safety and Effectiveness, Baltimore.
Dr. Alexander, who also voted no in March, said that post hoc data presented at the meeting were not enough to assuage concerns that led him and others to reject the drug in March.
A challenging situation
Amylyx is currently leading the 48-week international, phase 3, placebo-controlled PHOENIX clinical trial of AMX0035. The study has enrolled about half of its 600-patient target.
“Undoubtedly, the results of the phase 3 study would be highly informative for a regulatory decision on the current ... review for AMX0035,” said Emily Freilich, MD, of the FDA.
However, results aren’t expected until late 2023 or early 2024, which “places the agency in a challenging situation of potentially making a regulatory decision that may not be subsequently confirmed by the results of the ongoing study.”
In June, Amylyx received conditional approval in Canada for the drug, but final approval depends on the outcome of the PHOENIX trial. The FDA does not offer a conditional approval track.
“If AMX0035 is not approved now, the FDA anticipated decision will likely happen in 2025, underscoring the critical importance of today’s outcome,” said Tammy Sarnelli, MPAHC, global head of Regulatory Affairs for Amylyx Pharmaceuticals.
If the FDA were to approve AMX0035 and results from the PHOENIX trial ultimately fail to prove efficacy, Justin Klee, co-CEO and cofounder of Amylyx Pharmaceuticals, said the company would withdraw the drug.
“To be clear, if PHOENIX is not successful, we will do what is right for patients, which includes voluntarily removing the product from the market,” Mr. Klee said.
Regardless of the company’s decision, FDA officials noted that the agency does have the ability to recall a drug from the market if studies show that it no longer meets requirements for approval.
“The FDA, with all due respect, significantly understates the complexity and likelihood of their pulling a product from the market,” Dr. Alexander said. “Whether or not they can ultimately pull a product from the market is no substitute for the evidentiary thresholds that are required for market access.”
A version of this article first appeared on Medscape.com.
COVID-19 linked to increased Alzheimer’s risk
The study of more than 6 million people aged 65 years or older found a 50%-80% increased risk for AD in the year after COVID-19; the risk was especially high for women older than 85 years.
However, the investigators were quick to point out that the observational retrospective study offers no evidence that COVID-19 causes AD. There could be a viral etiology at play, or the connection could be related to inflammation in neural tissue from the SARS-CoV-2 infection. Or it could simply be that exposure to the health care system for COVID-19 increased the odds of detection of existing undiagnosed AD cases.
Whatever the case, these findings point to a potential spike in AD cases, which is a cause for concern, study investigator Pamela Davis, MD, PhD, a professor in the Center for Community Health Integration at Case Western Reserve University, Cleveland, said in an interview.
“COVID may be giving us a legacy of ongoing medical difficulties,” Dr. Davis said. “We were already concerned about having a very large care burden and cost burden from Alzheimer’s disease. If this is another burden that’s increased by COVID, this is something we’re really going to have to prepare for.”
The findings were published online in Journal of Alzheimer’s Disease.
Increased risk
Earlier research points to a potential link between COVID-19 and increased risk for AD and Parkinson’s disease.
For the current study, researchers analyzed anonymous electronic health records of 6.2 million adults aged 65 years or older who received medical treatment between February 2020 and May 2021 and had no prior diagnosis of AD. The database includes information on almost 30% of the entire U.S. population.
Overall, there were 410,748 cases of COVID-19 during the study period.
The overall risk for new diagnosis of AD in the COVID-19 cohort was close to double that of those who did not have COVID-19 (0.68% vs. 0.35%, respectively).
After propensity-score matching, those who have had COVID-19 had a significantly higher risk for an AD diagnosis compared with those who were not infected (hazard ratio [HR], 1.69; 95% confidence interval [CI],1.53-1.72).
Risk for AD was elevated in all age groups, regardless of gender or ethnicity. Researchers did not collect data on COVID-19 severity, and the medical codes for long COVID were not published until after the study had ended.
Those with the highest risk were individuals older than 85 years (HR, 1.89; 95% CI, 1.73-2.07) and women (HR, 1.82; 95% CI, 1.69-1.97).
“We expected to see some impact, but I was surprised that it was as potent as it was,” Dr. Davis said.
Association, not causation
Heather Snyder, PhD, Alzheimer’s Association vice president of medical and scientific relations, who commented on the findings for this article, called the study interesting but emphasized caution in interpreting the results.
“Because this study only showed an association through medical records, we cannot know what the underlying mechanisms driving this association are without more research,” Dr. Snyder said. “If you have had COVID-19, it doesn’t mean you’re going to get dementia. But if you have had COVID-19 and are experiencing long-term symptoms including cognitive difficulties, talk to your doctor.”
Dr. Davis agreed, noting that this type of study offers information on association, but not causation. “I do think that this makes it imperative that we continue to follow the population for what’s going on in various neurodegenerative diseases,” Dr. Davis said.
The study was funded by the National Institute of Aging, National Institute on Alcohol Abuse and Alcoholism, the Clinical and Translational Science Collaborative of Cleveland, and the National Cancer Institute. Dr. Synder reports no relevant financial conflicts.
A version of this article first appeared on Medscape.com.
The study of more than 6 million people aged 65 years or older found a 50%-80% increased risk for AD in the year after COVID-19; the risk was especially high for women older than 85 years.
However, the investigators were quick to point out that the observational retrospective study offers no evidence that COVID-19 causes AD. There could be a viral etiology at play, or the connection could be related to inflammation in neural tissue from the SARS-CoV-2 infection. Or it could simply be that exposure to the health care system for COVID-19 increased the odds of detection of existing undiagnosed AD cases.
Whatever the case, these findings point to a potential spike in AD cases, which is a cause for concern, study investigator Pamela Davis, MD, PhD, a professor in the Center for Community Health Integration at Case Western Reserve University, Cleveland, said in an interview.
“COVID may be giving us a legacy of ongoing medical difficulties,” Dr. Davis said. “We were already concerned about having a very large care burden and cost burden from Alzheimer’s disease. If this is another burden that’s increased by COVID, this is something we’re really going to have to prepare for.”
The findings were published online in Journal of Alzheimer’s Disease.
Increased risk
Earlier research points to a potential link between COVID-19 and increased risk for AD and Parkinson’s disease.
For the current study, researchers analyzed anonymous electronic health records of 6.2 million adults aged 65 years or older who received medical treatment between February 2020 and May 2021 and had no prior diagnosis of AD. The database includes information on almost 30% of the entire U.S. population.
Overall, there were 410,748 cases of COVID-19 during the study period.
The overall risk for new diagnosis of AD in the COVID-19 cohort was close to double that of those who did not have COVID-19 (0.68% vs. 0.35%, respectively).
After propensity-score matching, those who have had COVID-19 had a significantly higher risk for an AD diagnosis compared with those who were not infected (hazard ratio [HR], 1.69; 95% confidence interval [CI],1.53-1.72).
Risk for AD was elevated in all age groups, regardless of gender or ethnicity. Researchers did not collect data on COVID-19 severity, and the medical codes for long COVID were not published until after the study had ended.
Those with the highest risk were individuals older than 85 years (HR, 1.89; 95% CI, 1.73-2.07) and women (HR, 1.82; 95% CI, 1.69-1.97).
“We expected to see some impact, but I was surprised that it was as potent as it was,” Dr. Davis said.
Association, not causation
Heather Snyder, PhD, Alzheimer’s Association vice president of medical and scientific relations, who commented on the findings for this article, called the study interesting but emphasized caution in interpreting the results.
“Because this study only showed an association through medical records, we cannot know what the underlying mechanisms driving this association are without more research,” Dr. Snyder said. “If you have had COVID-19, it doesn’t mean you’re going to get dementia. But if you have had COVID-19 and are experiencing long-term symptoms including cognitive difficulties, talk to your doctor.”
Dr. Davis agreed, noting that this type of study offers information on association, but not causation. “I do think that this makes it imperative that we continue to follow the population for what’s going on in various neurodegenerative diseases,” Dr. Davis said.
The study was funded by the National Institute of Aging, National Institute on Alcohol Abuse and Alcoholism, the Clinical and Translational Science Collaborative of Cleveland, and the National Cancer Institute. Dr. Synder reports no relevant financial conflicts.
A version of this article first appeared on Medscape.com.
The study of more than 6 million people aged 65 years or older found a 50%-80% increased risk for AD in the year after COVID-19; the risk was especially high for women older than 85 years.
However, the investigators were quick to point out that the observational retrospective study offers no evidence that COVID-19 causes AD. There could be a viral etiology at play, or the connection could be related to inflammation in neural tissue from the SARS-CoV-2 infection. Or it could simply be that exposure to the health care system for COVID-19 increased the odds of detection of existing undiagnosed AD cases.
Whatever the case, these findings point to a potential spike in AD cases, which is a cause for concern, study investigator Pamela Davis, MD, PhD, a professor in the Center for Community Health Integration at Case Western Reserve University, Cleveland, said in an interview.
“COVID may be giving us a legacy of ongoing medical difficulties,” Dr. Davis said. “We were already concerned about having a very large care burden and cost burden from Alzheimer’s disease. If this is another burden that’s increased by COVID, this is something we’re really going to have to prepare for.”
The findings were published online in Journal of Alzheimer’s Disease.
Increased risk
Earlier research points to a potential link between COVID-19 and increased risk for AD and Parkinson’s disease.
For the current study, researchers analyzed anonymous electronic health records of 6.2 million adults aged 65 years or older who received medical treatment between February 2020 and May 2021 and had no prior diagnosis of AD. The database includes information on almost 30% of the entire U.S. population.
Overall, there were 410,748 cases of COVID-19 during the study period.
The overall risk for new diagnosis of AD in the COVID-19 cohort was close to double that of those who did not have COVID-19 (0.68% vs. 0.35%, respectively).
After propensity-score matching, those who have had COVID-19 had a significantly higher risk for an AD diagnosis compared with those who were not infected (hazard ratio [HR], 1.69; 95% confidence interval [CI],1.53-1.72).
