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It took 160 years but, in February 2023, the Food and Drug Administration approved the first drug specifically designed to treat the rare neuromuscular disease Friedreich ataxia (FA). The disease, first described in 1863 by German physician Nikolaus Friedreich, has an estimated incidence of 1 in 50,000 worldwide. It is the most common form of hereditary ataxia, accounting for approximately 50% of all cases of ataxia and approximately 75% of cases among patients younger than 25 years in the United States.1
FA typically presents in childhood or early adolescence; in some patients, symptoms manifest in the middle of the third decade of life. Patients exhibit symptoms such as ataxia that becomes worse over time, gait ataxia, impaired sensation in the extremities that can spread centrally, loss of normal reflexes, especially in the knees, speech disorders (dysarthria), muscle spasticity, scoliosis, and dysphagia.
Severity of disease ranges from relatively mild to completely disabling. Symptoms are progressive; patients almost inevitably require ambulatory support or a wheelchair. They might develop diabetes mellitus and can lose hearing and vision as the disease progresses. Hypertrophic cardiomyopathy is the most common cause of death among FA patients. Some patients who have less severe features might live into their 60s – even beyond that age.2There is no cure for FA. Until recently, no therapy was available other than supportive care to address associated neuromuscular, cardiovascular, and metabolic complications.
Making the diagnosis
Genetic testing can provide a definitive diagnosis of FA. (The genetic etiology of the disease is described later in this article.)
In addition to genetic screening, the workup includes a thorough medical history and physical examination that focuses on problems with balance, proprioception, absence of reflexes, and neurological signs. Tests include electromyography, nerve-conduction studies, electrocardiography, a metabolic profile, and MRI of the brain and spinal cord.
MRI utility in FA. In a paper published in July 2023 in Brain Communications, investigators from the University of Minnesota, Minneapolis, reported that various MRI techniques can be combined to detect early-stage alterations and disease progression in patients with FA.3 The researchers compared images taken at baseline and at 1, 2, and 3 years in 28 FA patients and 20 age- and gender-matched controls.
They observed that, compared with controls, patients with FA had lower cerebellar white matter volume but not lower cerebellar gray matter volume; larger cerebellar peduncle, thalamus, and brain stem structures; and a higher volume of the fourth ventricle. Using diffusion-tensor imaging and fixel-based analysis of diffusion MRI metrics, they also detected microstructural differences in several brain regions – especially in the cerebellum and corticospinal tract.
“Over time, many of these macrostructural and microstructural alterations progressed, especially cerebellar gray- and white-matter volume and microstructures of the superior cerebellar peduncle, the posterior limb of the internal capsule, and the superior corona radiata,” the investigators reported. In addition, “linear regressions showed significant associations between many of those imaging metrics and clinical scales.”
Pathophysiological basis of FA
The underlying genetic pathology of FA was first described in 1996 by investigators from the University of Valencia (Spain). They reported that FA is caused by a mutation in FXN (formerly X25), a gene that encodes for the protein frataxin, which is important for producing mitochondrial adenosine triphosphate and managing iron stores.4
The mutation results in multiple guanine-adenine-adenine repeats in FXN, or, in a few cases, a point mutation or deletion in 1 allele of FXN, with multiple GAA repeats in the other allele. A hallmark of FA is impairment of cellular antioxidative defense mechanisms – a major cause of disease progression.
The GAA repeat leads to methylation of the promoter region of FXN. This results in production and accumulation in cells of an abnormal, ineffective form of frataxin and oxidative damage to cells, particularly those that require larger amounts of energy, such as cells in the brain, heart, and pancreas.
“You would expect that the cells would be revving up all of their endogenous defenses,” David Lynch, MD, PhD, director of the Friedreich ataxia program at Children’s Hospital of Philadelphia, explained in an interview. “These oxidative damage responses are controlled by a DNA response element called the antioxidant response element, and it’s activated by the transcription factor Nrf2 [nuclear factor erythroid 2–related factor 2].”
Treatment options have been limited
Omaveloxolone. Dr. Lynch is principal investigator for the MOXIe trial of the safety, pharmacodynamics, and efficacy of omaveloxolone (marketed as Skyclarys [Reata Pharmaceuticals]),5 which received FDA orphan drug, fast track, priority review, and rare pediatric disease designations for the treatment of FA and, in February 2023, formal FDA approval.6 Development of this drug, which activates Nrf2 and induces antioxidant target genes, arose from basic science investigation into mechanisms by which cells respond to stresses.
“Omaveloxolone works on the Nrf2 pathway, which is, paradoxically, deficient in FA,” Dr. Lynch said. “This pathway should be active all the time. You would expect that, in cells from Friedreich ataxia in a person or an animal model of the disease, you’d see that Nrf2 would be very active but, in fact, what you find is the opposite,” Dr. Lynch explained. “It’s relatively inefficient, it’s localized in the cell, and the antioxidant response element genes – the things we all use to protect ourselves from mitochondrial damage – are all relatively turned off.”
