Omaveloxolone approved for patients aged 16 years and older with Friedreich ataxia (FRDA): A therapeutics bulletin of the American College of Medical Genetics and Genomics (ACMG)

Arthur Lenahan, Sho Yano, Brett Graham, Kuntal Sen, Omaveloxolone approved for patients aged 16 years and older with Friedreich ataxia (FRDA): A therapeutics bulletin of the American College of Medical Genetics and Genomics (ACMG), Genetics in Medicine Open, Volume 1, Issue 1, 2023, 100832, ISSN 2949-7744, doi:10.1016/j.gimo.2023.100832. 

Omaveloxolone (trade name: SKYCLARYS) is a Nrf2 activator that increases cellular resilience to oxidative stress that has been FDA approved for patients with FRDA who are 16 years and older. Omaveloxolone received orphan drug, fast track, priority review, and rare pediatric disease designations. Omaveloxolone is a semisynthetic triterpenoid administered orally once daily.

CO105 A Retrospective Study Characterizing Age at Loss of Ambulation Among Patients With Friedreich Ataxia Using Health Administrative Claims Data in the United States

A. Salvucci, C. Qian, L. Powell, D. Lynch, G. Vasco, K. Johnston, I. Tomazos, CO105 A Retrospective Study Characterizing Age at Loss of Ambulation Among Patients With Friedreich Ataxia Using Health Administrative Claims Data in the United States, Value in Health, Volume 26, Issue 12, Supplement, 2023, Pages S33-S34, ISSN 1098-3015, doi:10.1016/j.jval.2023.09.177. 

 In this cross-sectional analysis, most patients who were diagnosed with FA before the ages of 24 years experienced LOA and wheelchair use before the age of 16 years. While limitations exist in ascertainment of LOA using claims data, findings suggest that those who had earlier onset of FA also had earlier LOA.

Mitochondrial impairment, decreased sirtuin activity and protein acetylation in dorsal root ganglia in Friedreich Ataxia models

Arabela Sanz-Alcázar, Elena Britti, Fabien Delaspre, Marta Medina-Carbonero, Maria Pazos-Gil, Jordi Tamarit, Joaquim Ros & Elisa Cabiscol​. Mitochondrial impairment, decreased sirtuin activity and protein acetylation in dorsal root ganglia in Friedreich Ataxia models. Cell. Mol. Life Sci. 81, 12 (2024). doi:10.1007/s00018-023-05064-4 

 The NAD+/NADH ratio was reduced and sirtuin activity was impaired. We identified alpha tubulin as the major acetylated protein from DRG homogenates whose levels were increased in FXNI151F mice compared to WT mice. In the mitochondria, superoxide dismutase (SOD2), a SirT3 substrate, displayed increased acetylation in frataxin-deficient DRG neurons. Since SOD2 acetylation inactivates the enzyme, and higher levels of mitochondrial superoxide anion were detected, oxidative stress markers were analyzed. Elevated levels of hydroxynonenal bound to proteins and mitochondrial Fe2+ accumulation was detected when frataxin decreased. Honokiol, a SirT3 activator, restores mitochondrial respiration, decreases SOD2 acetylation and reduces mitochondrial superoxide levels. Altogether, these results provide data at the molecular level of the consequences of electron transport chain dysfunction, which starts negative feedback, contributing to neuron lethality. This is especially important in sensory neurons which have greater susceptibility to frataxin deficiency compared to other tissues.

Predictors of Survival in Friedreich's Ataxia: A Prospective Cohort Study

Indelicato, E., Reetz, K., Maier, S., Nachbauer, W., Amprosi, M., Giunti, P., Mariotti, C., Durr, A., de Rivera Garrido, F.J.R., Klopstock, T., Schöls, L., Klockgether, T., Bürk, K., Pandolfo, M., Didszun, C., Grobe-Einsler, M., Nanetti, L., Nenning, L., Kiechl, S., Dichtl, W., Ulmer, H., Schulz, J.B., Boesch, S. and (2023), Predictors of Survival in Friedreich's Ataxia: A Prospective Cohort Study. Mov Disord. doi:10.1002/mds.29687 

Arrhythmias, progressive neurological disability, and diabetes mellitus influence the overall survival in FA. We built a survival prognostic score which identifies patients meriting closer surveillance and who may benefit from early invasive cardiac monitoring and therapy.