Risk for AD was elevated in all age groups, regardless of gender or ethnicity. Researchers did not collect data on COVID-19 severity, and the medical codes for long COVID were not published until after the study had ended.
Those with the highest risk were individuals older than 85 years (HR, 1.89; 95% CI, 1.73-2.07) and women (HR, 1.82; 95% CI, 1.69-1.97).
“We expected to see some impact, but I was surprised that it was as potent as it was,” Dr. Davis said.
Association, not causation
Heather Snyder, PhD, Alzheimer’s Association vice president of medical and scientific relations, who commented on the findings for this article, called the study interesting but emphasized caution in interpreting the results.
“Because this study only showed an association through medical records, we cannot know what the underlying mechanisms driving this association are without more research,” Dr. Snyder said. “If you have had COVID-19, it doesn’t mean you’re going to get dementia. But if you have had COVID-19 and are experiencing long-term symptoms including cognitive difficulties, talk to your doctor.”
Dr. Davis agreed, noting that this type of study offers information on association, but not causation. “I do think that this makes it imperative that we continue to follow the population for what’s going on in various neurodegenerative diseases,” Dr. Davis said.
The study was funded by the National Institute of Aging, National Institute on Alcohol Abuse and Alcoholism, the Clinical and Translational Science Collaborative of Cleveland, and the National Cancer Institute. Dr. Synder reports no relevant financial conflicts.
A version of this article first appeared on Medscape.com.
FROM THE JOURNAL OF ALZHEIMER’S DISEASE
Vitamins or cocoa: Which preserves cognition?
Unexpected results from a phase 3 trial exploring the effect of multivitamins and cognition have now been published.
Originally presented last November at the 14th Clinical Trials on Alzheimer’s Disease (CTAD) conference, this is the first large-scale, long-term randomized controlled trial to examine the effects of cocoa extract and multivitamins on global cognition. The trial’s primary focus was on cocoa extract, which earlier studies suggest may preserve cognitive function. Analyzing the effect of multivitamins was a secondary outcome.
Showing vitamins, but not cocoa, were beneficial is the exact opposite of what researchers expected. Still, the results offer an interesting new direction for future study, lead investigator Laura D. Baker, PhD, professor of gerontology and geriatric medicine at Wake Forest University, Winston-Salem, N.C., said in an interview.
“This study made us take notice of a pathway for possible cognitive protection,” Dr. Baker said. “Without this study, we would never have looked down that road.”
The full results were published online in Alzheimer’s and Dementia.
Unexpected effect
The COSMOS-Mind study is a substudy to a larger parent trial called COSMOS. It investigated the effects of cocoa extract and a standard multivitamin-mineral on cardiovascular and cancer outcomes in more than 21,000 older participants.
In COSMOS-Mind, researchers tested whether daily intake of cocoa extract vs. placebo and a multivitamin-mineral vs. placebo improved cognition in older adults.
More than 2,200 participants aged 65 and older were enrolled and followed for 3 years. They completed tests over the telephone at baseline and annually to evaluate memory and other cognitive abilities.
Results showed cocoa extract had no effect on global cognition compared with placebo (mean z-score, 0.03; P = .28). Daily multivitamin use, however, did show significant benefits on global cognition vs. placebo (mean z, 0.07, P = .007).
The beneficial effect was most pronounced in participants with a history of cardiovascular disease (no history 0.06 vs. history 0.14; P = .01).
Researchers found similar protective effects for memory and executive function.
Dr. Baker suggested one possible explanation for the positive effects of multivitamins may be the boost in micronutrients and essential minerals they provided.
“With nutrient-deficient diets plus a high prevalence of cardiovascular disease, diabetes, and other medical comorbidities that we know impact the bioavailability of these nutrients, we are possibly dealing with older adults who are at below optimum in terms of their essential micronutrients and minerals,” she said.
“Even suboptimum levels of micronutrients and essential minerals can have significant consequences for brain health,” she added.
More research needed
Intriguing as the results may be, more work is needed before the findings could affect nutritional guidance, according to Maria C. Carrillo, PhD, chief science officer for the Alzheimer’s Association.
“While the Alzheimer’s Association is encouraged by these results, we are not ready to recommend widespread use of a multivitamin supplement to reduce risk of cognitive decline in older adults,” Dr. Carrillo said in a statement.
“For now, and until there is more data, people should talk with their health care providers about the benefits and risks of all dietary supplements, including multivitamins,” she added.
Dr. Baker agreed, noting that the study was not designed to measure multivitamin use as a primary outcome. In addition, nearly 90% of the participants were non-Hispanic White, which is not representative of the overall population demographics.
The investigators are now designing another, larger trial that would include a more diverse participant pool. It will be aimed specifically at learning more about how and why multivitamins seem to offer a protective effect on cognition, Dr. Baker noted.
The study was funded by the National Institute on Aging of the National Institutes of Health. Dr. Baker and Dr. Carrillo report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Unexpected results from a phase 3 trial exploring the effect of multivitamins and cognition have now been published.
Originally presented last November at the 14th Clinical Trials on Alzheimer’s Disease (CTAD) conference, this is the first large-scale, long-term randomized controlled trial to examine the effects of cocoa extract and multivitamins on global cognition. The trial’s primary focus was on cocoa extract, which earlier studies suggest may preserve cognitive function. Analyzing the effect of multivitamins was a secondary outcome.
Showing vitamins, but not cocoa, were beneficial is the exact opposite of what researchers expected. Still, the results offer an interesting new direction for future study, lead investigator Laura D. Baker, PhD, professor of gerontology and geriatric medicine at Wake Forest University, Winston-Salem, N.C., said in an interview.
“This study made us take notice of a pathway for possible cognitive protection,” Dr. Baker said. “Without this study, we would never have looked down that road.”
The full results were published online in Alzheimer’s and Dementia.
Unexpected effect
The COSMOS-Mind study is a substudy to a larger parent trial called COSMOS. It investigated the effects of cocoa extract and a standard multivitamin-mineral on cardiovascular and cancer outcomes in more than 21,000 older participants.
In COSMOS-Mind, researchers tested whether daily intake of cocoa extract vs. placebo and a multivitamin-mineral vs. placebo improved cognition in older adults.
More than 2,200 participants aged 65 and older were enrolled and followed for 3 years. They completed tests over the telephone at baseline and annually to evaluate memory and other cognitive abilities.
Results showed cocoa extract had no effect on global cognition compared with placebo (mean z-score, 0.03; P = .28). Daily multivitamin use, however, did show significant benefits on global cognition vs. placebo (mean z, 0.07, P = .007).
The beneficial effect was most pronounced in participants with a history of cardiovascular disease (no history 0.06 vs. history 0.14; P = .01).
Researchers found similar protective effects for memory and executive function.
Dr. Baker suggested one possible explanation for the positive effects of multivitamins may be the boost in micronutrients and essential minerals they provided.
“With nutrient-deficient diets plus a high prevalence of cardiovascular disease, diabetes, and other medical comorbidities that we know impact the bioavailability of these nutrients, we are possibly dealing with older adults who are at below optimum in terms of their essential micronutrients and minerals,” she said.
“Even suboptimum levels of micronutrients and essential minerals can have significant consequences for brain health,” she added.
More research needed
Intriguing as the results may be, more work is needed before the findings could affect nutritional guidance, according to Maria C. Carrillo, PhD, chief science officer for the Alzheimer’s Association.
“While the Alzheimer’s Association is encouraged by these results, we are not ready to recommend widespread use of a multivitamin supplement to reduce risk of cognitive decline in older adults,” Dr. Carrillo said in a statement.
“For now, and until there is more data, people should talk with their health care providers about the benefits and risks of all dietary supplements, including multivitamins,” she added.
Dr. Baker agreed, noting that the study was not designed to measure multivitamin use as a primary outcome. In addition, nearly 90% of the participants were non-Hispanic White, which is not representative of the overall population demographics.
The investigators are now designing another, larger trial that would include a more diverse participant pool. It will be aimed specifically at learning more about how and why multivitamins seem to offer a protective effect on cognition, Dr. Baker noted.
The study was funded by the National Institute on Aging of the National Institutes of Health. Dr. Baker and Dr. Carrillo report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Unexpected results from a phase 3 trial exploring the effect of multivitamins and cognition have now been published.
Originally presented last November at the 14th Clinical Trials on Alzheimer’s Disease (CTAD) conference, this is the first large-scale, long-term randomized controlled trial to examine the effects of cocoa extract and multivitamins on global cognition. The trial’s primary focus was on cocoa extract, which earlier studies suggest may preserve cognitive function. Analyzing the effect of multivitamins was a secondary outcome.
Showing vitamins, but not cocoa, were beneficial is the exact opposite of what researchers expected. Still, the results offer an interesting new direction for future study, lead investigator Laura D. Baker, PhD, professor of gerontology and geriatric medicine at Wake Forest University, Winston-Salem, N.C., said in an interview.
“This study made us take notice of a pathway for possible cognitive protection,” Dr. Baker said. “Without this study, we would never have looked down that road.”
The full results were published online in Alzheimer’s and Dementia.
Unexpected effect
The COSMOS-Mind study is a substudy to a larger parent trial called COSMOS. It investigated the effects of cocoa extract and a standard multivitamin-mineral on cardiovascular and cancer outcomes in more than 21,000 older participants.
In COSMOS-Mind, researchers tested whether daily intake of cocoa extract vs. placebo and a multivitamin-mineral vs. placebo improved cognition in older adults.
More than 2,200 participants aged 65 and older were enrolled and followed for 3 years. They completed tests over the telephone at baseline and annually to evaluate memory and other cognitive abilities.
Results showed cocoa extract had no effect on global cognition compared with placebo (mean z-score, 0.03; P = .28). Daily multivitamin use, however, did show significant benefits on global cognition vs. placebo (mean z, 0.07, P = .007).
The beneficial effect was most pronounced in participants with a history of cardiovascular disease (no history 0.06 vs. history 0.14; P = .01).
Researchers found similar protective effects for memory and executive function.