In the first phase of MOXIe, 103 patients with FA were randomly assigned to receive either omaveloxolone, 15 mg orally (51 patients), or placebo (52 patients) for 48 weeks.
The primary endpoint was change in the modified Friedreich’s Ataxia Rating Scale (mFARS) score at 48 weeks. The scale is a clinically validated neurological instrument that evaluates upper- and lower-limb coordination, upright stability, and bulbar function.
Patients assigned to placebo had worsening of function at 48 weeks (mean increase in mFARS score, 0.85). In contrast, patients assigned to omaveloxolone had a mean decrease in the mFARS score of –1.56, indicating improvement. The between-group difference of –2.41 points was statistically significant in favor of omaveloxolone (P = .038).
In a 3-year, post hoc, propensity-matched analysis, patients assigned to omaveloxolone had lower mFARS scores than a matched set of untreated patients in a study of the natural history of FA.7Dimethyl fumarate (marketed as Tecfidera [Biogen]), approved in the United States and other countries for the treatment of patients with relapsing forms of multiple sclerosis, also has Nrf2 as a therapeutic target, although its precise mechanism of action is unclear. Clinical trials of this agent for the treatment of FA are under consideration in Europe, Dr. Lynch said.
Apart from these agents, treatment of patients with FA largely centers on management of metabolic and cardiac complications; physical and occupational therapy; devices such as orthopedic shoes, canes, and wheelchairs; and, when indicated, surgery to correct skeletal problems or for implantation of a cardiac-assist device.
The FA therapeutic pipeline
According to the Friedreich’s Ataxia Research Alliance, other approaches to improving mitochondrial function and reducing oxidative stress in FA are under investigation or awaiting approval, including elamipretide, for which FDA approval is pending for Barth syndrome (a rare, X-linked disorder) and for primary mitochondrial myopathy; nicotinamide adenine dinucleotide (NAD+, a coenzyme for redox reactions) plus exercise; and MIB-626, a crystalline form of nicotinamide mononucleotide, a precursor of NAD+.
Vatiquinone, an investigational inhibitor of 15-lipoxygenase, a regulator of energetic and oxidative stress pathways, failed to meet its primary endpoint of significant improvement on the mFARS score at 72 weeks of follow-up in the MOVE-FA trial, according to the manufacturer, PTC Therapeutics.8Another therapeutic approach under investigation is modulation of frataxin-controlled metabolic pathways with leriglitazone, an orally available selective peroxisome proliferator-activated receptor gamma agonist,9 or with the prodrug precursor of monomethyl fumarate plus dimethyl fumarate.
CTI-1601, a recombinant fusion protein intended to deliver human frataxin into the mitochondria of patients with FA, is in phase 1 trials. This compound has been granted rare pediatric disease designation, fast track designation, and orphan drug status by the FDA, according to the manufacturer, Larimar Therapeutics.10Etravirine, a nonnucleoside reverse transcriptase inhibitor approved for treating HIV infection, has been demonstrated to increase the frataxin protein in cells derived from FA patients and in the heart and skeletal muscle of frataxin-deficient YG8 mice. This agent recently completed a phase 2 trial in patients with FA.11
Gene therapy: Promising
Given the genetic etiology of FA, gene therapy strategies aimed at either increasing FA gene expression or editing the genome to replace defective FXN are under active investigation.
Increasing FA gene expression. DT-216 (Design Therapeutics) is a novel, gene-targeted chimera small molecule designed to target the GAA repeat expansion mutation and restore FXN expression. This agent completed phase 1 dosing studies in 2022.
Oligonucleotides, which are nucleic acid polymers primarily used for gene silencing, are also being explored for increasing the expression of FXN, in research at the University of Texas Southwestern Medical Center, Dallas, and the University of Massachusetts, Worcester.
Gene replacement strategies under investigation to treat FA include LX2006 (Lexeo Therapeutics), a gene replacement therapy using an adeno-associated viral vector to deliver FXN intravenously, with the goal of getting the gene into myocardial cells and increasing the frataxin level in mitochondria.
A similar approach is being taken by Ronald G. Crystal, MD, and colleagues at Weill Cornell Medicine, New York. The group is designing phase 1 studies of AAVrh.10hFXN, a serotype rh.10 adeno-associated virus coding for human frataxin, with the goal of treating cardiac manifestations of FA.12FA researcher Arnulf H. Koeppen, MD, from the Samuel S. Stratton Department of Veterans Affairs Medical Center, Albany, N.Y., and Albany Medical College, said in an interview that gene replacement therapy in FA is focused on the heart “because there is no blood-heart barrier, but there is a blood-brain barrier that makes it more complicated for gene therapy to reach the brain.”