Generation and characterization of two human iPSC lines, IGIBi014-A and IGIBi015-A, from Friedreich's ataxia (FRDA) patients with pathogenic (GAA/TTC)n repeat expansion in first intron of the Frataxin (FXN) gene

Ahmad I, Kapoor H, Kumar Srivastava A, Faruq M. Generation and characterization of two human iPSC lines, IGIBi014-A and IGIBi015-A, from Friedreich's ataxia (FRDA) patients with pathogenic (GAA/TTC)n repeat expansion in first intron of the Frataxin (FXN) gene. Stem Cell Res. 2023 Dec 16;74:103289. doi: 10.1016/j.scr.2023.103289. Epub ahead of print. PMID: 38141359. 

We generated two iPSC lines from FRDA patients with biallelic expansion of GAA repeats in the first intron ofFXNgene.IGIBi014-A and IGIBi015-Aboth iPSC lines demonstrated characteristics of pluripotency, normal karyotypes (46, XY),the capacity to differentiate into all three germ layers, and the ability to sustain the GAA repeat expansion with decreased FXN mRNA expression. These cell lines will be utilized to comprehend the pathophysiology of the illness and the FRDA's predictive phenotypes.

Loss of filamentous actin, tight junction protein expression, and paracellular barrier integrity in Frataxin-deficient human brain microvascular endothelial cells -implications for blood-brain barrier physiology in Friedreich's Ataxia

Frances M. SMITH, Daniel Kosman; Front. Mol. Biosci. Sec. Lipids, Membranes and Membranous Organelles, Volume 10 - 2023 | doi:10.3389/fmolb.2023.1299201

We identified that insufficient FXN levels in the hBMVEC BBB model causes changes in cytoskeletal architecture and tight junction protein abundance, coincident with increased barrier permeability. Changes in the integrity of the BBB may be related to patient brain iron accumulation, neuroinflammation, neurodegeneration, and stroke. Furthermore, our findings implicate other barrier cells, e.g., the cardiac microvasculature, as loci of disease pathology in FRDA.

EFICACIA Y SEGURIDAD DE LA OMAVELOXOLONA EN LA ATAXIA DE FRIEDREICH

Resumen-SIIC en castellano:  Disorders 38(2):313-320. Autores: Lynch D R, Chin MP, Meyer CJ 

Filadelfia, EE.UU. En pacientes con ataxia de Friedreich, el tratamiento prolongado con omaveloxolona se asocia con beneficios sostenidos; se pone de manifiesto la importante del inicio precoz del tratamiento, ya que los pacientes que lo hacen tardíamente no llegaron a presentar la misma mejoría, respecto de los tratados tempranamente con omaveloxolona.

Conclusión Los resultados de la fase abierta de extensión del MOXIE confirman los beneficios sostenidos del tratamiento con omaveloxolona, sobre el curso natural de la enfermedad, en pacientes con AF. Se demuestra también la importancia del inicio temprano del tratamiento, ya que los beneficios observados en los pacientes del grupo omaveloxolona-omaveloxolona no fueron alcanzados por los pacientes originalmente asignados a placebo. Los pacientes que recibieron omaveloxolona desde el principio, presentaron mejora sostenida de la evolución natural de la enfermedad, al cabo de más de 2.5 años de tratamiento.

JNS-101 by Jupiter Neurosciences for Friedreich Ataxia: Likelihood of Approval

December 21, 2023. JNS-101 is under clinical development by Jupiter Neurosciences and currently in Phase II for Friedreich Ataxia. According to GlobalData, Phase II drugs for Friedreich Ataxia does not have sufficient historical data to build an indication benchmark PTSR for Phase II. 