Dr. Baker suggested one possible explanation for the positive effects of multivitamins may be the boost in micronutrients and essential minerals they provided.
“With nutrient-deficient diets plus a high prevalence of cardiovascular disease, diabetes, and other medical comorbidities that we know impact the bioavailability of these nutrients, we are possibly dealing with older adults who are at below optimum in terms of their essential micronutrients and minerals,” she said.
“Even suboptimum levels of micronutrients and essential minerals can have significant consequences for brain health,” she added.
More research needed
Intriguing as the results may be, more work is needed before the findings could affect nutritional guidance, according to Maria C. Carrillo, PhD, chief science officer for the Alzheimer’s Association.
“While the Alzheimer’s Association is encouraged by these results, we are not ready to recommend widespread use of a multivitamin supplement to reduce risk of cognitive decline in older adults,” Dr. Carrillo said in a statement.
“For now, and until there is more data, people should talk with their health care providers about the benefits and risks of all dietary supplements, including multivitamins,” she added.
Dr. Baker agreed, noting that the study was not designed to measure multivitamin use as a primary outcome. In addition, nearly 90% of the participants were non-Hispanic White, which is not representative of the overall population demographics.
The investigators are now designing another, larger trial that would include a more diverse participant pool. It will be aimed specifically at learning more about how and why multivitamins seem to offer a protective effect on cognition, Dr. Baker noted.
The study was funded by the National Institute on Aging of the National Institutes of Health. Dr. Baker and Dr. Carrillo report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ALZHEIMER’S AND DEMENTIA
Yoga, CBT provide long-term improvement in insomnia, worry
new research suggests.
The study is the first to compare the long-term effects from the two interventions; and the results offer clinicians and patients two effective choices for reducing worry and anxiety, researchers noted.
“Anxiety can be a really big problem for older adults,” lead investigator Suzanne Danhauer, PhD, professor of social sciences and health policy at Wake Forest University, Winston-Salem, N.C., said in an interview.
“So to find something they can do that lasts ... and has some enduring impact on their quality of life and their mental health, and they’re both nonpharmacologic treatments, I think for a lot of older people that’s really attractive,” Dr. Danhauer said.
The findings are published in the September issue of the American Journal of Geriatric Psychiatry.
Long-term benefits
The two-stage randomized preference trial included 500 community-dwelling individuals over age 60 who scored 26 or above on the Penn State Worry Questionnaire–Abbreviated (PSWQ-A), indicating heightened anxiety and worry.
Half the group took part in a randomized, controlled trial comparing CBT (n = 125) with yoga (n = 125). The other half participated in a preference trial where they were allowed to choose between CBT (n = 120) and yoga (n = 130).
Participants completed 20 yoga sessions over 10 weeks or 10 weekly CBT calls between May 2017 and November 2018.
Measures used included the PSWQ-A, the Insomnia Severity Index (ISI), the Patient Reported Outcomes Measurement Information System (PROMIS) Short Form v1.0 – Anxiety 8a, and the PROMIS-29 to assess depression, fatigue, physical function, social participation, and pain.
In 2020, the researchers published results at 11 weeks showing improvements from baseline in all areas. The scores for anxiety and worry were similar between the CBT and yoga groups, but CBT yielded significantly higher improvement in insomnia.
At 37 weeks, about 6 months after the interventions had ended, the investigators found even greater improvements from baseline in all areas measured – except physical function.
However, at that point, there were no significant differences between the two interventions in either the randomized controlled trial or the preference trial. There were also no differences in the results between the two trial designs.
“There were some little differences, but by and large we found both interventions to be efficacious,” Dr. Danhauer said. “This gives clinicians [the] choice to be able to say, ‘you can try either one of these and they’re probably going to help.’ ”
Beyond statistically significant
The researchers also found the improvements were not just statistically significant, but were also clinically meaningful for worry, anxiety, and insomnia.
Meaningful changes were defined as a decrease of at least 5.5 points on the PSWQ-A for worry, a decrease of at least 3 points on the PROMIS Anxiety scale for anxiety, and a decrease of at least 6 points in the ISI for insomnia.
At long-term follow-up, the majority of participants in both the CBT and yoga arms of the randomized, controlled trial demonstrated meaningful change in worry (85.7% and 77.6%, respectively), anxiety (82.1% and 80.8%), and insomnia (52.8% and 44.3%).
The majority of participants also reported meaningful improvements in generalized anxiety symptoms, depressive symptoms, and fatigue, but not for physical function, pain interference, or pain intensity.
“That’s the part to me that’s particularly notable. The improvements weren’t just statistically significant, they were clinically meaningful as well,” Dr. Danhauer said.
“When it comes right down to people’s lives, they want differences they can feel and see and not just what a P value looks like,” she added.
Real-world impact
In an accompanying editorial, Carmen Andreescu, MD, associate professor of psychiatry at the University of Pittsburgh, agreed that the results have “real-world impact.”
“Clinicians can direct their patients toward interventions that may be beneficial, consolidate the results over time and avoid fueling the well-trained worry cognitive loop with concerns related to potential side effects,” Dr. Andreescu wrote.
She adds that interventions such as these “may increase accessibility and provide relief for the immediate suffering of our patients.”
The study was funded by the Patient-Centered Outcomes Research Institute Program. Dr. Danhauer and Dr. Andreescu reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
new research suggests.
The study is the first to compare the long-term effects from the two interventions; and the results offer clinicians and patients two effective choices for reducing worry and anxiety, researchers noted.
“Anxiety can be a really big problem for older adults,” lead investigator Suzanne Danhauer, PhD, professor of social sciences and health policy at Wake Forest University, Winston-Salem, N.C., said in an interview.
“So to find something they can do that lasts ... and has some enduring impact on their quality of life and their mental health, and they’re both nonpharmacologic treatments, I think for a lot of older people that’s really attractive,” Dr. Danhauer said.
The findings are published in the September issue of the American Journal of Geriatric Psychiatry.
Long-term benefits
The two-stage randomized preference trial included 500 community-dwelling individuals over age 60 who scored 26 or above on the Penn State Worry Questionnaire–Abbreviated (PSWQ-A), indicating heightened anxiety and worry.
Half the group took part in a randomized, controlled trial comparing CBT (n = 125) with yoga (n = 125). The other half participated in a preference trial where they were allowed to choose between CBT (n = 120) and yoga (n = 130).
Participants completed 20 yoga sessions over 10 weeks or 10 weekly CBT calls between May 2017 and November 2018.
Measures used included the PSWQ-A, the Insomnia Severity Index (ISI), the Patient Reported Outcomes Measurement Information System (PROMIS) Short Form v1.0 – Anxiety 8a, and the PROMIS-29 to assess depression, fatigue, physical function, social participation, and pain.
In 2020, the researchers published results at 11 weeks showing improvements from baseline in all areas. The scores for anxiety and worry were similar between the CBT and yoga groups, but CBT yielded significantly higher improvement in insomnia.
At 37 weeks, about 6 months after the interventions had ended, the investigators found even greater improvements from baseline in all areas measured – except physical function.
However, at that point, there were no significant differences between the two interventions in either the randomized controlled trial or the preference trial. There were also no differences in the results between the two trial designs.
“There were some little differences, but by and large we found both interventions to be efficacious,” Dr. Danhauer said. “This gives clinicians [the] choice to be able to say, ‘you can try either one of these and they’re probably going to help.’ ”
Beyond statistically significant
The researchers also found the improvements were not just statistically significant, but were also clinically meaningful for worry, anxiety, and insomnia.
Meaningful changes were defined as a decrease of at least 5.5 points on the PSWQ-A for worry, a decrease of at least 3 points on the PROMIS Anxiety scale for anxiety, and a decrease of at least 6 points in the ISI for insomnia.
At long-term follow-up, the majority of participants in both the CBT and yoga arms of the randomized, controlled trial demonstrated meaningful change in worry (85.7% and 77.6%, respectively), anxiety (82.1% and 80.8%), and insomnia (52.8% and 44.3%).
The majority of participants also reported meaningful improvements in generalized anxiety symptoms, depressive symptoms, and fatigue, but not for physical function, pain interference, or pain intensity.
“That’s the part to me that’s particularly notable. The improvements weren’t just statistically significant, they were clinically meaningful as well,” Dr. Danhauer said.
“When it comes right down to people’s lives, they want differences they can feel and see and not just what a P value looks like,” she added.
Real-world impact
In an accompanying editorial, Carmen Andreescu, MD, associate professor of psychiatry at the University of Pittsburgh, agreed that the results have “real-world impact.”
“Clinicians can direct their patients toward interventions that may be beneficial, consolidate the results over time and avoid fueling the well-trained worry cognitive loop with concerns related to potential side effects,” Dr. Andreescu wrote.
She adds that interventions such as these “may increase accessibility and provide relief for the immediate suffering of our patients.”
The study was funded by the Patient-Centered Outcomes Research Institute Program. Dr. Danhauer and Dr. Andreescu reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
new research suggests.
The study is the first to compare the long-term effects from the two interventions; and the results offer clinicians and patients two effective choices for reducing worry and anxiety, researchers noted.
“Anxiety can be a really big problem for older adults,” lead investigator Suzanne Danhauer, PhD, professor of social sciences and health policy at Wake Forest University, Winston-Salem, N.C., said in an interview.
“So to find something they can do that lasts ... and has some enduring impact on their quality of life and their mental health, and they’re both nonpharmacologic treatments, I think for a lot of older people that’s really attractive,” Dr. Danhauer said.
The findings are published in the September issue of the American Journal of Geriatric Psychiatry.
Long-term benefits
The two-stage randomized preference trial included 500 community-dwelling individuals over age 60 who scored 26 or above on the Penn State Worry Questionnaire–Abbreviated (PSWQ-A), indicating heightened anxiety and worry.
Half the group took part in a randomized, controlled trial comparing CBT (n = 125) with yoga (n = 125). The other half participated in a preference trial where they were allowed to choose between CBT (n = 120) and yoga (n = 130).
Participants completed 20 yoga sessions over 10 weeks or 10 weekly CBT calls between May 2017 and November 2018.