Future directions
Dr. Koeppen, Dr. Lynch, and colleagues Ian H. Harding, PhD, from Monash University, Melbourne, and Massimo Pandolfo, MD, McGill University, Montreal, conducted an extensive review of FA with a focus on challenges that researchers and drug developers face crafting therapies for this complex disorder.13
They noted that FA is “characterized by marked differences in the vulnerability of neuronal systems. In general, the proprioceptive system appears to be affected early, while later in the disease, the dentate nucleus of the cerebellum and, to some degree, the corticospinal tracts degenerate.”
The authors took a deep dive into the evidence, old and new, to evaluate the effects of FA on the central and peripheral nervous systems and to look at the course of neuropathologic changes associated with the disease. They propose a comprehensive approach to identify nervous system locations that are likely to be most successfully targeted at different disease time points.
“The proprioceptive system, usually considered a major target for frataxin-restoring treatments, shows substantial evidence of hypoplasia and/or early developmental loss, with minimal evidence of progression over time,” they wrote. “It seems likely that this system is not an ideal target for therapies given after early childhood. Targeting the [dentate nucleus] of the cerebellum is likely to be most effective early in the course of the disease, when it is functionally affected, but still shows limited atrophy. The corticospinal tract degenerates over time contributing to disease progression throughout its late stages and may be considered a target.”
David Lynch, MD, PhD, and Arnulf Koeppen, MD, disclose support from the Friedreich’s Ataxia Research Alliance. Dr. Lynch also discloses support from the National Institutes of Health, U.S. Food and Drug Administration, Muscular Dystrophy Association, Reata Pharmaceuticals, and Retrotope.
References
1. Williams CT and De Jesus O. Friedreich ataxia. StatPearls. 2023 Jun 27. https://www.ncbi.nlm.nih.gov/books/NBK563199/.
2. National Institute of Neurological Disorders and Stroke. Friedreich ataxia. 2023 Sep 2. https://www.ninds.nih.gov/health-information/disorders/friedreich-ataxia.
3. Adanyeguh IM et al. Brain Commun. 2023;5(4):fcad196. doi: 10.1093/braincomms/fcad196.
4. Camapuzano V et al. Science. 1996;271(5254):1423-7. doi: 10.1126/science.271.5254.1423.
5. RTA 408 capsules in patients with Friedreich’s ataxia–MOXIe. ClinicalTrials. gov Identifier: NCT02255435. 2022 Dec 6. https://clinicaltrials.gov/study/NCT02255435.
6. Food and Drug Administration. FDA approves first treatment for Friedreich’s ataxia. 2023 Feb 28. www.fda.gov/drugs/news-events-human-drugs/fda-approves-first-treatment-friedreichs-ataxia#.
7. Lynch DR et al. Ann Clin Transl Neurol. 2023 Sep 10. doi: 10.1002/acn3.51897
8. PTC Therapeutics. PTC Therapeutics announces topline results from vatiquinone MOVE-FA registration-directed trial. 2023 May 23. https://ir.ptcbio.com/news-releases/news-release-details/ptc-therapeutics-announces-topline-results-vatiquinone-move-fa.
9. Minoryx Therapeutics. The FRAMES Clinical Study in FRDA. https://www.minoryx.com/clinical-studies/clinical-study-frames/.
10. Larimar Therapeutics. CTI-1601 for Friedreich’s ataxia. https://larimartx.com/our-programs/cti-1601/.
11. Safety and efficacy of etravirine in Friedreich ataxia patients (FAEST1). ClinicalTrials.gov Identifier: NCT04273165. 2023 Mar 20. https://clinicaltrials.gov/study/NCT04273165.
12. Phase IA study of AAVrh.10hFXN gene therapy for the cardiomyopathy of Friedreich’s ataxia. ClinicalTrials.gov Identifier: NCT05302271. https://clinicaltrials.gov/study/NCT05302271.
13. Harding IH et al. Hum Gene Ther. 2020;31(23-24):1226-36. doi: 10.1089/hum.2020.264
It took 160 years but, in February 2023, the Food and Drug Administration approved the first drug specifically designed to treat the rare neuromuscular disease Friedreich ataxia (FA). The disease, first described in 1863 by German physician Nikolaus Friedreich, has an estimated incidence of 1 in 50,000 worldwide. It is the most common form of hereditary ataxia, accounting for approximately 50% of all cases of ataxia and approximately 75% of cases among patients younger than 25 years in the United States.1
FA typically presents in childhood or early adolescence; in some patients, symptoms manifest in the middle of the third decade of life. Patients exhibit symptoms such as ataxia that becomes worse over time, gait ataxia, impaired sensation in the extremities that can spread centrally, loss of normal reflexes, especially in the knees, speech disorders (dysarthria), muscle spasticity, scoliosis, and dysphagia.
