Omaveloxolone: an activator of Nrf2 for the treatment of Friedreich ataxia

ABSTRACT

Introduction

Friedreich ataxia (FRDA) is a rare autosomal recessive degenerative disorder characterized by ataxia, dysarthria, diabetes, cardiomyopathy, scoliosis, and occasionally vision loss in late-stage disease. The discovery of the abnormal gene in FRDA and its product frataxin has provided insight into the pathophysiology and mechanisms of treatment.

Areas covered

Although the neurologic phenotype of FRDA is well defined, there are currently no established pharmacological treatments. Omaveloxolone, a nuclear factor erythroid 2-related factor 2 (Nrf2) activator, is currently under review by the Food and Drug Administration (FDA) and has the potential to be the first approved treatment for FRDA. In the present report, we have reviewed the basic and clinical literature on Nrf2 deficiency in FRDA, and evidence for the benefit of omaveloxolone.

Expert opinion

The present perspective suggests that omaveloxolone is a rational and efficacious therapy that is possibly disease modifying in treatment of FRDA.

KEYWORDS:

• Nrf2 activator
• KEAP1
• antioxidant response element

Article highlights

• Friedreich Ataxia (FRDA) is an autosomal recessive neurodegenerative disorder characterized by ataxia, cardiomyopathy, scoliosis, diabetes, vision loss, and hearing difficulties with no current approved treatment.

• The pathophysiology of FRDA includes disruption of transcription of the small mitochondrial protein frataxin, responsible for mitochondrial homeostasis and iron metabolism, with dysfunction leading to oxidative stress, cellular dysfunction, and suppression of nuclear factor erythroid 2-related factor 2 (Nrf2) signaling.

• Many drugs have undergone research for FRDA treatment, such as Resveratrol, deferiprone, idebenone, and gamma interferon, Vatiquinone, Elamipretide, Leriglitazone, Nicotinamide Riboside, DT216, CT1691, and gene therapy methods.

• Omaveloxolone, or RTA-408, is an Nrf2 activator, which decreases the vulnerability of cells to oxidative stress and therefore cell death and tissue degradation. It is well tolerated with no significant long term adverse events.

• The clinical efficacy of omaveloxolone has been assessed through a two-part, multicenter, double-blind phase II/III trial called MOXIe, with Part II showing a 1.5-year reversal of progression, generally felt to be a clinically meaningful amount.

• While omavaloxolone is not a cure for FRDA, it does represent the first agent targeting downstream events to reach NDA submission.

Declaration of interests

DR Lynch receives grants from FARA, the Muscular Dystrophy Association, the National Institutes of Health, Reata Pharmaceuticals, and Retrotope. The Children’s Hospital of Philadelphia receives a grant from Reata Pharmaceuticals with DR Lynch as the primary investigator for the MOXIe Trial. V Profeta, M Wells, K McIntyre, and C Park all work at the Children’s Hospital of Philadelphia in the Friedreich Ataxia Clinic. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they have received public speaking honoraria from Alexion, argenx, Biogen, Mylan, Novartis, Roche, Sanofi, Teva; have received compensation for advisory boards or consultation fees from Alexion, Almirall, argenx, Avexis, Biogen, Forward Pharma, Lexeo Therapeutics, Merck, Novartis, Novatek, Reata, Roche, Sanofi, Takeda; have acted as Principal Investigator in clinical trials sponsored by Alexion, argenx, Immunovant, Novartis, Prilenia, Sanofi.

Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

List of abbreviations.

Additional information

Funding

This paper was not funded.