NeuroVoices: David R. Lynch, MD, PhD, on the First Potentially Approved Friedreich Ataxia Treatment

The professor of neurology at the University of Pennsylvania Perelman School of Medicine discussed the state of care for Friedrich ataxia and omaveloxolone’s potential to become its first approved therapy.

Friedreich ataxia, a rare, inherited, degenerative disease that damages the spinal cord, peripheral nerves, and cerebellum portion of the brain, currently has no FDA-approved therapies available to treat it.1 Although, a therapy with the potential to fill this gap in care has emerged from the pipeline in recent months.

Omaveloxolone (Reata Pharmaceuticals), has shown potential for this patient population after an analysis from the phase 2 MOXIe trial (NCT02255435) revealed a significant difference in modified Friedrich’s Ataxia Rating Scale (mFARS) of –2.18 points (±0.96) between treatment with omaveloxolone and placebo groups.2 Lead author David R. Lynch, MD, PhD, professor of neurology, University of Pennsylvania Perelman School of Medicine, told NeurologyLive that he believes there is good reason to hold out hope in this drug.

Lynch connected with NeurologyLive for a new iteration of NeuroVoices to discuss the findings from the MOXIe trial, why the mechanistic action of omaveloxolone makes it so effective to treat these patients, and whether it has legitimate potential to break through the treatment landscape.

NeurologyLive: Can you discuss your results in detail? Did anything stand out?

David R. Lynch, MD, PhD: In the poster session presented at MDS Virtual Congress, we’re looking at the ongoing extension data from the MOXIe trial, the original, double-blind, placebo-controlled, phase 3 study of omaveloxolone in Friedreich ataxia. As reported previously, that study had positive results. Individuals on the drug did much better than those on placebo and reversed their disease for about the equivalent of a year or year and a half. Additionally, they maintained that improvement for at least a year, thus was clinically significant.

In a previous reanalysis, we showed that in the extension period, people who were new to the drug were markedly improved compared to a preceding placebo period in which they were not on the drug. That’s a second way in which the open-label period of omaveloxolone benefited people with FA [Friedrich ataxia]. In this case, we’ve analyzed the data from the extension period as a delayed-start phenotype. We compared people who were on placebo during the first part of the study who then received the active drug to those who were on an active drug during the first quarter of the study and continued treatment. The data were reasonably compelling.

In each case, there was no difference between the effects of the people who were all on drug during the second part. They were statistically not different. In addition, if you look at the slopes as they changed in the extension period, you find that they were equivalent, and were roughly about one-fourth as fast as natural history data. Responder analysis also showed that people responded during this period like natural history data. This again shows that omaveloxolone is beneficial to people with Friedrich ataxia in this delayed-start approach.

What about the mechanistic action of this drug makes it so efficacious and attractive for this patient population?

It’s a different type of drug than any antioxidant has been tried before. It’s an activator of the transcription factor NRF2. That’s a transcription factor in all of us that should control our body’s response to mitochondrial disease into free radical production. That transcription factor is paradoxically turned off in FA [Friedrich ataxia]. It should be going gangbusters when, in fact, it's downregulated. The thought here is that this drug could reverse that paradoxical downregulation, and thus improve the phenotype of the disease and reverse or slow their progression. That appears to be what has been found. It's very different than an antioxidant—it is probably much more long-lasting, and it's harder for the body to recognize that we're trying to trick it when introducing the drug.

For a patient population that lacks an FDA-approved therapy, what are the greatest unmet needs?

At this moment, the current unmet need is everything. That is to say, we have no way to slow the progression, and most of the symptomatology is fully treated in a very modest manner. This doesn't directly address the individual symptomatology but does go at the mechanism of the disease, the events immediately downstream from the deficiency of the causal protein for frataxin. It should, theoretically at the right stage, have some benefit on all aspects of the disease, and perhaps more importantly, for at least some period of time, slow the progression, which is really what the delayed start study shows.

Do you think omaveloxolone has the potential to be the first approved therapy for Friedrich ataxia?

I think it does have the chance to be the first approved drug for Friedreich ataxia. There have now been 3 different approaches to the calculation of the data, which show a significant benefit every time. I know that people in the industry have met with the FDA to talk about things and I think it stands a good chance of being the first drug. What this would mean is it offers a big hope for slowing the progression, or at least temporarily stabilizing things. I don't think this is a cure. It does not reverse the deficiency of frataxin, but it has the potential to forestall damage until a time comes along where we can directly go at the restoration of frataxin. That's a very important thing to do.

Transcript edited for clarity. For more iterations of NeuroVoices, click here.

1. Friedrich ataxia fact sheet. National Institutes of Health. Updated March 16, 2020. Accessed September 28, 2021.
2. Lynch DR, Chin MP, Boesch S, et al. Efficacy of omaveloxolone in patients with Friedrich’s ataxia: delayed-start study. Presented at MDS Virtual Congress; September 17-22, 2021. Poster LBA 2.