Measures used included the PSWQ-A, the Insomnia Severity Index (ISI), the Patient Reported Outcomes Measurement Information System (PROMIS) Short Form v1.0 – Anxiety 8a, and the PROMIS-29 to assess depression, fatigue, physical function, social participation, and pain.
In 2020, the researchers published results at 11 weeks showing improvements from baseline in all areas. The scores for anxiety and worry were similar between the CBT and yoga groups, but CBT yielded significantly higher improvement in insomnia.
At 37 weeks, about 6 months after the interventions had ended, the investigators found even greater improvements from baseline in all areas measured – except physical function.
However, at that point, there were no significant differences between the two interventions in either the randomized controlled trial or the preference trial. There were also no differences in the results between the two trial designs.
“There were some little differences, but by and large we found both interventions to be efficacious,” Dr. Danhauer said. “This gives clinicians [the] choice to be able to say, ‘you can try either one of these and they’re probably going to help.’ ”
Beyond statistically significant
The researchers also found the improvements were not just statistically significant, but were also clinically meaningful for worry, anxiety, and insomnia.
Meaningful changes were defined as a decrease of at least 5.5 points on the PSWQ-A for worry, a decrease of at least 3 points on the PROMIS Anxiety scale for anxiety, and a decrease of at least 6 points in the ISI for insomnia.
At long-term follow-up, the majority of participants in both the CBT and yoga arms of the randomized, controlled trial demonstrated meaningful change in worry (85.7% and 77.6%, respectively), anxiety (82.1% and 80.8%), and insomnia (52.8% and 44.3%).
The majority of participants also reported meaningful improvements in generalized anxiety symptoms, depressive symptoms, and fatigue, but not for physical function, pain interference, or pain intensity.
“That’s the part to me that’s particularly notable. The improvements weren’t just statistically significant, they were clinically meaningful as well,” Dr. Danhauer said.
“When it comes right down to people’s lives, they want differences they can feel and see and not just what a P value looks like,” she added.
Real-world impact
In an accompanying editorial, Carmen Andreescu, MD, associate professor of psychiatry at the University of Pittsburgh, agreed that the results have “real-world impact.”
“Clinicians can direct their patients toward interventions that may be beneficial, consolidate the results over time and avoid fueling the well-trained worry cognitive loop with concerns related to potential side effects,” Dr. Andreescu wrote.
She adds that interventions such as these “may increase accessibility and provide relief for the immediate suffering of our patients.”
The study was funded by the Patient-Centered Outcomes Research Institute Program. Dr. Danhauer and Dr. Andreescu reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY
Blood type linked to higher risk for early onset stroke
Conversely, results from a meta-analysis of nearly 17,000 cases of ischemic stroke in adults younger than 60 years showed that having type O blood reduced the risk for EOS by 12%.
In addition, the associations with risk were significantly stronger in EOS than in those with late-onset stroke (LOS), pointing to a stronger role for prothrombotic factors in younger patients, the researchers noted.
“What this is telling us is that maybe what makes you susceptible to stroke as a young adult is the blood type, which is really giving you a much higher risk of clotting and stroke compared to later onset,” coinvestigator Braxton Mitchell, PhD, professor of medicine and epidemiology and public health at the University of Maryland, Baltimore, said in an interview.
The findings were published online in Neurology.
Strong association
The genome-wide association study (GWAS) was done as part of the Genetics of Early Onset Ischemic Stroke Consortium, a collaboration of 48 different studies across North America, Europe, Japan, Pakistan, and Australia. It assessed early onset ischemic stroke in patients aged 18-59 years.
Researchers included data from 16,927 patients with stroke. Of these, 5,825 had a stroke before age 60, defined as early onset. GWAS results were also examined for nearly 600,000 individuals without stroke.
Results showed two genetic variants tied to blood types A and O emerged as highly associated with risk for early stroke.
Researchers found that the protective effects of type O were significantly stronger with EOS vs. LOS (odds ratio [OR], 0.88 vs. 0.96, respectively; P = .001). Likewise, the association between type A and increased EOS risk was significantly stronger than that found in LOS (OR, 1.16 vs. 1.05; P = .005).
Using polygenic risk scores, the investigators also found that the greater genetic risk for venous thromboembolism, another prothrombotic condition, was more strongly associated with EOS compared with LOS (P = .008).
Previous studies have shown a link between stroke risk and variants of the ABO gene, which determines blood type. The new analysis suggests that type A and O gene variants represent nearly all of those genetically linked with early stroke, the researchers noted.
While the findings point to blood type as a risk factor for stroke in younger people, Dr. Mitchell cautions that “at the moment, blood group does not have implications for preventive care.”
“The risk of stroke due to blood type is smaller than other risk factors that we know about, like smoking and hypertension,” he said. “I would be much more worried about these other risk factors, especially because those may be modifiable.”
He noted the next step in the study is to assess how blood type interacts with other known risk factors to raise stroke risk.
“There may be a subset of people where, if you have blood type A and you have some of these other risk factors, it’s possible that you may be at particularly high risk,” Dr. Mitchell said.
More research needed on younger patients
In an accompanying editorial, Jennifer Juhl Majersik, MD, associate professor of neurology at the University of Utah, Salt Lake City, and Paul Lacaze, PhD, associate professor and head of the public health genomics program at Monash University, Australia, noted that the study fills a gap in stroke research, which often focuses mostly on older individuals.
“In approximately 40% of people with EOS, the stroke is cryptogenic, and there is scant data from clinical trials to guide the selection of preventative strategies in this population, as people with EOS are often excluded from trials,” Dr. Majersik and Dr. Lacaze wrote.
“This work has deepened our understanding of EOS pathophysiology,” they added.
The editorialists noted that future research can build on the results from this analysis, “with the goal of a more precise understanding of stroke pathophysiology, leading to targeted preventative treatments for EOS and a reduction in disability in patients’ most productive years.”
Dr. Mitchell echoed the call for greater inclusion of young patients with stroke in clinical trials.
“As we’re learning, stroke in older folks isn’t the same as stroke in younger people,” he said. “There are many shared risk factors but there are also some that are different ... so there really is a need to include younger people.”
A version of this article first appeared on Medscape.com.
Conversely, results from a meta-analysis of nearly 17,000 cases of ischemic stroke in adults younger than 60 years showed that having type O blood reduced the risk for EOS by 12%.
In addition, the associations with risk were significantly stronger in EOS than in those with late-onset stroke (LOS), pointing to a stronger role for prothrombotic factors in younger patients, the researchers noted.
“What this is telling us is that maybe what makes you susceptible to stroke as a young adult is the blood type, which is really giving you a much higher risk of clotting and stroke compared to later onset,” coinvestigator Braxton Mitchell, PhD, professor of medicine and epidemiology and public health at the University of Maryland, Baltimore, said in an interview.
The findings were published online in Neurology.
Strong association
The genome-wide association study (GWAS) was done as part of the Genetics of Early Onset Ischemic Stroke Consortium, a collaboration of 48 different studies across North America, Europe, Japan, Pakistan, and Australia. It assessed early onset ischemic stroke in patients aged 18-59 years.
Researchers included data from 16,927 patients with stroke. Of these, 5,825 had a stroke before age 60, defined as early onset. GWAS results were also examined for nearly 600,000 individuals without stroke.
Results showed two genetic variants tied to blood types A and O emerged as highly associated with risk for early stroke.
Researchers found that the protective effects of type O were significantly stronger with EOS vs. LOS (odds ratio [OR], 0.88 vs. 0.96, respectively; P = .001). Likewise, the association between type A and increased EOS risk was significantly stronger than that found in LOS (OR, 1.16 vs. 1.05; P = .005).
Using polygenic risk scores, the investigators also found that the greater genetic risk for venous thromboembolism, another prothrombotic condition, was more strongly associated with EOS compared with LOS (P = .008).
Previous studies have shown a link between stroke risk and variants of the ABO gene, which determines blood type. The new analysis suggests that type A and O gene variants represent nearly all of those genetically linked with early stroke, the researchers noted.
While the findings point to blood type as a risk factor for stroke in younger people, Dr. Mitchell cautions that “at the moment, blood group does not have implications for preventive care.”
“The risk of stroke due to blood type is smaller than other risk factors that we know about, like smoking and hypertension,” he said. “I would be much more worried about these other risk factors, especially because those may be modifiable.”
He noted the next step in the study is to assess how blood type interacts with other known risk factors to raise stroke risk.
“There may be a subset of people where, if you have blood type A and you have some of these other risk factors, it’s possible that you may be at particularly high risk,” Dr. Mitchell said.
More research needed on younger patients
In an accompanying editorial, Jennifer Juhl Majersik, MD, associate professor of neurology at the University of Utah, Salt Lake City, and Paul Lacaze, PhD, associate professor and head of the public health genomics program at Monash University, Australia, noted that the study fills a gap in stroke research, which often focuses mostly on older individuals.
“In approximately 40% of people with EOS, the stroke is cryptogenic, and there is scant data from clinical trials to guide the selection of preventative strategies in this population, as people with EOS are often excluded from trials,” Dr. Majersik and Dr. Lacaze wrote.
“This work has deepened our understanding of EOS pathophysiology,” they added.
The editorialists noted that future research can build on the results from this analysis, “with the goal of a more precise understanding of stroke pathophysiology, leading to targeted preventative treatments for EOS and a reduction in disability in patients’ most productive years.”
Dr. Mitchell echoed the call for greater inclusion of young patients with stroke in clinical trials.
“As we’re learning, stroke in older folks isn’t the same as stroke in younger people,” he said. “There are many shared risk factors but there are also some that are different ... so there really is a need to include younger people.”
A version of this article first appeared on Medscape.com.
Conversely, results from a meta-analysis of nearly 17,000 cases of ischemic stroke in adults younger than 60 years showed that having type O blood reduced the risk for EOS by 12%.
In addition, the associations with risk were significantly stronger in EOS than in those with late-onset stroke (LOS), pointing to a stronger role for prothrombotic factors in younger patients, the researchers noted.
