RTA 408 (omaveloxolone) is a small molecule Nrf2 activator, being developed by Reata Pharmaceuticals in collaboration with AbbVie as a potential treatment of Friedreich’s ataxia (FA). An inherited disorder, FA is caused by defects in the FXN gene that encodes for frataxin — a protein that regulates iron levels in mitochondria, a cell’s power producers.

A lack of frataxin results in the accumulation of free iron (not bound by frataxin) in mitochondria, leading to impaired energy production (in the form of ATP, the energy currency of a cell), 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 FA patients, and putting them a higher risk of developing cardiomyopathy (heart muscle disease) and diabetes.

RTA 408 has been shown to increase the number of mitochondria, improve mitochondrial efficiency, and boost energy production in mitochondria — all of which would potentially be beneficial for FA patients.

How RTA 408 works

RTA 408 works by activating a protein called nuclear factor erythroid-derived 2-related factor 2 (Nrf2), which is a transcription factor or protein that activates the expression of genes involved in promoting mitochondrial function.

Nrf2 activation further increases the production of ATP and antioxidant molecules.

Nrf2 activation also blocks, or inhibits, inflammation (by inhibiting a protein called NF-κB) and the production of reactive oxygen species to protect against oxidative stress.

Preclinical studies

In preclinical studies, frataxin deficiency was shown to be associated with a significant decrease in the expression 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 correlate with impaired neurologic function in FA patients.

In mouse models, RTA 408 has been shown to improve energy production in cells by directly activating the body’s anti-oxidative pathways via Nrf2. These results suggest that RTA 408 may improve mitochondrial function in FA patients.

Specifically, RTA 408 demonstrated in mouse models an ability to increase glucose uptake, fatty-acid oxidation, and oxygen consumption, all of which are direct signs of a healthier cellular metabolism.

RTA 408 in clinical trials

A two-part, randomized and placebo-controlled Phase 2/3 clinical trial (NCT02255435), called MOXIe, aims to evaluate the safety, efficacy, and pharmacodynamics of oral RTA 408 in the treatment of FA. MOXIe is currently recruiting FA patients, ages 16-40, who are able to perform 10-15 minutes of exercise on a recumbent exercise bike. The trial, sponsored by Reata and supported by the Friedreich’s Ataxia Research Alliance, started in 2015 and is currently enrolling at sites in the U.S., U.K., Austria and Australia. It is expected to conclude in 2019.

The trial’s first part was a randomized, placebo-controlled, double-blind, dose-escalation study to evaluate the safety of multiple oral doses of RTA 408 in FA patients. Here, 69 patients were given escalating doses (between 5 and 300 mg, oral capsules) once daily for 12 weeks to determine the maximum tolerated dose. Results showed that RTA 408 induced Nrf2 in patients and this was associated with improvements in mitochondrial and neurological function. All doses improved the patients’ neurological function, with the maximum therapeutic effect observed at the 160 mg dose.

The second part, expected to begin toward the end of 2017, is a randomized, placebo-controlled, double-blind, parallel-group study that will evaluate the safety and efficacy of 150 mg of RTA 408 in about 100 FA patients, who will be randomized 1:1 to receive either RTA 408 or a placebo.

An extension study will also assess the long-term safety and tolerability of RTA 408 in those who completed the MOXIe study. Patients will remain blinded to what treatment they were previously given, but in the extension study will receive open-label RTA 408 at 150 mg once a day.

Other information

The U.S. Food and Drug Administration (FDA) designated RTA 408 an orphan drug that might treat FA patients on June 22, 2017. This designation provides Reata with certain incentives to advance its development, including tax credits for clinical testing, exemption from a prescription drug user fee, and seven years of market exclusivity.

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