JNS-101 is under development for the treatment of Friedreich’s ataxia. The drug candidate is a micronized formulation of pharmaceutical grade trans-resveratrol. The drug candidate is administered through oral route. It acts by targeting frataxin.

MIB-626 by Metro International Biotech for Friedreich Ataxia: Likelihood of Approval

December 21, 2023. MIB-626 is under clinical development by Metro International Biotech and currently in Phase II for Friedreich Ataxia. According to GlobalData, Phase II drugs for Friedreich Ataxia does not have sufficient historical data to build an indication benchmark PTSR for Phase II. 

MIB-626 is under development for the treatment of Friedreich’s ataxia (FA), coronavirus disease 2019 (COVID-19), acute renal failure (ARF) (acute kidney injury), mild dementia and Leber’s hereditary optic neuropathy. The drug candidate is a crystallized precursor of nicotinamide adenine dinucleotide (NAD+). It is administered through oral route. 

It was also under development for the treatment of muscle endurance (musculoskeletal disorders) and mitochondrial myopathy.

Skyclarys* (omaveloxolone) received a positive opinion from the CHMP for the treatment of Friedreich’s ataxia

Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) 11-14 December 2023. Skyclarys* (omaveloxolone) received a positive opinion from the CHMP for the treatment of Friedreich’s ataxia, an inherited disease causing a range of symptoms that worsen over time, including difficulty walking, inability to co-ordinate movements, muscle weakness, speech problems, damage to the heart muscle and diabetes. 

 Skyclarys 

 INN: omaveloxolone 

Marketing-authorisation applicant: Reata Ireland Limited 

Therapeutic indication: Treatment of Friedreich’s ataxia 

Skyclarys: Pending EC decision

Biogen press release: CAMBRIDGE, Mass., Dec. 15, 2023 (GLOBE NEWSWIRE) 

Lexeo Therapeutics Reports Third Quarter 2023 Financial Results and Operational Highlights

NEW YORK, Dec. 11, 2023 (GLOBE NEWSWIRE) --LEXEO Therapeutics, Inc..Received clearance of LX2006 Clinical Trial Application (CTA) in Canada for the treatment of FA cardiomyopathy; activated first clinical trial site outside of the United States. 

 LX2006 for the Treatment of FA Cardiomyopathy: Received clearance of CTA in Canada for LX2006 for the treatment of FA cardiomyopathy and activated the first clinical trial site for the SUNRISE-FA Phase 1/2 clinical trial outside of the United States. 

LX2006 for the treatment of Friedreich’s ataxia cardiomyopathy: Interim data readout in mid-2024

Frataxin analysis using triple quadrupole mass spectrometry: application to a large heterogeneous clinical cohort

Lynch, D.R., Rojsajjakul, T., Subramony, S.H. et al. Frataxin analysis using triple quadrupole mass spectrometry: application to a large heterogeneous clinical cohort. J Neurol (2023). doi:10.1007/s00415-023-12118-x 

The present data show that assay of FXN-M and FXN-E levels in blood provides an appropriate biofluid for assessing their repletion in particular clinical contexts.

Impact of specialist ataxia centres on health service resource utilisation and costs across Europe: cross-sectional survey

Morris, S., Vallortigara, J., Greenfield, J. et al. Impact of specialist ataxia centres on health service resource utilisation and costs across Europe: cross-sectional survey. Orphanet J Rare Dis 18, 382 (2023). doi:10.1186/s13023-023-02971-4 

Within each country, resource use and costs were broadly similar for specialist ataxia centre and non-specialist ataxia centre groups. There were differences between countries in terms of health care contacts and costs.