“What this is telling us is that maybe what makes you susceptible to stroke as a young adult is the blood type, which is really giving you a much higher risk of clotting and stroke compared to later onset,” coinvestigator Braxton Mitchell, PhD, professor of medicine and epidemiology and public health at the University of Maryland, Baltimore, said in an interview.
The findings were published online in Neurology.
Strong association
The genome-wide association study (GWAS) was done as part of the Genetics of Early Onset Ischemic Stroke Consortium, a collaboration of 48 different studies across North America, Europe, Japan, Pakistan, and Australia. It assessed early onset ischemic stroke in patients aged 18-59 years.
Researchers included data from 16,927 patients with stroke. Of these, 5,825 had a stroke before age 60, defined as early onset. GWAS results were also examined for nearly 600,000 individuals without stroke.
Results showed two genetic variants tied to blood types A and O emerged as highly associated with risk for early stroke.
Researchers found that the protective effects of type O were significantly stronger with EOS vs. LOS (odds ratio [OR], 0.88 vs. 0.96, respectively; P = .001). Likewise, the association between type A and increased EOS risk was significantly stronger than that found in LOS (OR, 1.16 vs. 1.05; P = .005).
Using polygenic risk scores, the investigators also found that the greater genetic risk for venous thromboembolism, another prothrombotic condition, was more strongly associated with EOS compared with LOS (P = .008).
Previous studies have shown a link between stroke risk and variants of the ABO gene, which determines blood type. The new analysis suggests that type A and O gene variants represent nearly all of those genetically linked with early stroke, the researchers noted.
While the findings point to blood type as a risk factor for stroke in younger people, Dr. Mitchell cautions that “at the moment, blood group does not have implications for preventive care.”
“The risk of stroke due to blood type is smaller than other risk factors that we know about, like smoking and hypertension,” he said. “I would be much more worried about these other risk factors, especially because those may be modifiable.”
He noted the next step in the study is to assess how blood type interacts with other known risk factors to raise stroke risk.
“There may be a subset of people where, if you have blood type A and you have some of these other risk factors, it’s possible that you may be at particularly high risk,” Dr. Mitchell said.
More research needed on younger patients
In an accompanying editorial, Jennifer Juhl Majersik, MD, associate professor of neurology at the University of Utah, Salt Lake City, and Paul Lacaze, PhD, associate professor and head of the public health genomics program at Monash University, Australia, noted that the study fills a gap in stroke research, which often focuses mostly on older individuals.
“In approximately 40% of people with EOS, the stroke is cryptogenic, and there is scant data from clinical trials to guide the selection of preventative strategies in this population, as people with EOS are often excluded from trials,” Dr. Majersik and Dr. Lacaze wrote.
“This work has deepened our understanding of EOS pathophysiology,” they added.
The editorialists noted that future research can build on the results from this analysis, “with the goal of a more precise understanding of stroke pathophysiology, leading to targeted preventative treatments for EOS and a reduction in disability in patients’ most productive years.”
Dr. Mitchell echoed the call for greater inclusion of young patients with stroke in clinical trials.
“As we’re learning, stroke in older folks isn’t the same as stroke in younger people,” he said. “There are many shared risk factors but there are also some that are different ... so there really is a need to include younger people.”
A version of this article first appeared on Medscape.com.
FROM NEUROLOGY
Digital therapy may ‘rewire’ the brain to improve tinnitus
, new research suggests. In a randomized controlled trial, results at 12 weeks showed patients with tinnitus reported clinically meaningful reductions in ratings of annoyance, inability to ignore, unpleasantness, and loudness after using a digital polytherapeutic app prototype that focuses on relief, relaxation, and attention-focused retraining. In addition, their improvements were significantly greater than for the control group, which received a common white noise app.
Researchers called the results “promising” for a condition that has no cure and few successful treatments. “What this therapy does is essentially rewire the brain in a way that de-emphasizes the sound of the tinnitus to a background noise that has no meaning or relevance to the listener,” lead author Grant Searchfield, PhD, associate professor of audiology at the University of Auckland, New Zealand, said in a press release.
The findings were published online in Frontiers in Neurology.
Worldwide problem
A recent study showed more than 740 million adults worldwide (nearly 15% of the population) have experienced at least one symptom of tinnitus – and about 120 million are severely affected. Tinnitus is the perception of a ringing, buzzing, whistling, or hissing noise in one or both ears when no external source of the sound is present. Often caused by damage to the auditory system, tinnitus can also be a symptom of a wide range of medical conditions and has been identified as a side effect of COVID-19 vaccination. In its most severe form, which is associated with hearing loss, tinnitus can also affect a patient’s mental, emotional, and social health.
For the current study, participants with tinnitus were randomly assigned to a popular app that uses white noise (control group, n = 30) or to the UpSilent app (n = 31). The UpSilent group received a smartphone app, Bluetooth bone conduction headphones, a Bluetooth neck pillow speaker for sleep, and written counseling materials. Participants in the control group received a widely available app called “White Noise” and in-ear wired headphones.
‘Quicker and more effective’
Both groups reported reductions in ratings of annoyance, inability to ignore, unpleasantness, and loudness at 12 weeks. But significantly more of the UpSilent group reported clinically meaningful improvement compared with the control group (65% vs. 43%, respectively; P = .049).
“Earlier trials have found white noise, goal-based counseling, goal-oriented games, and other technology-based therapies are effective for some people some of the time,” Dr. Searchfield said. “This is quicker and more effective, taking 12 weeks rather than 12 months for more individuals to gain some control,” he added.
The investigators noted that the study was not designed to determine which of the app’s functions of passive listening, active listening, or counseling contributed to symptom improvement.
The next step will be to refine the prototype and proceed to larger local and international trials with a view toward approval by the U.S. Food and Drug Administration, they reported.
The researchers hope the app will be clinically available in about 6 months.
The study was funded by Return on Science, Auckland UniServices. Dr. Searchfield is a founder and scientific officer for TrueSilence, a spinout company of the University of Auckland, and has a financial interest in TrueSilence. His coauthor has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, new research suggests. In a randomized controlled trial, results at 12 weeks showed patients with tinnitus reported clinically meaningful reductions in ratings of annoyance, inability to ignore, unpleasantness, and loudness after using a digital polytherapeutic app prototype that focuses on relief, relaxation, and attention-focused retraining. In addition, their improvements were significantly greater than for the control group, which received a common white noise app.
Researchers called the results “promising” for a condition that has no cure and few successful treatments. “What this therapy does is essentially rewire the brain in a way that de-emphasizes the sound of the tinnitus to a background noise that has no meaning or relevance to the listener,” lead author Grant Searchfield, PhD, associate professor of audiology at the University of Auckland, New Zealand, said in a press release.
The findings were published online in Frontiers in Neurology.
Worldwide problem
A recent study showed more than 740 million adults worldwide (nearly 15% of the population) have experienced at least one symptom of tinnitus – and about 120 million are severely affected. Tinnitus is the perception of a ringing, buzzing, whistling, or hissing noise in one or both ears when no external source of the sound is present. Often caused by damage to the auditory system, tinnitus can also be a symptom of a wide range of medical conditions and has been identified as a side effect of COVID-19 vaccination. In its most severe form, which is associated with hearing loss, tinnitus can also affect a patient’s mental, emotional, and social health.
For the current study, participants with tinnitus were randomly assigned to a popular app that uses white noise (control group, n = 30) or to the UpSilent app (n = 31). The UpSilent group received a smartphone app, Bluetooth bone conduction headphones, a Bluetooth neck pillow speaker for sleep, and written counseling materials. Participants in the control group received a widely available app called “White Noise” and in-ear wired headphones.
‘Quicker and more effective’
Both groups reported reductions in ratings of annoyance, inability to ignore, unpleasantness, and loudness at 12 weeks. But significantly more of the UpSilent group reported clinically meaningful improvement compared with the control group (65% vs. 43%, respectively; P = .049).
“Earlier trials have found white noise, goal-based counseling, goal-oriented games, and other technology-based therapies are effective for some people some of the time,” Dr. Searchfield said. “This is quicker and more effective, taking 12 weeks rather than 12 months for more individuals to gain some control,” he added.
The investigators noted that the study was not designed to determine which of the app’s functions of passive listening, active listening, or counseling contributed to symptom improvement.
The next step will be to refine the prototype and proceed to larger local and international trials with a view toward approval by the U.S. Food and Drug Administration, they reported.
The researchers hope the app will be clinically available in about 6 months.
The study was funded by Return on Science, Auckland UniServices. Dr. Searchfield is a founder and scientific officer for TrueSilence, a spinout company of the University of Auckland, and has a financial interest in TrueSilence. His coauthor has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, new research suggests. In a randomized controlled trial, results at 12 weeks showed patients with tinnitus reported clinically meaningful reductions in ratings of annoyance, inability to ignore, unpleasantness, and loudness after using a digital polytherapeutic app prototype that focuses on relief, relaxation, and attention-focused retraining. In addition, their improvements were significantly greater than for the control group, which received a common white noise app.
Researchers called the results “promising” for a condition that has no cure and few successful treatments. “What this therapy does is essentially rewire the brain in a way that de-emphasizes the sound of the tinnitus to a background noise that has no meaning or relevance to the listener,” lead author Grant Searchfield, PhD, associate professor of audiology at the University of Auckland, New Zealand, said in a press release.
The findings were published online in Frontiers in Neurology.
Worldwide problem
A recent study showed more than 740 million adults worldwide (nearly 15% of the population) have experienced at least one symptom of tinnitus – and about 120 million are severely affected. Tinnitus is the perception of a ringing, buzzing, whistling, or hissing noise in one or both ears when no external source of the sound is present. Often caused by damage to the auditory system, tinnitus can also be a symptom of a wide range of medical conditions and has been identified as a side effect of COVID-19 vaccination. In its most severe form, which is associated with hearing loss, tinnitus can also affect a patient’s mental, emotional, and social health.