Severity of disease ranges from relatively mild to completely disabling. Symptoms are progressive; patients almost inevitably require ambulatory support or a wheelchair. They might develop diabetes mellitus and can lose hearing and vision as the disease progresses. Hypertrophic cardiomyopathy is the most common cause of death among FA patients. Some patients who have less severe features might live into their 60s – even beyond that age.2There is no cure for FA. Until recently, no therapy was available other than supportive care to address associated neuromuscular, cardiovascular, and metabolic complications.
Making the diagnosis
Genetic testing can provide a definitive diagnosis of FA. (The genetic etiology of the disease is described later in this article.)
In addition to genetic screening, the workup includes a thorough medical history and physical examination that focuses on problems with balance, proprioception, absence of reflexes, and neurological signs. Tests include electromyography, nerve-conduction studies, electrocardiography, a metabolic profile, and MRI of the brain and spinal cord.
MRI utility in FA. In a paper published in July 2023 in Brain Communications, investigators from the University of Minnesota, Minneapolis, reported that various MRI techniques can be combined to detect early-stage alterations and disease progression in patients with FA.3 The researchers compared images taken at baseline and at 1, 2, and 3 years in 28 FA patients and 20 age- and gender-matched controls.
They observed that, compared with controls, patients with FA had lower cerebellar white matter volume but not lower cerebellar gray matter volume; larger cerebellar peduncle, thalamus, and brain stem structures; and a higher volume of the fourth ventricle. Using diffusion-tensor imaging and fixel-based analysis of diffusion MRI metrics, they also detected microstructural differences in several brain regions – especially in the cerebellum and corticospinal tract.
“Over time, many of these macrostructural and microstructural alterations progressed, especially cerebellar gray- and white-matter volume and microstructures of the superior cerebellar peduncle, the posterior limb of the internal capsule, and the superior corona radiata,” the investigators reported. In addition, “linear regressions showed significant associations between many of those imaging metrics and clinical scales.”
Pathophysiological basis of FA
The underlying genetic pathology of FA was first described in 1996 by investigators from the University of Valencia (Spain). They reported that FA is caused by a mutation in FXN (formerly X25), a gene that encodes for the protein frataxin, which is important for producing mitochondrial adenosine triphosphate and managing iron stores.4
The mutation results in multiple guanine-adenine-adenine repeats in FXN, or, in a few cases, a point mutation or deletion in 1 allele of FXN, with multiple GAA repeats in the other allele. A hallmark of FA is impairment of cellular antioxidative defense mechanisms – a major cause of disease progression.
The GAA repeat leads to methylation of the promoter region of FXN. This results in production and accumulation in cells of an abnormal, ineffective form of frataxin and oxidative damage to cells, particularly those that require larger amounts of energy, such as cells in the brain, heart, and pancreas.
“You would expect that the cells would be revving up all of their endogenous defenses,” David Lynch, MD, PhD, director of the Friedreich ataxia program at Children’s Hospital of Philadelphia, explained in an interview. “These oxidative damage responses are controlled by a DNA response element called the antioxidant response element, and it’s activated by the transcription factor Nrf2 [nuclear factor erythroid 2–related factor 2].”
Treatment options have been limited
Omaveloxolone. Dr. Lynch is principal investigator for the MOXIe trial of the safety, pharmacodynamics, and efficacy of omaveloxolone (marketed as Skyclarys [Reata Pharmaceuticals]),5 which received FDA orphan drug, fast track, priority review, and rare pediatric disease designations for the treatment of FA and, in February 2023, formal FDA approval.6 Development of this drug, which activates Nrf2 and induces antioxidant target genes, arose from basic science investigation into mechanisms by which cells respond to stresses.
“Omaveloxolone works on the Nrf2 pathway, which is, paradoxically, deficient in FA,” Dr. Lynch said. “This pathway should be active all the time. You would expect that, in cells from Friedreich ataxia in a person or an animal model of the disease, you’d see that Nrf2 would be very active but, in fact, what you find is the opposite,” Dr. Lynch explained. “It’s relatively inefficient, it’s localized in the cell, and the antioxidant response element genes – the things we all use to protect ourselves from mitochondrial damage – are all relatively turned off.”
In the first phase of MOXIe, 103 patients with FA were randomly assigned to receive either omaveloxolone, 15 mg orally (51 patients), or placebo (52 patients) for 48 weeks.
The primary endpoint was change in the modified Friedreich’s Ataxia Rating Scale (mFARS) score at 48 weeks. The scale is a clinically validated neurological instrument that evaluates upper- and lower-limb coordination, upright stability, and bulbar function.
Patients assigned to placebo had worsening of function at 48 weeks (mean increase in mFARS score, 0.85). In contrast, patients assigned to omaveloxolone had a mean decrease in the mFARS score of –1.56, indicating improvement. The between-group difference of –2.41 points was statistically significant in favor of omaveloxolone (P = .038).
