Biogen Received European Commission Approval for SKYCLARYS® (omaveloxolone), the First Therapy to Treat Friedreich’s Ataxia

CAMBRIDGE, Mass., Feb. 12, 2024 (GLOBE NEWSWIRE) -- Biogen Inc. (Nasdaq: BIIB) announced the European Commission (EC) has authorized SKYCLARYS® (omaveloxolone) for the treatment of Friedreich’s ataxia (FA) in adults and adolescents aged 16 years and older.

Real-world evidence for coverage determination of treatments for rare diseases

Dayer, V.W., Drummond, M.F., Dabbous, O. et al. Real-world evidence for coverage determination of treatments for rare diseases. Orphanet J Rare Dis 19, 47 (2024). doi.10.1186/s13023-024-03041-z

Health technology assessment (HTA) decisions for pharmaceuticals are complex and evolving. New rare disease treatments are often approved more quickly through accelerated approval schemes, creating more uncertainties about clinical evidence and budget impact at the time of market entry. The use of real-world evidence (RWE), including early coverage with evidence development, has been suggested as a means to support HTA decisions for rare disease treatments. However, the collection and use of RWE poses substantial challenges. These challenges are compounded when considered in the context of treatments for rare diseases. In this paper, we describe the methodological challenges to developing and using prospective and retrospective RWE for HTA decisions, for rare diseases in particular. We focus attention on key elements of study design and analyses, including patient selection and recruitment, appropriate adjustment for confounding and other sources of bias, outcome selection, and data quality monitoring. We conclude by offering suggestions to help address some of the most vexing challenges. The role of RWE in coverage and pricing determination will grow. It is, therefore, necessary for researchers, manufacturers, HTA agencies, and payers to ensure that rigorous and appropriate scientific principles are followed when using RWE as part of decision-making.

Searching for Frataxin Function: Exploring the Analogy with Nqo15, the Frataxin-like Protein of Respiratory Complex I from Thermus thermophilus

Doni, D.; Cavallari, E.; Noguera, M.E.; Gentili, H.G.; Cavion, F.; Parisi, G.; Fornasari, M.S.; Sartori, G.; Santos, J.; Bellanda, M.; et al. Searching for Frataxin Function: Exploring the Analogy with Nqo15, the Frataxin-like Protein of Respiratory Complex I from Thermus thermophilus. Int. J. Mol. Sci. 2024, 25, 1912. doi:10.3390/ijms25031912

 Nqo15’s iron-binding properties were studied using NMR, fluorescence, and specific assays and its desulfurase activation by biochemical assays. We found that the recombinant Nqo15 isolated from complex I is monomeric, stable, folded in solution, and highly dynamic. Nqo15 does not share the iron-binding properties of FXN or its desulfurase activation function.

Safety, pharmacokinetics, and pharmacodynamics of nomlabofusp (CTI-1601) in Friedreich's ataxia

Clayton, R., Galas, T., Scherer, N., Farmer, J., Ruiz, N., Hamdani, M., Schecter, D. and Bettoun, D. (2024), Safety, pharmacokinetics, and pharmacodynamics of nomlabofusp (CTI-1601) in Friedreich's ataxia. Ann Clin Transl Neurol. doi:10.1002/acn3.51971 

 Patients aged 19–69 years were enrolled (SAD, N = 28; MAD, N = 27). Nomlabofusp was generally well tolerated through 13 days. Most adverse events were mild and resolved quickly. No serious adverse events or deaths were reported. Peak nomlabofusp plasma concentrations occurred 15 min after subcutaneous administration. Nomlabofusp plasma exposures increased with increasing doses and daily administration and decreased with reduced dosing frequency. Increased frataxin concentrations were observed in buccal cells, skin, and platelets with higher and more frequent nomlabofusp administration.

Absence of functional deficits in rats following systemic administration of an AAV9 vector despite moderate peripheral nerve and dorsal root ganglia findings: a clinically silent peripheral neuropathy

Cheryl Tyszkiewicz, Seo-Kyoung Hwang, Jamie K. DaSilva, Ramesh C. Kovi, Kelly A. Fader, Madhu P. Sirivelu, June Liu, Chris Somps, Jon Cook, Chang-Ning Liu, Helen Wang, Absence of functional deficits in rats following systemic administration of an AAV9 vector despite moderate peripheral nerve and dorsal root ganglia findings: a clinically silent peripheral neuropathy, NeuroToxicology, 2024, ISSN 0161-813X, doi:10.1016/j.neuro.2024.02.001. 

 These findings demonstrate that there is no detectable functional consequence to the minimal-to-moderate neurodegeneration observed with our AAV9 vector treatment in rats, suggesting a functional tolerance or reserve for loss of DRG neurons after systemic administration of AAV9 vector.