For the current study, participants with tinnitus were randomly assigned to a popular app that uses white noise (control group, n = 30) or to the UpSilent app (n = 31). The UpSilent group received a smartphone app, Bluetooth bone conduction headphones, a Bluetooth neck pillow speaker for sleep, and written counseling materials. Participants in the control group received a widely available app called “White Noise” and in-ear wired headphones.
‘Quicker and more effective’
Both groups reported reductions in ratings of annoyance, inability to ignore, unpleasantness, and loudness at 12 weeks. But significantly more of the UpSilent group reported clinically meaningful improvement compared with the control group (65% vs. 43%, respectively; P = .049).
“Earlier trials have found white noise, goal-based counseling, goal-oriented games, and other technology-based therapies are effective for some people some of the time,” Dr. Searchfield said. “This is quicker and more effective, taking 12 weeks rather than 12 months for more individuals to gain some control,” he added.
The investigators noted that the study was not designed to determine which of the app’s functions of passive listening, active listening, or counseling contributed to symptom improvement.
The next step will be to refine the prototype and proceed to larger local and international trials with a view toward approval by the U.S. Food and Drug Administration, they reported.
The researchers hope the app will be clinically available in about 6 months.
The study was funded by Return on Science, Auckland UniServices. Dr. Searchfield is a founder and scientific officer for TrueSilence, a spinout company of the University of Auckland, and has a financial interest in TrueSilence. His coauthor has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM FRONTIERS IN NEUROLOGY
APA task force highlights U.S. psychiatric bed crisis
The model, introduced in a recent report from the organization, can predict how changes in any component of mental health care in a community, including mobile trauma teams and assertive community treatment, will affect other components and the overall capacity to care for patients with mental illness.
Leaders of the APA task force that drafted the report noted that communities can use the model to confront the ongoing mental health crisis brought about by a lack of inpatient beds, a shortage of mental health professionals, shorter inpatient stays, and a rising number of individuals with mental illness.
The report was first released at the APA’s annual meeting in May 2022 and was discussed in further detail at a press briefing in mid-August.
“Part of the wisdom of the APA leadership of releasing this report in this format now is to keep attention and awareness on the issue and acknowledge that there is a terrible shortage of beds,” Anita Everett, MD, past president of the APA and chair of the report’s task force, told briefing attendees.
“We need to have ongoing conversations about how we can solve this problem,” said Dr. Everett, who is also director of the Center for Mental Health Services at the Substance Abuse and Mental Health Services Administration.
A virtual world
The report describes both historic and current psychiatric bed use and discusses how the availability of community resources affects the need for inpatient care. It includes analyses of inpatient medical care spending and describes barriers to accessing inpatient psychiatric care.
Historically, the number of state-operated psychiatric hospital beds in the United States was 337 per 100,000 people in the mid-1950s. Today, that figure is about 11.7 state psychiatric hospital beds per 100,000 people, the report says.
The average length of an inpatient stay has also decreased significantly both for adults and children. Pediatric length of stay declined from 12.2 days to 4.4 days between 1990 and 2000.
Launched in 2020, the APA Presidential Task Force on the Assessment of Psychiatric Bed Needs in the United States includes more than 30 mental health professionals and members of the APA administration.
The group was charged with drafting a report that explains and defines the current mental health crisis. They were also charged with developing a method for calculating the number of psychiatric beds needed in any given community.
Task force leaders said the model considers how individuals enter the mental health care system and are routed to appropriate services, how long they remain in the system, and the capacity of the system to respond to demand.
The model is based on a “virtual world” that has a number of care components. These include mobile crisis teams, intensive team-based outpatient care, community-based crisis beds, psychiatric hospital beds, and residential and step-down programs.
The model factors in the magnitude of the need for beds in many service areas. Factors include population size, estimates of the rate of acute mental health crises per 100,000 population, adequacy of the community mental health system, the intersection between the mental health and criminal justice systems, and outpatient and inpatient capacities.
The model computes the estimated number of patients waiting in the emergency department, crisis receiving centers, and jail, as well as average wait times. It also calculates the percentage of use of the various services.
The model will be continually updated and can be modified to better reflect the current situation in any given community.
Real-world testing
A team led by the University of Michigan, Ann Arbor, and two area hospitals is testing the APA model by using it to calculate the number of beds needed in their community.
“Because the model is focused on the continuum of care services, it allows communities to try to focus on what is the right mix of services needed to try to reduce the need for in-patient hospitalization and measure the impact of development of resources across the continuum, including inpatient beds, to try to achieve the right mix,” Gregory Dalack, MD, chair of the department of psychiatry at the University of Michigan Health System, told this news organization.
Ultimately, Dr. Dalack expects that the model will tell the team something they already know: that additional psychiatric beds are needed in their community.
However, meeting the needs of patients and families is not just about beds, he noted. The model will help provide a fuller picture of psychiatric care and will take into account existing services from many aspects of the care field.
“If we put all the focus just on hospital beds, we are only addressing one part of the challenge,” Dr. Dalack said.
The challenge is also about “identifying what resources/services are already in the continuum of care, where expansion of those or development of new programs might be needed, and what the impact is on the system, particularly with folks who arrive in the emergency room who might need inpatient admission,” he added.
Dr. Everett said the APA leadership team is now actively recruiting others to test the model in their communities, which will help to calibrate the system.
A version of this article first appeared on Medscape.com.
The model, introduced in a recent report from the organization, can predict how changes in any component of mental health care in a community, including mobile trauma teams and assertive community treatment, will affect other components and the overall capacity to care for patients with mental illness.
Leaders of the APA task force that drafted the report noted that communities can use the model to confront the ongoing mental health crisis brought about by a lack of inpatient beds, a shortage of mental health professionals, shorter inpatient stays, and a rising number of individuals with mental illness.
The report was first released at the APA’s annual meeting in May 2022 and was discussed in further detail at a press briefing in mid-August.
“Part of the wisdom of the APA leadership of releasing this report in this format now is to keep attention and awareness on the issue and acknowledge that there is a terrible shortage of beds,” Anita Everett, MD, past president of the APA and chair of the report’s task force, told briefing attendees.
“We need to have ongoing conversations about how we can solve this problem,” said Dr. Everett, who is also director of the Center for Mental Health Services at the Substance Abuse and Mental Health Services Administration.
A virtual world
The report describes both historic and current psychiatric bed use and discusses how the availability of community resources affects the need for inpatient care. It includes analyses of inpatient medical care spending and describes barriers to accessing inpatient psychiatric care.
Historically, the number of state-operated psychiatric hospital beds in the United States was 337 per 100,000 people in the mid-1950s. Today, that figure is about 11.7 state psychiatric hospital beds per 100,000 people, the report says.
The average length of an inpatient stay has also decreased significantly both for adults and children. Pediatric length of stay declined from 12.2 days to 4.4 days between 1990 and 2000.
Launched in 2020, the APA Presidential Task Force on the Assessment of Psychiatric Bed Needs in the United States includes more than 30 mental health professionals and members of the APA administration.
The group was charged with drafting a report that explains and defines the current mental health crisis. They were also charged with developing a method for calculating the number of psychiatric beds needed in any given community.
Task force leaders said the model considers how individuals enter the mental health care system and are routed to appropriate services, how long they remain in the system, and the capacity of the system to respond to demand.
The model is based on a “virtual world” that has a number of care components. These include mobile crisis teams, intensive team-based outpatient care, community-based crisis beds, psychiatric hospital beds, and residential and step-down programs.
The model factors in the magnitude of the need for beds in many service areas. Factors include population size, estimates of the rate of acute mental health crises per 100,000 population, adequacy of the community mental health system, the intersection between the mental health and criminal justice systems, and outpatient and inpatient capacities.
The model computes the estimated number of patients waiting in the emergency department, crisis receiving centers, and jail, as well as average wait times. It also calculates the percentage of use of the various services.
The model will be continually updated and can be modified to better reflect the current situation in any given community.
Real-world testing
A team led by the University of Michigan, Ann Arbor, and two area hospitals is testing the APA model by using it to calculate the number of beds needed in their community.
“Because the model is focused on the continuum of care services, it allows communities to try to focus on what is the right mix of services needed to try to reduce the need for in-patient hospitalization and measure the impact of development of resources across the continuum, including inpatient beds, to try to achieve the right mix,” Gregory Dalack, MD, chair of the department of psychiatry at the University of Michigan Health System, told this news organization.
Ultimately, Dr. Dalack expects that the model will tell the team something they already know: that additional psychiatric beds are needed in their community.
However, meeting the needs of patients and families is not just about beds, he noted. The model will help provide a fuller picture of psychiatric care and will take into account existing services from many aspects of the care field.
“If we put all the focus just on hospital beds, we are only addressing one part of the challenge,” Dr. Dalack said.
The challenge is also about “identifying what resources/services are already in the continuum of care, where expansion of those or development of new programs might be needed, and what the impact is on the system, particularly with folks who arrive in the emergency room who might need inpatient admission,” he added.
Dr. Everett said the APA leadership team is now actively recruiting others to test the model in their communities, which will help to calibrate the system.
A version of this article first appeared on Medscape.com.
The model, introduced in a recent report from the organization, can predict how changes in any component of mental health care in a community, including mobile trauma teams and assertive community treatment, will affect other components and the overall capacity to care for patients with mental illness.
Leaders of the APA task force that drafted the report noted that communities can use the model to confront the ongoing mental health crisis brought about by a lack of inpatient beds, a shortage of mental health professionals, shorter inpatient stays, and a rising number of individuals with mental illness.
The report was first released at the APA’s annual meeting in May 2022 and was discussed in further detail at a press briefing in mid-August.
“Part of the wisdom of the APA leadership of releasing this report in this format now is to keep attention and awareness on the issue and acknowledge that there is a terrible shortage of beds,” Anita Everett, MD, past president of the APA and chair of the report’s task force, told briefing attendees.
“We need to have ongoing conversations about how we can solve this problem,” said Dr. Everett, who is also director of the Center for Mental Health Services at the Substance Abuse and Mental Health Services Administration.
