A Milestone in the Treatment of Ataxias: Approval of Omaveloxolone for Friedreich Ataxia

Subramony SH, Lynch DL. A Milestone in the Treatment of Ataxias: Approval of Omaveloxolone for Friedreich Ataxia. Cerebellum (London, England). 2023 May. DOI: 10.1007/s12311-023-01568-8. PMID: 37219716. 

The exciting news about the US FDA approval of omaveloxolone as the first-ever drug to be approved for an inherited ataxia is welcome news for patients and families that deal with this devastating disease as well as for health care providers and investigators with an interest in this and other rare diseases. This event is the culmination of long and fruitful collaboration between patients, their families, clinicians, laboratory researchers, patient advocacy organizations, industry, and regulatory agencies. The process has generated intense discussion about outcome measures, biomarkers, trial design, and the nature of approval process for such diseases. It also has brought hope and enthusiasm for increasingly better therapies for genetic diseases in general.

Characterisation of the Cognitive Profile of Patients Suffering From Friedreich's Ataxia (CPCAF)

ClinicalTrials.gov Identifier: NCT05874388. First Posted: May 24, 2023. Sponsors and Collaborators: Institut National de la Santé Et de la Recherche Médicale, France

The role of behavioural and cognitive assessment in the clinical trial The effectiveness of a treatment is ultimately determined by the elimination of the physiological cause of the disease and the alleviation of the symptoms that patients suffer. However, new treatments rarely eliminate all causes and symptoms of the disease. As long as the effectiveness of a treatment is unknown, it is subtle changes in parameters that decide whether the approach taken is worth pursuing. For a clinical trial which is supposed to evaluate the effectiveness of a treatment for Friedreich's Ataxia, it is therefore necessary to evaluate subtle changes in the functioning of the motor and cognitive system induced by the treatment. For this reason, the project is assembling a battery of tests that quantify the most important aspects of motor, cognitive and speech function in patients with FA. These tests are designed with the specific needs of FA patients in mind, i.e. on the one hand, the tests assess functions that are particularly important in view of the symptoms of Friedreich's disease indicated in the scientific literature, and on the other hand, the psychometric characteristics of the tests are adapted to the general abilities of FA patients. In this respect, it is important to point out that the expansion of the GAA repetition in people with Friedreich's disease varies from 150 to 1,000 triples (compared to 7 to 25 in the rest of the population), and that this large variation in the genotype of FA patients could potentially influence the cognitive profile of the participants. Previous studies have suggested the relationship between the number of repeats of the GAA triplet of the FXN gene and performance in cognitive assessment tests. Specifically, while in FA patients both alleles of the FXN gene contain an unusually high number of GAA repeats, performance in cognitive tests would correlate with the number of GAA repeats in the allele that contains fewer such repeats. Using this test battery, we are therefore able to achieve our main objective, i.e. to characterise the cognitive profile of FA patients as a function of the number of GAA triplet repeats of the FXN gene. Specifically, the test battery will establish whether motor, executive and speech symptoms affect patients differently according to their particular genetic characteristics.

PTC Therapeutics Discontinues Some Programs In Gene Therapy

May 23, 2023. (RTTNews) - PTC Therapeutics Inc. (PTCT) said that it has discontinued pre-clinical and early research programs in gene therapy as part of a strategic portfolio prioritization. The discontinued gene therapy programs include preclinical stage programs in Friedreich ataxia and Angelman syndrome as well as several other programs targeting rare CNS and ophthalmological disorders of high unmet medical need at various stages of preclinical development. 

 In a separate press release, PTC Therapeutics said that phase 3 trial of vatiquinone in patients with Friedreich ataxia did not meet its primary endpoint of statistically significant change in mFARS score at 72 weeks in the primary analysis population.

 However, vatiquinone treatment did demonstrate significant benefit on key disease subscales and secondary endpoints. In addition, in the population of subjects that completed the study protocol, significance was reached in the mFARS endpoint and several secondary endpoints.

PTC Therapeutics Announces Topline Results from Vatiquinone MOVE-FA Registration-Directed Trial Twitter Facebook LinkedIn GooglePlus Pinterest

SOUTH PLAINFIELD, N.J. , May 23, 2023 /PRNewswire/ -- PTC Therapeutics, Inc. (NASDAQ: PTCT) today reported topline results from the MOVE-FA trial of vatiquinone in patients with Friedreich ataxia. The study did not meet its primary endpoint of statistically significant change in mFARS score at 72 weeks in the primary analysis population. However, vatiquinone treatment did demonstrate significant benefit on key disease subscales and secondary endpoints. In addition, in the population of subjects that completed the study protocol, significance was reached in the mFARS endpoint and several secondary endpoints.