In a 3-year, post hoc, propensity-matched analysis, patients assigned to omaveloxolone had lower mFARS scores than a matched set of untreated patients in a study of the natural history of FA.7Dimethyl fumarate (marketed as Tecfidera [Biogen]), approved in the United States and other countries for the treatment of patients with relapsing forms of multiple sclerosis, also has Nrf2 as a therapeutic target, although its precise mechanism of action is unclear. Clinical trials of this agent for the treatment of FA are under consideration in Europe, Dr. Lynch said.
Apart from these agents, treatment of patients with FA largely centers on management of metabolic and cardiac complications; physical and occupational therapy; devices such as orthopedic shoes, canes, and wheelchairs; and, when indicated, surgery to correct skeletal problems or for implantation of a cardiac-assist device.
The FA therapeutic pipeline
According to the Friedreich’s Ataxia Research Alliance, other approaches to improving mitochondrial function and reducing oxidative stress in FA are under investigation or awaiting approval, including elamipretide, for which FDA approval is pending for Barth syndrome (a rare, X-linked disorder) and for primary mitochondrial myopathy; nicotinamide adenine dinucleotide (NAD+, a coenzyme for redox reactions) plus exercise; and MIB-626, a crystalline form of nicotinamide mononucleotide, a precursor of NAD+.
Vatiquinone, an investigational inhibitor of 15-lipoxygenase, a regulator of energetic and oxidative stress pathways, failed to meet its primary endpoint of significant improvement on the mFARS score at 72 weeks of follow-up in the MOVE-FA trial, according to the manufacturer, PTC Therapeutics.8Another therapeutic approach under investigation is modulation of frataxin-controlled metabolic pathways with leriglitazone, an orally available selective peroxisome proliferator-activated receptor gamma agonist,9 or with the prodrug precursor of monomethyl fumarate plus dimethyl fumarate.
CTI-1601, a recombinant fusion protein intended to deliver human frataxin into the mitochondria of patients with FA, is in phase 1 trials. This compound has been granted rare pediatric disease designation, fast track designation, and orphan drug status by the FDA, according to the manufacturer, Larimar Therapeutics.10Etravirine, a nonnucleoside reverse transcriptase inhibitor approved for treating HIV infection, has been demonstrated to increase the frataxin protein in cells derived from FA patients and in the heart and skeletal muscle of frataxin-deficient YG8 mice. This agent recently completed a phase 2 trial in patients with FA.11
Gene therapy: Promising
Given the genetic etiology of FA, gene therapy strategies aimed at either increasing FA gene expression or editing the genome to replace defective FXN are under active investigation.
Increasing FA gene expression. DT-216 (Design Therapeutics) is a novel, gene-targeted chimera small molecule designed to target the GAA repeat expansion mutation and restore FXN expression. This agent completed phase 1 dosing studies in 2022.
Oligonucleotides, which are nucleic acid polymers primarily used for gene silencing, are also being explored for increasing the expression of FXN, in research at the University of Texas Southwestern Medical Center, Dallas, and the University of Massachusetts, Worcester.
Gene replacement strategies under investigation to treat FA include LX2006 (Lexeo Therapeutics), a gene replacement therapy using an adeno-associated viral vector to deliver FXN intravenously, with the goal of getting the gene into myocardial cells and increasing the frataxin level in mitochondria.
A similar approach is being taken by Ronald G. Crystal, MD, and colleagues at Weill Cornell Medicine, New York. The group is designing phase 1 studies of AAVrh.10hFXN, a serotype rh.10 adeno-associated virus coding for human frataxin, with the goal of treating cardiac manifestations of FA.12FA researcher Arnulf H. Koeppen, MD, from the Samuel S. Stratton Department of Veterans Affairs Medical Center, Albany, N.Y., and Albany Medical College, said in an interview that gene replacement therapy in FA is focused on the heart “because there is no blood-heart barrier, but there is a blood-brain barrier that makes it more complicated for gene therapy to reach the brain.”
Future directions
Dr. Koeppen, Dr. Lynch, and colleagues Ian H. Harding, PhD, from Monash University, Melbourne, and Massimo Pandolfo, MD, McGill University, Montreal, conducted an extensive review of FA with a focus on challenges that researchers and drug developers face crafting therapies for this complex disorder.13
They noted that FA is “characterized by marked differences in the vulnerability of neuronal systems. In general, the proprioceptive system appears to be affected early, while later in the disease, the dentate nucleus of the cerebellum and, to some degree, the corticospinal tracts degenerate.”
The authors took a deep dive into the evidence, old and new, to evaluate the effects of FA on the central and peripheral nervous systems and to look at the course of neuropathologic changes associated with the disease. They propose a comprehensive approach to identify nervous system locations that are likely to be most successfully targeted at different disease time points.