A virtual world
The report describes both historic and current psychiatric bed use and discusses how the availability of community resources affects the need for inpatient care. It includes analyses of inpatient medical care spending and describes barriers to accessing inpatient psychiatric care.
Historically, the number of state-operated psychiatric hospital beds in the United States was 337 per 100,000 people in the mid-1950s. Today, that figure is about 11.7 state psychiatric hospital beds per 100,000 people, the report says.
The average length of an inpatient stay has also decreased significantly both for adults and children. Pediatric length of stay declined from 12.2 days to 4.4 days between 1990 and 2000.
Launched in 2020, the APA Presidential Task Force on the Assessment of Psychiatric Bed Needs in the United States includes more than 30 mental health professionals and members of the APA administration.
The group was charged with drafting a report that explains and defines the current mental health crisis. They were also charged with developing a method for calculating the number of psychiatric beds needed in any given community.
Task force leaders said the model considers how individuals enter the mental health care system and are routed to appropriate services, how long they remain in the system, and the capacity of the system to respond to demand.
The model is based on a “virtual world” that has a number of care components. These include mobile crisis teams, intensive team-based outpatient care, community-based crisis beds, psychiatric hospital beds, and residential and step-down programs.
The model factors in the magnitude of the need for beds in many service areas. Factors include population size, estimates of the rate of acute mental health crises per 100,000 population, adequacy of the community mental health system, the intersection between the mental health and criminal justice systems, and outpatient and inpatient capacities.
The model computes the estimated number of patients waiting in the emergency department, crisis receiving centers, and jail, as well as average wait times. It also calculates the percentage of use of the various services.
The model will be continually updated and can be modified to better reflect the current situation in any given community.
Real-world testing
A team led by the University of Michigan, Ann Arbor, and two area hospitals is testing the APA model by using it to calculate the number of beds needed in their community.
“Because the model is focused on the continuum of care services, it allows communities to try to focus on what is the right mix of services needed to try to reduce the need for in-patient hospitalization and measure the impact of development of resources across the continuum, including inpatient beds, to try to achieve the right mix,” Gregory Dalack, MD, chair of the department of psychiatry at the University of Michigan Health System, told this news organization.
Ultimately, Dr. Dalack expects that the model will tell the team something they already know: that additional psychiatric beds are needed in their community.
However, meeting the needs of patients and families is not just about beds, he noted. The model will help provide a fuller picture of psychiatric care and will take into account existing services from many aspects of the care field.
“If we put all the focus just on hospital beds, we are only addressing one part of the challenge,” Dr. Dalack said.
The challenge is also about “identifying what resources/services are already in the continuum of care, where expansion of those or development of new programs might be needed, and what the impact is on the system, particularly with folks who arrive in the emergency room who might need inpatient admission,” he added.
Dr. Everett said the APA leadership team is now actively recruiting others to test the model in their communities, which will help to calibrate the system.
A version of this article first appeared on Medscape.com.
Two deaths from liver failure linked to spinal muscular atrophy drug
, according to a statement issued by the drug›s manufacturer.
The patients were 4 months and 28 months of age and lived in Russia and Kazakhstan. They died 5-6 weeks after infusion with Zolgensma and approximately 1-10 days after the initiation of a corticosteroid taper.
These are the first known fatal cases of acute liver failure associated with the drug, which the company notes was a known side effect included in the product label and in a boxed warning in the United States.
“Following two recent patient fatalities, and in alignment with health authorities, we will be updating the labeling to specify that fatal acute liver failure has been reported,” the statement reads.
“While this is important safety information, it is not a new safety signal,” it adds.
Rare genetic disorder
SMA is a rare genetic disorder that affects about 1 in 10,000 newborns. Patients with SMA lack a working copy of the survival motor neuron 1 (SMN1) gene, which encodes a protein called SMN that is critical for the maintenance and function of motor neurons.
Without this protein, motor neurons eventually die, causing debilitating and progressive muscle weakness that affects the ability to walk, eat, and breathe.
Zolgensma, a one-time gene replacement therapy delivered via intravenous infusion, replaces the function of the missing or nonworking SMN1 gene with a new, working copy of the SMN1 gene.
The first gene therapy treatment for SMA, it was approved by the U.S. Food and Drug Administration in 2019 for patients with SMA up to 2 years of age. It is also the most expensive drug in the world, costing about $2.1 million for a one-time treatment.
“We have notified health authorities in all markets where Zolgensma is used, including FDA, and are communicating to relevant healthcare professionals as an additional step in markets where this action is supported by health authorities,” the manufacturer’s statement says.
Studies have suggested that the treatment›s effects persist more than 5 years after infusion.
Clinical trials currently underway by Novartis are studying the drug’s long-term efficacy and safety and its potential use in older patients.
The company is also leading the phase 3 clinical trial STEER to test intrathecal (IT) administration of the drug in patients ages 2-18 years who have type 2 SMA.
That trial began late last year after the FDA lifted a 2-year partial hold on an earlier study. The FDA halted the STRONG trial in 2019, citing concerns from animal studies that IT administration may result in dorsal root ganglia injury. The partial hold was released last fall following positive study results in nonhuman primates.
None of the current trials will be affected by the two deaths reported this week, according to a Novartis spokesperson.
A version of this article first appeared on Medscape.com.
, according to a statement issued by the drug›s manufacturer.
The patients were 4 months and 28 months of age and lived in Russia and Kazakhstan. They died 5-6 weeks after infusion with Zolgensma and approximately 1-10 days after the initiation of a corticosteroid taper.
These are the first known fatal cases of acute liver failure associated with the drug, which the company notes was a known side effect included in the product label and in a boxed warning in the United States.
“Following two recent patient fatalities, and in alignment with health authorities, we will be updating the labeling to specify that fatal acute liver failure has been reported,” the statement reads.
“While this is important safety information, it is not a new safety signal,” it adds.
Rare genetic disorder
SMA is a rare genetic disorder that affects about 1 in 10,000 newborns. Patients with SMA lack a working copy of the survival motor neuron 1 (SMN1) gene, which encodes a protein called SMN that is critical for the maintenance and function of motor neurons.
Without this protein, motor neurons eventually die, causing debilitating and progressive muscle weakness that affects the ability to walk, eat, and breathe.
Zolgensma, a one-time gene replacement therapy delivered via intravenous infusion, replaces the function of the missing or nonworking SMN1 gene with a new, working copy of the SMN1 gene.
The first gene therapy treatment for SMA, it was approved by the U.S. Food and Drug Administration in 2019 for patients with SMA up to 2 years of age. It is also the most expensive drug in the world, costing about $2.1 million for a one-time treatment.
“We have notified health authorities in all markets where Zolgensma is used, including FDA, and are communicating to relevant healthcare professionals as an additional step in markets where this action is supported by health authorities,” the manufacturer’s statement says.
Studies have suggested that the treatment›s effects persist more than 5 years after infusion.
Clinical trials currently underway by Novartis are studying the drug’s long-term efficacy and safety and its potential use in older patients.
The company is also leading the phase 3 clinical trial STEER to test intrathecal (IT) administration of the drug in patients ages 2-18 years who have type 2 SMA.
That trial began late last year after the FDA lifted a 2-year partial hold on an earlier study. The FDA halted the STRONG trial in 2019, citing concerns from animal studies that IT administration may result in dorsal root ganglia injury. The partial hold was released last fall following positive study results in nonhuman primates.
None of the current trials will be affected by the two deaths reported this week, according to a Novartis spokesperson.
A version of this article first appeared on Medscape.com.
, according to a statement issued by the drug›s manufacturer.
The patients were 4 months and 28 months of age and lived in Russia and Kazakhstan. They died 5-6 weeks after infusion with Zolgensma and approximately 1-10 days after the initiation of a corticosteroid taper.
These are the first known fatal cases of acute liver failure associated with the drug, which the company notes was a known side effect included in the product label and in a boxed warning in the United States.
“Following two recent patient fatalities, and in alignment with health authorities, we will be updating the labeling to specify that fatal acute liver failure has been reported,” the statement reads.
“While this is important safety information, it is not a new safety signal,” it adds.
Rare genetic disorder
SMA is a rare genetic disorder that affects about 1 in 10,000 newborns. Patients with SMA lack a working copy of the survival motor neuron 1 (SMN1) gene, which encodes a protein called SMN that is critical for the maintenance and function of motor neurons.
Without this protein, motor neurons eventually die, causing debilitating and progressive muscle weakness that affects the ability to walk, eat, and breathe.
Zolgensma, a one-time gene replacement therapy delivered via intravenous infusion, replaces the function of the missing or nonworking SMN1 gene with a new, working copy of the SMN1 gene.
The first gene therapy treatment for SMA, it was approved by the U.S. Food and Drug Administration in 2019 for patients with SMA up to 2 years of age. It is also the most expensive drug in the world, costing about $2.1 million for a one-time treatment.
“We have notified health authorities in all markets where Zolgensma is used, including FDA, and are communicating to relevant healthcare professionals as an additional step in markets where this action is supported by health authorities,” the manufacturer’s statement says.
Studies have suggested that the treatment›s effects persist more than 5 years after infusion.
Clinical trials currently underway by Novartis are studying the drug’s long-term efficacy and safety and its potential use in older patients.
The company is also leading the phase 3 clinical trial STEER to test intrathecal (IT) administration of the drug in patients ages 2-18 years who have type 2 SMA.
That trial began late last year after the FDA lifted a 2-year partial hold on an earlier study. The FDA halted the STRONG trial in 2019, citing concerns from animal studies that IT administration may result in dorsal root ganglia injury. The partial hold was released last fall following positive study results in nonhuman primates.
None of the current trials will be affected by the two deaths reported this week, according to a Novartis spokesperson.
A version of this article first appeared on Medscape.com.
Mixed results for intensive home care for psychiatric crises
Intensive home treatment may offer an alternative to inpatient care for patients in acute psychiatric crisis – but the intervention is no outright substitute, new research suggests.
However, there was no difference between treatment groups in improvement in quality of life or patient satisfaction; and a reduction in symptom severity noted after 6 weeks of home treatment faded within 6 months.
