The study, “Safety, pharmacodynamics, and potential benefit of omaveloxolone in Friedreich ataxia,” was published in the journal Annals of Clinical and Translational Neurology.
FA is caused by mutations in the FXN gene, reducing the production of the frataxin protein. Cells derived from FA patients have shown suppressed activation of a protein called Nrf2, which could contribute to oxidative stress, mitochondrial dysfunction (referring to impaired mitochondria, the cellular power plants), and lower production of ATP (cells’ “currency” of energy).
Omaveloxolone is being developed by Reata Pharmaceuticals and AbbVie, and has orphan drug designations in the European Union and the U.S. It is an Nrf2 activator that prevents Nrf2 ubiquitination — tagging with ubiquitin, marking the protein for to be destroyed — which increases its levels.
Prior studies in cells from patients with FA revealed that Nrf2 activation boosts mitochondrial function in a dose-dependent manner, while also increasing the levels of antioxidant agents and blocking inflammation. However, at higher concentrations, this effect on mitochondrial function declines, which is associated with loss of cell viability.
The team conducted a two-part, international, randomized and double-blind Phase 2 study (NCT02255435), named MOXIe, to assess omaveloxolone‘s safety, effectiveness pharmacokinetics (its absorption, distribution, metabolism and excretion in the body) and pharmacodynamics (its effects and mechanism of action).
Overall, this trial — sponsored by Reata, in collaboration with AbbVie and the Friedreich’s Ataxia Research Alliance (FARA) — intended to determine whether omaveloxolone (RTA 408) may be a suitable therapy candidate for further development in FA.
In total, 69 patients (age 16-37, 37 females, mean age 25.6 years) were included in the study’s first part. Age at FA onset was 15.3 years. Of note, 90% of the patients were able to walk.
The participants received escalating doses of omaveloxolone (52 patients) or placebo (17) orally once per day for 12 weeks. The potential treatment was given at dose levels within 2.5–300 mg/day in subgroups of eight patients each, aiming to define the appropriate doses for part two.
Multiple clinical assessments of muscular and neurological function were used, including: peak work during exercise testing with a stationary bicycle; neurological abilities (as assessed by the modified Friedreich’s ataxia rating scale (mFARS); the timed 25-foot walk test of mobility and leg function; the nine-hole peg test of upper extremity function; low contrast vision; health related quality of life, and; laboratory testing for safety and biochemistry.
In line with previously reported results, treatment with omaveloxolone was well-tolerated, with adverse events (side effects) — most commonly upper respiratory tract infections (40% of doses) and headaches (17%) — being generally mild. Only one patient on omaveloxolone discontinued treatment, due to a skin rash.
Optimal pharmacodynamic changes were found at doses of 80 and 160 mg/day, as reflected by Nrf2 protein targets such as ferritin, the enzyme aspartate amino transferase, which may reflect improvements in glucose metabolism, the team noted, and lessened metabolic alterations in platelets.
Also, as reported previously, no significant changes were observed in peak work in maximal exercise testing. Results of the nine-hole peg test time, the 25-foot timed walk test, and low-contrast visual acuity test also did not reveal differences in comparison with baseline.
However, at 160 mg/day, omaveloxolone improved mFARS scores by 3.8 points compared to study start and by 2.3 points vs. placebo. This benefit was best at 12 weeks and greater in the 37 patients without neuromuscular foot deformity (pes cavus, Latin for “hollow foot”), as shown by a 6.0-point improvement from baseline and by 4.4-point benefit vs. placebo. This subset of patients also showed greater improvements in the 25-foot timed walk test and in exercise testing, compared with placebo.
Overall, “treatment of [FA] patients with omaveloxolone at the optimal dose level of 160 mg/day appears to improve neurological function,” the scientists wrote. “Although the effect of [omaveloxolone] in longer term studies must be tested and its site of action identified, the present study provides a solid rationale for optimism in future studies,” they added.
Of note, two of study’s authors received grants from FARA and Reata. A third author is an employee of FARA.