“The proprioceptive system, usually considered a major target for frataxin-restoring treatments, shows substantial evidence of hypoplasia and/or early developmental loss, with minimal evidence of progression over time,” they wrote. “It seems likely that this system is not an ideal target for therapies given after early childhood. Targeting the [dentate nucleus] of the cerebellum is likely to be most effective early in the course of the disease, when it is functionally affected, but still shows limited atrophy. The corticospinal tract degenerates over time contributing to disease progression throughout its late stages and may be considered a target.”
David Lynch, MD, PhD, and Arnulf Koeppen, MD, disclose support from the Friedreich’s Ataxia Research Alliance. Dr. Lynch also discloses support from the National Institutes of Health, U.S. Food and Drug Administration, Muscular Dystrophy Association, Reata Pharmaceuticals, and Retrotope.
References
1. Williams CT and De Jesus O. Friedreich ataxia. StatPearls. 2023 Jun 27. https://www.ncbi.nlm.nih.gov/books/NBK563199/.
2. National Institute of Neurological Disorders and Stroke. Friedreich ataxia. 2023 Sep 2. https://www.ninds.nih.gov/health-information/disorders/friedreich-ataxia.
3. Adanyeguh IM et al. Brain Commun. 2023;5(4):fcad196. doi: 10.1093/braincomms/fcad196.
4. Camapuzano V et al. Science. 1996;271(5254):1423-7. doi: 10.1126/science.271.5254.1423.
5. RTA 408 capsules in patients with Friedreich’s ataxia–MOXIe. ClinicalTrials. gov Identifier: NCT02255435. 2022 Dec 6. https://clinicaltrials.gov/study/NCT02255435.
6. Food and Drug Administration. FDA approves first treatment for Friedreich’s ataxia. 2023 Feb 28. www.fda.gov/drugs/news-events-human-drugs/fda-approves-first-treatment-friedreichs-ataxia#.
7. Lynch DR et al. Ann Clin Transl Neurol. 2023 Sep 10. doi: 10.1002/acn3.51897
8. PTC Therapeutics. PTC Therapeutics announces topline results from vatiquinone MOVE-FA registration-directed trial. 2023 May 23. https://ir.ptcbio.com/news-releases/news-release-details/ptc-therapeutics-announces-topline-results-vatiquinone-move-fa.
9. Minoryx Therapeutics. The FRAMES Clinical Study in FRDA. https://www.minoryx.com/clinical-studies/clinical-study-frames/.
10. Larimar Therapeutics. CTI-1601 for Friedreich’s ataxia. https://larimartx.com/our-programs/cti-1601/.
11. Safety and efficacy of etravirine in Friedreich ataxia patients (FAEST1). ClinicalTrials.gov Identifier: NCT04273165. 2023 Mar 20. https://clinicaltrials.gov/study/NCT04273165.
12. Phase IA study of AAVrh.10hFXN gene therapy for the cardiomyopathy of Friedreich’s ataxia. ClinicalTrials.gov Identifier: NCT05302271. https://clinicaltrials.gov/study/NCT05302271.
13. Harding IH et al. Hum Gene Ther. 2020;31(23-24):1226-36. doi: 10.1089/hum.2020.264
It took 160 years but, in February 2023, the Food and Drug Administration approved the first drug specifically designed to treat the rare neuromuscular disease Friedreich ataxia (FA). The disease, first described in 1863 by German physician Nikolaus Friedreich, has an estimated incidence of 1 in 50,000 worldwide. It is the most common form of hereditary ataxia, accounting for approximately 50% of all cases of ataxia and approximately 75% of cases among patients younger than 25 years in the United States.1
FA typically presents in childhood or early adolescence; in some patients, symptoms manifest in the middle of the third decade of life. Patients exhibit symptoms such as ataxia that becomes worse over time, gait ataxia, impaired sensation in the extremities that can spread centrally, loss of normal reflexes, especially in the knees, speech disorders (dysarthria), muscle spasticity, scoliosis, and dysphagia.
Severity of disease ranges from relatively mild to completely disabling. Symptoms are progressive; patients almost inevitably require ambulatory support or a wheelchair. They might develop diabetes mellitus and can lose hearing and vision as the disease progresses. Hypertrophic cardiomyopathy is the most common cause of death among FA patients. Some patients who have less severe features might live into their 60s – even beyond that age.2There is no cure for FA. Until recently, no therapy was available other than supportive care to address associated neuromuscular, cardiovascular, and metabolic complications.
Making the diagnosis
Genetic testing can provide a definitive diagnosis of FA. (The genetic etiology of the disease is described later in this article.)
In addition to genetic screening, the workup includes a thorough medical history and physical examination that focuses on problems with balance, proprioception, absence of reflexes, and neurological signs. Tests include electromyography, nerve-conduction studies, electrocardiography, a metabolic profile, and MRI of the brain and spinal cord.