“We found no differences in admission rates either, which suggests that intensive home treatment is not a substitute for inpatient care but a different treatment opportunity for psychiatric patients in crisis,” Jurgen Cornelis, MD, Arkin Institute for Mental Health, Amsterdam, and colleagues write.
The findings were published online in The Lancet Psychiatry.
Increasingly popular
“Intensive home treatment is increasingly popular as an alternative to hospitalization. It was developed to prevent or reduce levels of inpatient care and facilitate the transition between inpatient care and low-intensity outpatient care,” the investigators write.
However, there have previously been only two randomized controlled trials published that assessed this type of care, resulting in “somewhat conflicting findings,” they add.
For the current study, participants presented to psychiatric emergency wards at two medical centers in the Netherlands. They were included only if they were able to offer informed consent within 14 days.
The intensive home treatment group (n = 183) worked with a multidisciplinary team that designed a care plan tailored to their specific crisis. Treatment components included pharmacotherapy, up to three home visits each day, psychoeducation, brief supportive and cognitive behavioral therapy, social care, and support and empowerment of the patient’s informal care system.
The usual care group (n = 63) commonly received a combination of highly intensive inpatient treatment in the first phase and outpatient treatment up to two times a week in the second phase. Treatment included similar components as those in intensive home treatment.
The most common primary clinical diagnosis in both groups was mood disorder, followed by psychotic disorders, personality disorders, or anxiety disorders.
The home treatment group had a significantly higher total mean item score on the Brief Psychiatric Rating Scale (BPRS) at baseline (2.23 vs. 2.04, P = .04).
Mixed results
Results at 6 weeks showed the number of hospital days was 25.3% lower in the home treatment group, compared with those who received usual care.
That trend continued at 1 year, with the intensive home treatment group recording 36.6% fewer hospital days than the usual care group (mean, 42.5 days vs. 67 days, respectively; P = .03).
However, the number of patients who were admitted in the first 6 weeks and at 1 year stayed the same, as did the mean number of admissions per patient over 12 months.
The home treatment group reported significantly fewer symptoms on the BPRS depression and anxiety scale at 6 weeks, compared with the usual treatment group (P = .025), but that difference was not maintained after 6 months.
The number of adverse events, including suicide attempts, was similar between the groups. Three patients in the home treatment group and two in the usual care group died by suicide.
“Future research should focus on which components of intensive home treatment or hospitalization can be used when, for whom, and meet which goals, so that both hospital care and intensive home treatment can be used proportionally and efficiently for patients in psychiatric crisis,” the investigators write.
Not generalizable?
In an accompanying editorial, Claire Henderson, PhD, Institute of Psychiatry, Psychology, and Neuroscience at King’s College London, noted that generalizing the study’s results to other countries could be problematic, especially to regions such as North America, which have shorter lengths of stay for psychiatric hospitalization.
“Future trials looking at intensive home treatment would be most informative if done in countries with relatively short lengths of stay, and without separate crisis services for people receiving assertive community treatment,” Dr. Henderson writes.
The study was funded by De Stichting tot Steun Vereniging voor Christelijke Verzorging van Geestes-en Zenuwzieken. The investigators and Dr. Henderson have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Intensive home treatment may offer an alternative to inpatient care for patients in acute psychiatric crisis – but the intervention is no outright substitute, new research suggests.
However, there was no difference between treatment groups in improvement in quality of life or patient satisfaction; and a reduction in symptom severity noted after 6 weeks of home treatment faded within 6 months.
“We found no differences in admission rates either, which suggests that intensive home treatment is not a substitute for inpatient care but a different treatment opportunity for psychiatric patients in crisis,” Jurgen Cornelis, MD, Arkin Institute for Mental Health, Amsterdam, and colleagues write.
The findings were published online in The Lancet Psychiatry.
Increasingly popular
“Intensive home treatment is increasingly popular as an alternative to hospitalization. It was developed to prevent or reduce levels of inpatient care and facilitate the transition between inpatient care and low-intensity outpatient care,” the investigators write.
However, there have previously been only two randomized controlled trials published that assessed this type of care, resulting in “somewhat conflicting findings,” they add.
For the current study, participants presented to psychiatric emergency wards at two medical centers in the Netherlands. They were included only if they were able to offer informed consent within 14 days.
The intensive home treatment group (n = 183) worked with a multidisciplinary team that designed a care plan tailored to their specific crisis. Treatment components included pharmacotherapy, up to three home visits each day, psychoeducation, brief supportive and cognitive behavioral therapy, social care, and support and empowerment of the patient’s informal care system.
The usual care group (n = 63) commonly received a combination of highly intensive inpatient treatment in the first phase and outpatient treatment up to two times a week in the second phase. Treatment included similar components as those in intensive home treatment.
The most common primary clinical diagnosis in both groups was mood disorder, followed by psychotic disorders, personality disorders, or anxiety disorders.
The home treatment group had a significantly higher total mean item score on the Brief Psychiatric Rating Scale (BPRS) at baseline (2.23 vs. 2.04, P = .04).
Mixed results
Results at 6 weeks showed the number of hospital days was 25.3% lower in the home treatment group, compared with those who received usual care.
That trend continued at 1 year, with the intensive home treatment group recording 36.6% fewer hospital days than the usual care group (mean, 42.5 days vs. 67 days, respectively; P = .03).
However, the number of patients who were admitted in the first 6 weeks and at 1 year stayed the same, as did the mean number of admissions per patient over 12 months.
The home treatment group reported significantly fewer symptoms on the BPRS depression and anxiety scale at 6 weeks, compared with the usual treatment group (P = .025), but that difference was not maintained after 6 months.
The number of adverse events, including suicide attempts, was similar between the groups. Three patients in the home treatment group and two in the usual care group died by suicide.
“Future research should focus on which components of intensive home treatment or hospitalization can be used when, for whom, and meet which goals, so that both hospital care and intensive home treatment can be used proportionally and efficiently for patients in psychiatric crisis,” the investigators write.
Not generalizable?
In an accompanying editorial, Claire Henderson, PhD, Institute of Psychiatry, Psychology, and Neuroscience at King’s College London, noted that generalizing the study’s results to other countries could be problematic, especially to regions such as North America, which have shorter lengths of stay for psychiatric hospitalization.
“Future trials looking at intensive home treatment would be most informative if done in countries with relatively short lengths of stay, and without separate crisis services for people receiving assertive community treatment,” Dr. Henderson writes.
The study was funded by De Stichting tot Steun Vereniging voor Christelijke Verzorging van Geestes-en Zenuwzieken. The investigators and Dr. Henderson have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Intensive home treatment may offer an alternative to inpatient care for patients in acute psychiatric crisis – but the intervention is no outright substitute, new research suggests.
However, there was no difference between treatment groups in improvement in quality of life or patient satisfaction; and a reduction in symptom severity noted after 6 weeks of home treatment faded within 6 months.
“We found no differences in admission rates either, which suggests that intensive home treatment is not a substitute for inpatient care but a different treatment opportunity for psychiatric patients in crisis,” Jurgen Cornelis, MD, Arkin Institute for Mental Health, Amsterdam, and colleagues write.
The findings were published online in The Lancet Psychiatry.
Increasingly popular
“Intensive home treatment is increasingly popular as an alternative to hospitalization. It was developed to prevent or reduce levels of inpatient care and facilitate the transition between inpatient care and low-intensity outpatient care,” the investigators write.
However, there have previously been only two randomized controlled trials published that assessed this type of care, resulting in “somewhat conflicting findings,” they add.
For the current study, participants presented to psychiatric emergency wards at two medical centers in the Netherlands. They were included only if they were able to offer informed consent within 14 days.
The intensive home treatment group (n = 183) worked with a multidisciplinary team that designed a care plan tailored to their specific crisis. Treatment components included pharmacotherapy, up to three home visits each day, psychoeducation, brief supportive and cognitive behavioral therapy, social care, and support and empowerment of the patient’s informal care system.
The usual care group (n = 63) commonly received a combination of highly intensive inpatient treatment in the first phase and outpatient treatment up to two times a week in the second phase. Treatment included similar components as those in intensive home treatment.
The most common primary clinical diagnosis in both groups was mood disorder, followed by psychotic disorders, personality disorders, or anxiety disorders.
The home treatment group had a significantly higher total mean item score on the Brief Psychiatric Rating Scale (BPRS) at baseline (2.23 vs. 2.04, P = .04).
Mixed results
Results at 6 weeks showed the number of hospital days was 25.3% lower in the home treatment group, compared with those who received usual care.
That trend continued at 1 year, with the intensive home treatment group recording 36.6% fewer hospital days than the usual care group (mean, 42.5 days vs. 67 days, respectively; P = .03).
However, the number of patients who were admitted in the first 6 weeks and at 1 year stayed the same, as did the mean number of admissions per patient over 12 months.
The home treatment group reported significantly fewer symptoms on the BPRS depression and anxiety scale at 6 weeks, compared with the usual treatment group (P = .025), but that difference was not maintained after 6 months.
The number of adverse events, including suicide attempts, was similar between the groups. Three patients in the home treatment group and two in the usual care group died by suicide.
“Future research should focus on which components of intensive home treatment or hospitalization can be used when, for whom, and meet which goals, so that both hospital care and intensive home treatment can be used proportionally and efficiently for patients in psychiatric crisis,” the investigators write.
Not generalizable?
In an accompanying editorial, Claire Henderson, PhD, Institute of Psychiatry, Psychology, and Neuroscience at King’s College London, noted that generalizing the study’s results to other countries could be problematic, especially to regions such as North America, which have shorter lengths of stay for psychiatric hospitalization.
“Future trials looking at intensive home treatment would be most informative if done in countries with relatively short lengths of stay, and without separate crisis services for people receiving assertive community treatment,” Dr. Henderson writes.
The study was funded by De Stichting tot Steun Vereniging voor Christelijke Verzorging van Geestes-en Zenuwzieken. The investigators and Dr. Henderson have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM THE LANCET PSYCHIATRY