RTA 408 (omaveloxolone) is a small molecule Nrf2 activator that could potentially be beneficial for patients with Friedreich’s ataxia. The treatment was being developed by Reata Pharmaceuticals in collaboration with AbbVie, but Reata reacquired worldwide rights to develop and commercialize RTA 408 in October 2019.
What is Friedreich’s ataxia?
Friedreich’s ataxia is an inherited disorder caused by defects in the FXN gene that encodes for frataxin — a protein that regulates iron levels in mitochondria, which are cellular components that produce energy inside cells.
Reduced levels of frataxin, due to the mutations in the FXN gene, result in the accumulation of free iron (not bound by frataxin) in mitochondria, leading to impaired energy production, oxidative stress (cell damage caused by the accumulation of reactive oxygen species), poor antioxidant defense provided by molecules that protect the cell from harmful reactive oxygen species, and damage to mitochondrial DNA. This results in progressive degeneration of the central and peripheral nervous systems, impairing movement and gait in Friedreich’s ataxia patients, and putting them a higher risk of developing cardiomyopathy (heart muscle disease) and diabetes.
Research has shown that RTA 408 can increase the number of mitochondria, improve mitochondrial efficiency, and boost energy production in mitochondria — all of which could potentially benefit Friedreich’s ataxia patients.
How does RTA 408 work?
RTA 408 works by activating a protein called nuclear factor erythroid-derived 2-related factor 2 (Nrf2), which is a transcription factor or a protein that activates the expression of genes involved in promoting mitochondrial function.
Nrf2 activation further increases the production of energy and antioxidant molecules. It also blocks or inhibits inflammation by inhibiting a protein called NF-κB and the production of reactive oxygen species.
Preclinical studies have shown that frataxin deficiency is associated with a significant decrease in the production of Nrf2 in tissues, leading to a heightened sensitivity to oxidative stress and poorer mitochondrial function. Low energy production by mitochondria, in turn, is known to be associated with impaired neurologic function in Friedreich’s ataxia patients.
Using mouse models, researchers have shown that RTA 408 can improve energy production in cells by directly activating the body’s anti-oxidative pathways via Nrf2. These results suggest that RTA 408 may also improve mitochondrial function in Friedreich’s ataxia patients.
RTA 408 in clinical trials
A two-part, randomized placebo-controlled Phase 2/3 clinical trial (NCT02255435) called MOXIe is evaluating the safety, efficacy, and pharmacodynamics (effect on the body) of oral RTA 408 in patients with Friedreich’s ataxia.
The first part of the trial is a randomized, placebo-controlled, double-blind, dose-escalation study to evaluate the safety of multiple oral doses of RTA 408 in Friedreich’s ataxia patients. Here, 69 patients were given escalating doses (oral capsules ranging from 5 to 300 mg) once daily for 12 weeks to determine the maximum tolerated dose of the treatment. Results showed that RTA 408 induced Nrf2 in patients, and this was associated with improvements in mitochondrial and neurological function. All doses improved neurological function, with the maximum therapeutic effect observed at the 160 mg dose.
The second part of the study is a randomized, placebo-controlled, double-blind, parallel-group study that is evaluating the safety and efficacy of 150 mg of RTA 408 in about 100 Friedreich’s ataxia patients, who are randomized 1:1 to receive either RTA 408 or a placebo.
Reata Pharmaceuticals announced in October 2019 that the study had met its primary endpoint: a significant improvement in neurological symptoms and muscle strength. The treatment was deemed safe and well-tolerated, with mild to moderate adverse events that included< headache, nausea, increased levels of liver enzymes, fatigue, and abdominal pain.
An extension study will assess the long-term safety and tolerability of RTA 408 in people who completed the MOXIe study. Participants will remain unaware of the treatment they were previously given but know that they will receive 150 mg of RTA 408 once a day in the extension study, which is expected to be completed in 2022.
The U.S. Food and Drug Administration designated RTA 408 an orphan drug. This designation provides Reata with certain incentives to advance the development of the treatment, including tax credits for clinical testing, exemption from a prescription drug user fee, and seven years of market exclusivity.
RTA 408 was also granted organ drug status by the European Union.
Last updated: Jan. 16, 2020
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