A peptide derived from TID1S rescues frataxin deficiency and mitochondrial defects in FRDA cellular models

Yi Na Dong, Lucie V. Ngaba, Jacob An, Miniat W. Adeshina, Nathan Warren, Jonathan Wong, David R. Lync, Front. Pharmacol. Sec. Neuropharmacology, Volume 15 - 2024, doi: 10.3389/fphar.2024.1352311  

The study of frataxin protein regulation might yield new approaches for FRDA treatment. Here, we report tumorous imaginal disc 1 (TID1), a mitochondrial J-protein cochaperone, as a binding partner of frataxin that negatively controls frataxin protein levels. TID1 interacts with frataxin both in vivo in mouse cortex and in vitro in cortical neurons. Acute and subacute depletion of frataxin using RNA interference markedly increases TID1 protein levels in multiple cell types. In addition, TID1 overexpression significantly increases frataxin precursor but decreases intermediate and mature frataxin levels in HEK293 cells. In primary cultured human skin fibroblasts, overexpression of TID1S results in decreased levels of mature frataxin and increased fragmentation of mitochondria. This effect is mediated by the last 6 amino acids of TID1S as a peptide made from this sequence rescues frataxin deficiency and mitochondrial defects in FRDA patient-derived cells. Our findings show that TID1 negatively modulates frataxin levels, and thereby suggests a novel therapeutic target for treating FRDA.

Nerve Ultrasound in Friedreich’s Ataxia: enlarged nerves as a Biomarker of disease severity

G. Di Pietro, E. Cioffi, P. Falco, E. Galosi, G. De Stefano, G. Di Stefano, C. Leone, V. Martines, S. Perotti, C. Casali, A. Truini, Nerve Ultrasound in Friedreich’s Ataxia: enlarged nerves as a Biomarker of disease severity, Clinical Neurophysiology, 2024, ISSN 1388-2457, doi:10.1016/j.clinph.2024.01.004 

 Our study now shows that high-resolution nerve ultrasound examination can detect nerve enlargements in patients with Friedreich's ataxia (mostly at the level of upper limbs). Neve ultrasound abnormalities correlate with clinically established variables in patients with Friedreich's ataxia. This technique, therefore, might be a promising biomarker for measuring disease severity and treatment effects in this rare and severely disabling condition.

Protective effect of FXN overexpression on ferroptosis in L-Glu-induced SH-SY5Y cells

Mengran Wang, Tingting Xuan, Haining Li, Jing An, Tianhui Hao, Jiang Cheng, Protective effect of FXN overexpression on ferroptosis in L-Glu-induced SH-SY5Y cells, Acta Histochemica, Volume 126, Issue 1, 2024, 152135, ISSN 0065-1281, doi:10.1016/j.acthis.2024.152135. 

 To conclude, our research demonstrates that an elevated expression of FXN effectively demonstrates a robust neuroprotective effect against oxidative damage induced by L-Glu. Moreover, it mitigates mitochondrial dysfunction and lipid metabolic dysregulation associated with ferroptosis. FXN overexpression holds promise in potential therapeutic strategies for AD by inhibiting ferroptosis in nerve cells and fostering their protection.

Anti-gene oligonucleotides targeting Friedreichs ataxia expanded GAA:TTC repeats increase Frataxin expression

Anti-gene oligonucleotides targeting Friedreichs ataxia expanded GAA:TTC repeats increase Frataxin expression, Negin Mozafari, Salome Isabel Marques Milagres, Cristina Simoes Jesus Rocha, Claudia Marina Vargiu, Fiona Freyberger, Osama Saher, Tea Umek, Pontus Blomberg, Per Trolle Jorgensen, Edvard Carl Igne Smith, Jesper Wengel, Rula L Zain, bioRxiv 2024.01.25.577034; doi:10.1101/2024.01.25.577034 

We examined numerous LNA-DNA AGOs and found that the design, length and their LNA composition have a high impact on the effectiveness of the treatment. Collectively, our results demonstrate the unique capability of specifically designed ONs targeting the GAA:TTC DNA repeats to upregulate FXN gene expression.

Omaveloxolone for the treatment of Friedreich Ataxia: clinical trial results and practical considerations

David R Lynch, Susan Perlman & Kim Schadt (2024) Omaveloxolone for the treatment of Friedreich Ataxia: clinical trial results and practical considerations, Expert Review of Neurotherapeutics, DOI: 10.1080/14737175.2024.2310617 

Omaveloxolone provides a significant advance in treatment of FRDA that is likely to be beneficial in a majority of the FRDA population. The data suggesting a benefit is consistent, and adverse issues are relatively modest. The major remaining questions are the subgroups that are most responsive and how long the beneficial effects will remain significant in FRDA patients.