Omaveloxolone slows neurological progression in earlier-onset Friedreich’s ataxia

The treatment effect of omaveloxolone in halting progression, based on change in the modified Friedreich's Ataxia Rating Scale (mFARS) score, is particularly pronounced in individuals with Friedreich's ataxia (FA) who had disease onset at ≤15 years of age, suggests a post hoc subgroup analysis of the MOXIe Part 2 trial presented at EAN 2024.

Relative to placebo, omaveloxolone improved the mFARS scores by a least squares (LS) mean of −3.61 points at 48 weeks in this age-of-onset subgroup (nominal p=0.0074). [EAN 2024, abstract EPR-206]

To interpret the treatment effect over a longer duration, data from the open-label extension (OLE) following MOXIe Part 2 were propensity-matched 1:1 with the cohort from FACOMS, a natural history study of FA. In the same earlier-onset subgroup, the matched controls progressed by 6.38 points on mFARS over 3 years, while those treated with omaveloxolone progressed by 3.42 points (difference, −2.96; p=0.0110).

“The FACOMS group progressed at a rate of 2 mFARS points per year over 3 years, while the omaveloxolone-treated group progressed at about half that rate,” the presenter Dr Shobhana Natarajan from Biogen Inc, Cambridge, Massachusetts, US, pointed out.

The most important progression predictor

Although rare, FA is the most common hereditary ataxia. The genetic cause of the condition is the presence of guanine-adenine-adenine (GAA) triplet expansions in the first intron of the FXN gene, which encodes a mitochondrial protein.

The mean age of onset of FA is around 14–16 years. An earlier onset is correlated with longer GAA repeat lengths; for every 100 repeats, the age of onset is 2.3–2.7 years earlier. [Lancet Neurol 2015;14:174-182; Neurology 2022;99:e1499-e1510] As such, “age of onset is considered the most important predictor of progression,” said Natarajan.

Following a dose-finding Part 1, MOXIe Part 2 was a double-blind, randomized, placebo-controlled, registrational, phase II trial which enrolled patients aged 16–40 years with FA. [Ann Clin Transl Neurol 2018;6:15-26; Ann Neurol 2021;89:212-225]

Patients included in the full analysis set (n=82) entered the trial at a mean age of 23.9 years, with a mean age of disease onset of 15.5 years.

Placebo and external controls

In subgroups defined by age of onset ≤15 and >15 years, omaveloxolone treatment resulted in largely similar improvements in mFARS scores, with LS mean reductions of −1.59 and −1.46 at week 48, respectively.

Because placebo-treated patients with earlier disease onset experienced more mFARS progression than those with later (LS mean change, 2.02 and −0.4, respectively), the placebo-corrected improvement with omaveloxolone at week 48 achieved nominal significance in the age of onset ≤15 years subgroup.

Among those with disease onset >15 years of age, the −1.07-point improvement with omaveloxolone vs placebo at week 48 fell short of statistical significance, yet the treatment delayed progression on mFARS over 3 years by 58.1 percent in the OLE vs the matched controls from FACOMS (LS mean change, 2.46 vs 5.87; difference, −3.41; p=0.0161).

Prior to the FDA's approval of omaveloxolone for FA in February 2023, the disease has no available therapies. Since then, the nuclear factor erythroid 2-related factor 2 activator has also been authorized in Europe for the treatment of FA in adults and adolescents aged ≥16 years.

The neuropathology of FA stems from the degeneration of the large sensory neurons in the dorsal root ganglia of the spinal cord. Ataxia, typically manifesting as generalized clumsiness and gait problems, is progressive and is usually accompanied by other hallmark symptoms, including limb muscle weakness, sensory neuropathy, areflexia, and scoliosis.

In Asia, a case of FA is most likely to be of Middle Eastern or Indian origin. [Neurology 2000;54:2322-2324; Can J Neurol Sci 2004;31:383-386]