MRI utility in FA. In a paper published in July 2023 in Brain Communications, investigators from the University of Minnesota, Minneapolis, reported that various MRI techniques can be combined to detect early-stage alterations and disease progression in patients with FA.3 The researchers compared images taken at baseline and at 1, 2, and 3 years in 28 FA patients and 20 age- and gender-matched controls.
They observed that, compared with controls, patients with FA had lower cerebellar white matter volume but not lower cerebellar gray matter volume; larger cerebellar peduncle, thalamus, and brain stem structures; and a higher volume of the fourth ventricle. Using diffusion-tensor imaging and fixel-based analysis of diffusion MRI metrics, they also detected microstructural differences in several brain regions – especially in the cerebellum and corticospinal tract.
“Over time, many of these macrostructural and microstructural alterations progressed, especially cerebellar gray- and white-matter volume and microstructures of the superior cerebellar peduncle, the posterior limb of the internal capsule, and the superior corona radiata,” the investigators reported. In addition, “linear regressions showed significant associations between many of those imaging metrics and clinical scales.”
Pathophysiological basis of FA
The underlying genetic pathology of FA was first described in 1996 by investigators from the University of Valencia (Spain). They reported that FA is caused by a mutation in FXN (formerly X25), a gene that encodes for the protein frataxin, which is important for producing mitochondrial adenosine triphosphate and managing iron stores.4
The mutation results in multiple guanine-adenine-adenine repeats in FXN, or, in a few cases, a point mutation or deletion in 1 allele of FXN, with multiple GAA repeats in the other allele. A hallmark of FA is impairment of cellular antioxidative defense mechanisms – a major cause of disease progression.
The GAA repeat leads to methylation of the promoter region of FXN. This results in production and accumulation in cells of an abnormal, ineffective form of frataxin and oxidative damage to cells, particularly those that require larger amounts of energy, such as cells in the brain, heart, and pancreas.
“You would expect that the cells would be revving up all of their endogenous defenses,” David Lynch, MD, PhD, director of the Friedreich ataxia program at Children’s Hospital of Philadelphia, explained in an interview. “These oxidative damage responses are controlled by a DNA response element called the antioxidant response element, and it’s activated by the transcription factor Nrf2 [nuclear factor erythroid 2–related factor 2].”
Treatment options have been limited
Omaveloxolone. Dr. Lynch is principal investigator for the MOXIe trial of the safety, pharmacodynamics, and efficacy of omaveloxolone (marketed as Skyclarys [Reata Pharmaceuticals]),5 which received FDA orphan drug, fast track, priority review, and rare pediatric disease designations for the treatment of FA and, in February 2023, formal FDA approval.6 Development of this drug, which activates Nrf2 and induces antioxidant target genes, arose from basic science investigation into mechanisms by which cells respond to stresses.
“Omaveloxolone works on the Nrf2 pathway, which is, paradoxically, deficient in FA,” Dr. Lynch said. “This pathway should be active all the time. You would expect that, in cells from Friedreich ataxia in a person or an animal model of the disease, you’d see that Nrf2 would be very active but, in fact, what you find is the opposite,” Dr. Lynch explained. “It’s relatively inefficient, it’s localized in the cell, and the antioxidant response element genes – the things we all use to protect ourselves from mitochondrial damage – are all relatively turned off.”
In the first phase of MOXIe, 103 patients with FA were randomly assigned to receive either omaveloxolone, 15 mg orally (51 patients), or placebo (52 patients) for 48 weeks.
The primary endpoint was change in the modified Friedreich’s Ataxia Rating Scale (mFARS) score at 48 weeks. The scale is a clinically validated neurological instrument that evaluates upper- and lower-limb coordination, upright stability, and bulbar function.
Patients assigned to placebo had worsening of function at 48 weeks (mean increase in mFARS score, 0.85). In contrast, patients assigned to omaveloxolone had a mean decrease in the mFARS score of –1.56, indicating improvement. The between-group difference of –2.41 points was statistically significant in favor of omaveloxolone (P = .038).
In a 3-year, post hoc, propensity-matched analysis, patients assigned to omaveloxolone had lower mFARS scores than a matched set of untreated patients in a study of the natural history of FA.7Dimethyl fumarate (marketed as Tecfidera [Biogen]), approved in the United States and other countries for the treatment of patients with relapsing forms of multiple sclerosis, also has Nrf2 as a therapeutic target, although its precise mechanism of action is unclear. Clinical trials of this agent for the treatment of FA are under consideration in Europe, Dr. Lynch said.
Apart from these agents, treatment of patients with FA largely centers on management of metabolic and cardiac complications; physical and occupational therapy; devices such as orthopedic shoes, canes, and wheelchairs; and, when indicated, surgery to correct skeletal problems or for implantation of a cardiac-assist device.