Human frataxin, the Friedreich ataxia deficient protein, interacts with mitochondrial respiratory chain

Davide D, Federica C, Marco B, Elisa B, Silvia M, Giulia T, Federica D, Ottaviani D, Elena M, Luigi L, Elisa G, Elena Z, Antonella R, Milena B, Geppo S, Donatella C, Leonardo S, Paola C. Human frataxin, the Friedreich ataxia deficient protein, interacts with mitochondrial respiratory chain. Cell Death Dis. 2023 Dec 8;14(12):805. doi: 10.1038/s41419-023-06320-y. PMID: 38062036. 

Using healthy cells and different FRDA cellular models we found that frataxin interacts with these three respiratory complexes. Furthermore, by EPR spectroscopy, we observed that in mitochondria from FRDA patients' cells the decreased level of frataxin specifically affects the FeS cluster content of complex I. Remarkably, we also found that the frataxin-like protein Nqo15 from T. thermophilus complex I ameliorates the mitochondrial respiratory phenotype when expressed in FRDA patient's cells.

Clinical stage and plasma neurofilament concentration in adults with Friedreich ataxia

Magnus Johnsson, Henrik Zetterberg, Kaj Blennow, Christopher Lindberg, Clinical stage and plasma neurofilament concentration in adults with Friedreich ataxia, Heliyon, 2023, e23347, ISSN 2405-8440, doi:10.1016/j.heliyon.2023.e23347. 

(Last) Magnus Johnsson, Henrik Zetterberg, Kaj Blennow, Christopher Lindberg, Clinical stage and plasma neurofilament concentration in adults with Friedreich ataxia, Heliyon, Volume 10, Issue 1, 2024, e23347, ISSN 2405-8440, doi.:10.1016/j.heliyon.2023.e23347.

FRDA is less prevalent in our region of Sweden than could be assumed. In concordance with previous studies from other authors, we find that p-NfL may be increased in patients with FRDA, but less so in older more clinically affected patients. Thus, we conclude that on an individual basis, p-NFL is of uncertain clinical value as a suitable biomarker.

Intensive Multimodal Treatment for A Young Adult with Friedreich Ataxia: A Case Report

Grace Battal, Nicolas Pinsault, Berthe Hanna-Boutros. Intensive Multimodal Treatment for A Young Adult with Friedreich Ataxia: A Case Report. International Journal of Physiotherapy and Research, 2023, 11 (3), pp.4508-4516. 10.16965/ijpr.2023.110 . hal-04134585 

 The FRDA patient displayed improvement in all outcome measures. Strength, ataxia severity and functional abilities were enhanced while a higher level of independence was gained. Our observations suggest that an intensive multimodal approach holds potential in the management of FRDA and call for further research.

A modified mouse model of Friedreich's ataxia with conditional Fxn allele homozygosity delays onset of cardiomyopathy

A modified mouse model of Friedreich's ataxia with conditional Fxn allele homozygosity delays onset of cardiomyopathy; Tyler L Perfitt, Claudia Huichalaf, Renea Gooch, Anna Kuperman, Youngwook Ahn, Xian Chen, Soumya Ullas, Dinesh Hirenallur-Shanthappa, Yutian Zhan, Diana Otis, Laurence O. Whiteley, Christine Bulawa, and Alain Martelli, American Journal of Physiology-Heart and Circulatory Physiology 0 0:0, doi:10.1152/ajpheart.00496.2023 

This modified model reproduced important pathophysiological and biochemical features of FA over a longer timescale than previous cardiac-specific mouse models, offering a larger window for studying potential therapeutics.

Novel intragenic deletion within the FXN gene in a patient with typical phenotype of Friedreich ataxia: may be more prevalent than we think?

Aguilera, C., Esteve-Garcia, A., Casasnovas, C. et al. Novel intragenic deletion within the FXN gene in a patient with typical phenotype of Friedreich ataxia: may be more prevalent than we think?. BMC Med Genomics 16, 312 (2023). doi:10.1186/s12920-023-01743-0 

We describe a patient presenting with novel intragenic deletion and an expansion on the FXN gene who shows the typical progression and clinical features of FRDA. We believe that parental sample testing should be performed in all FRDA patients that present an apparent biallelic expansion in order to offer proper genetic counselling.