Omaveloxolone show promise in Friedreich’s ataxia

Movement disorders

By Michael Woodhead

20 Oct 2020

A novel therapy omaveloxolone could potentially be beneficial for patients with Friedreich’s ataxia, according to results from a phase 2 trial that involved Australian centres.

The drug, which is a small molecule Nrf2 activator resulted in significantly improved neurological function compared to placebo in a one year randomised controlled trial involving 103 patients with Friedreich’s ataxia.

And with no approved treatments for Friedreich’s ataxia, the molecule offers a possible therapeutic breakthrough for people with the condition, said researchers in Annals of Neurology.

In a parallel-group RCT, 51 patients were assigned to treatment with omaveloxolone and 52 with placebo at 11 international centres , including eight patients from the Murdoch Children’s Research Institute, Melbourne.

Patients were aged 16 to 40 years of age with genetically confirmed Friedreich’s ataxia and baseline modified Friedreich’s Ataxia Rating Scale (mFARS) neurological scores between 20 and 80. Almost all were ambulatory.

The primary trial outcome was change from baseline in the mFARS score at 48 weeks.

For the  40 evaluable omaveloxolone patients the change was a reduction in neurological disability of -1.55 (± 0.69) compared with an increase of  +0.85 (± 0.64) among the placebo group. This represented a significant  difference between treatment groups of -2.40 (± 0.96; p=0.014).

The improvements with omaveloxolone  were seen across all components of neurological measures: bulbar, upper limb coordination, lower limb coordination, and the  greatest effects seen on the upright stability.

However, improvements in mFARS were less marked in people with pes cavus than those without pes cavus, which the researchers suggested might be due to this representing a subgroup of people with more severe, less reversible Friedreich’s ataxia.

Paediatric patients (< 18 years of age) showed the greatest benefit with an overall improvement in mFARS score of 4.16 compared to placebo.

Secondary outcomes measures of PGIC and CGIC scores improved in patients randomised  to omaveloxolone, but did not statistically differ between treatment groups.

Omaveloxolone was generally well tolerated, with transient effects in the first 12 weeks of treatment including headache, nausea, increased alanine  and aspartate aminotransferase  (ALT  and AST), fatigue, diarrhoea and abdominal pain.

The investigators said the magnitude of observed improvements  was  equivalent to approximately two years of disease progression.

“More importantly, the improvements in upright stability with omaveloxolone relative to placebo demonstrate an effect on the mFARS component that defines important clinical milestones in Friedreich’s ataxia, including loss of ambulation,” they wrote.

They said the mechanism of action was not clear but was presumably due to effects on mitochondrial function and Nrf2 signalling that are dysregulated in Friedreich’s ataxia.

“As Nrf2  dysfunction is found diffusely in Friedreich’s ataxia and because change is more easily demonstrated in patients with earlier stages of the disease, it seems likely that at least some benefit will be noted throughout the course of the illness. Thus, omaveloxolone may be a potential therapeutic agent in many if not all stages of Friedreich’s ataxia,” they concluded.

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