The FA therapeutic pipeline
According to the Friedreich’s Ataxia Research Alliance, other approaches to improving mitochondrial function and reducing oxidative stress in FA are under investigation or awaiting approval, including elamipretide, for which FDA approval is pending for Barth syndrome (a rare, X-linked disorder) and for primary mitochondrial myopathy; nicotinamide adenine dinucleotide (NAD+, a coenzyme for redox reactions) plus exercise; and MIB-626, a crystalline form of nicotinamide mononucleotide, a precursor of NAD+.
Vatiquinone, an investigational inhibitor of 15-lipoxygenase, a regulator of energetic and oxidative stress pathways, failed to meet its primary endpoint of significant improvement on the mFARS score at 72 weeks of follow-up in the MOVE-FA trial, according to the manufacturer, PTC Therapeutics.8Another therapeutic approach under investigation is modulation of frataxin-controlled metabolic pathways with leriglitazone, an orally available selective peroxisome proliferator-activated receptor gamma agonist,9 or with the prodrug precursor of monomethyl fumarate plus dimethyl fumarate.
CTI-1601, a recombinant fusion protein intended to deliver human frataxin into the mitochondria of patients with FA, is in phase 1 trials. This compound has been granted rare pediatric disease designation, fast track designation, and orphan drug status by the FDA, according to the manufacturer, Larimar Therapeutics.10Etravirine, a nonnucleoside reverse transcriptase inhibitor approved for treating HIV infection, has been demonstrated to increase the frataxin protein in cells derived from FA patients and in the heart and skeletal muscle of frataxin-deficient YG8 mice. This agent recently completed a phase 2 trial in patients with FA.11
Gene therapy: Promising
Given the genetic etiology of FA, gene therapy strategies aimed at either increasing FA gene expression or editing the genome to replace defective FXN are under active investigation.
Increasing FA gene expression. DT-216 (Design Therapeutics) is a novel, gene-targeted chimera small molecule designed to target the GAA repeat expansion mutation and restore FXN expression. This agent completed phase 1 dosing studies in 2022.
Oligonucleotides, which are nucleic acid polymers primarily used for gene silencing, are also being explored for increasing the expression of FXN, in research at the University of Texas Southwestern Medical Center, Dallas, and the University of Massachusetts, Worcester.
Gene replacement strategies under investigation to treat FA include LX2006 (Lexeo Therapeutics), a gene replacement therapy using an adeno-associated viral vector to deliver FXN intravenously, with the goal of getting the gene into myocardial cells and increasing the frataxin level in mitochondria.
A similar approach is being taken by Ronald G. Crystal, MD, and colleagues at Weill Cornell Medicine, New York. The group is designing phase 1 studies of AAVrh.10hFXN, a serotype rh.10 adeno-associated virus coding for human frataxin, with the goal of treating cardiac manifestations of FA.12FA researcher Arnulf H. Koeppen, MD, from the Samuel S. Stratton Department of Veterans Affairs Medical Center, Albany, N.Y., and Albany Medical College, said in an interview that gene replacement therapy in FA is focused on the heart “because there is no blood-heart barrier, but there is a blood-brain barrier that makes it more complicated for gene therapy to reach the brain.”
Future directions
Dr. Koeppen, Dr. Lynch, and colleagues Ian H. Harding, PhD, from Monash University, Melbourne, and Massimo Pandolfo, MD, McGill University, Montreal, conducted an extensive review of FA with a focus on challenges that researchers and drug developers face crafting therapies for this complex disorder.13
They noted that FA is “characterized by marked differences in the vulnerability of neuronal systems. In general, the proprioceptive system appears to be affected early, while later in the disease, the dentate nucleus of the cerebellum and, to some degree, the corticospinal tracts degenerate.”
The authors took a deep dive into the evidence, old and new, to evaluate the effects of FA on the central and peripheral nervous systems and to look at the course of neuropathologic changes associated with the disease. They propose a comprehensive approach to identify nervous system locations that are likely to be most successfully targeted at different disease time points.
“The proprioceptive system, usually considered a major target for frataxin-restoring treatments, shows substantial evidence of hypoplasia and/or early developmental loss, with minimal evidence of progression over time,” they wrote. “It seems likely that this system is not an ideal target for therapies given after early childhood. Targeting the [dentate nucleus] of the cerebellum is likely to be most effective early in the course of the disease, when it is functionally affected, but still shows limited atrophy. The corticospinal tract degenerates over time contributing to disease progression throughout its late stages and may be considered a target.”
David Lynch, MD, PhD, and Arnulf Koeppen, MD, disclose support from the Friedreich’s Ataxia Research Alliance. Dr. Lynch also discloses support from the National Institutes of Health, U.S. Food and Drug Administration, Muscular Dystrophy Association, Reata Pharmaceuticals, and Retrotope.
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