Large-scale expansions of Friedreich's ataxia GAA•TTC repeats in an experimental human system: role of DNA replication and prevention by LNA-DNA oligonucleotides and PNA oligomers

Anastasia Rastokina, Jorge Cebrián, Negin Mozafari, Nicholas H Mandel, C I Edvard Smith, Massimo Lopes, Rula Zain, Sergei M Mirkin, Large-scale expansions of Friedreich's ataxia GAA•TTC repeats in an experimental human system: role of DNA replication and prevention by LNA-DNA oligonucleotides and PNA oligomers, Nucleic Acids Research, 2023;, gkad441, doi:10.1093/nar/gkad441 

 In summary, we developed a first of a kind, genetically tractable experimental system to study large-scale expansions of FRDA GAA•TTC repeats in cultured human cells. Our candidate gene analysis implicates fork reversal and restoration in the process. We believe that this system could be a valuable tool for elucidating the mechanisms of large-scale expansions in humans and for evaluating the efficiency of perspective FRDA drugs targeting the instability of GAA•TTC repeats. Finally, we have showed that LNA-modified oligonucleotides and PNA oligomers targeting the GAA•TTC repeats prevent their expansion holding a promise to be developed as future therapeutics for the treatment of FRDA.

The Loss of Frataxin Impairs Microglia Homeostatic Functions in Friedreich’s Ataxia

Ferrara G. Abstracts of the Fifth Brainstorming Research Assembly for Young Neuroscientists (BraYn), Italy, 28-30 September 2022. Neurology International. 2023 Mar;15(1):415-496. DOI: 10.3390/neurolint15010028. PMID: 36976671; PMCID: PMC10056600. 

Martina Milani, Ilaria Della Valle, Riccardo Turchi, Flavia Tortolici, Daniele Lettieri Barbato, Katia Aquilano, Savina Apolloni and Nadia D’Ambrosi. These data suggest that microglia targeting could play a valuable role in ameliorating neuronal circuits in FRDA-affected CNS regions, consistent with other neurodegenerative conditions, where the modulation of microglia represents one of the most promising therapeutic strategies.

Neuropsychiatric symptoms in spinocerebellar ataxias and Friedreich ataxia

Karamazovova S, Matuskova V, Ismail Z, Vyhnalek M. Neuropsychiatric symptoms in spinocerebellar ataxias and Friedreich ataxia. Neuroscience and Biobehavioral Reviews. 2023 May;150:105205. DOI: 10.1016/j.neubiorev.2023.105205. PMID: 37137435. 

 Apart from its role in motor coordination, the importance of the cerebellum in cognitive and affective processes has been recognized in the past few decades. Spinocerebellar ataxias (SCA) and Friedreich ataxia (FRDA) are rare neurodegenerative diseases of the cerebellum presenting mainly with a progressive loss of gait and limb coordination, dysarthria, and other motor disturbances, but also a range of cognitive and neuropsychiatric symptoms.

Patient-Derived iPSC-Neurons and Microglia for Modeling Friedreich’s Ataxia Disease

1694 Patient-Derived iPSC-Neurons and Microglia for Modeling Friedreich’s Ataxia Disease; Priyanka Mishra, Anusha Sivakumar, Avalon Johnson, Emily Hansen, Jacqueline Nguyen, Nicole Coufal, Stephanie Cherqui. May 01, 2023 Volume 31 Issue 4 Supplement 1 S1-794 26th Annual Meeting of the American Society of Gene & Cell Therapy.

Utilising these two models, to understand the role of microglia in the neurodegeneration in FRDA, and its rescue by the gene corrected microglia.

Safety of Ascending Doses of AAVrh.10hFXN to Treat the Cardiac Manifestations of Friedreich’s Ataxia

1656 Safety of Ascending Doses of AAVrh.10hFXN to Treat the Cardiac Manifestations of Friedreich’s Ataxia; Jonathan B. Rosenberg, Alessandria Greco, Carlos Munoz Zuluaga, Monica La Russa Gertz, Melissa Yost-Bido, Nicholas C. Gorman, Alvin Chen, Vikrum Kooner, Bishnu P. De, Stephen M. Kaminsky, Rodolfo J. Ricart Arbona, Heather R. Martin, Sebastien Monette, Richie Khanna, Ronald G. Crystal, Dolan Sondhi. 

 On average, the increase in cardiac FXN expression after AAVrh.10hFXN administration with 5.7x1011 and 1.8x1012 gc/kg doses was 6.5 and 37%, respectively, over the PBS-treated controls. Together, these data identify the safe doses of AAVrh.10hFXN relevant for the treatment of the cardiac manifestations of FA.

Novel AAV Capsid Identification and Characterization for Neuromuscular and Cardiac Indications

1549 Novel AAV Capsid Identification and Characterization for Neuromuscular and Cardiac Indications; Jennifer C. G. Green, Jessica F. Boehler, Meghan S. Soustek, Jamie L. Marshall, Tiffany Willacy, Prushti Bhavsar, Kristy J. Brown, Sharon McGonigle, Carl Morris (Solid Biosciences). May 01, 2023 Volume 31Issue 4Supplement 1S1-794 26th Annual Meeting of the American Society of Gene & Cell Therapy.

 Adeno-associated virus (AAV) mediated gene therapy continues to be a promising therapeutic path for various diseases, including monogenic neuromuscular and cardiac indications such as Duchenne muscular dystrophy (DMD) and Friedreich’s ataxia (FA). However, the high systemic doses currently required to achieve widespread therapeutic benefit can pose potential safety risks. These risks could be decreased or eliminated if therapeuticbenefit could be achieved using lower doses through a more targeted and efficacious vector.