Designing phase II clinical trials in Friedreich ataxia

ABSTRACT

Introduction

Friedreich ataxia (FRDA) is an autosomal recessive disorder caused by deficiency of frataxin, an essential mitochondrial protein involved in iron sulfur cluster biogenesis, oxidative phosphorylation and other processes. FRDA most notably affects the heart, sensory neurons, spinal cord, cerebellum, and other brain regions, and manifests clinically as ataxia, sensory loss, dysarthria, spasticity, and hypertrophic cardiomyopathy. Therapeutic approaches in FRDA have consisted of two different approaches: (1) augmenting or restoring frataxin production and (2) modulating a variety of downstream processes related to mitochondrial dysfunction, including reactive oxygen species production, ferroptosis, or Nrf2 activation.

Areas covered

In this review, we summarize data from major phase II clinical trials in FRDA published between 2015 and 2020, which includes A0001/EPI743, Omaveloxolone, RT001, and Actimmune.

Expert opinion

A growing number of drug candidates are being tested in phase II clinical trials for FRDA; however, most have not met their primary endpoints, and none have received FDA approval. In this review, we aim to summarize completed phase II clinical trials in FRDA, outlining critical lessons that have been learned and that should be incorporated into future trial design to ultimately optimize drug development in FRDA.

KEYWORDS:

• Actimmune
• biomarkers
• endpoints
• EPI743
• Friedreich ataxia
• Omaveloxolone
• outcome measures
• phase II trials

Declaration of interest

D Lynch has received grant support from Reata, Retrotope, Horizon, and Edison relevant to the present work. 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.

List of abbreviations

FRDAFriedreich’s ataxiaFARSFriedreich’s ataxia rating scaleSARAscale for assessment and rating of ataxiamFARSmodified Friedreich’s ataxia rating scalePKpharmacokineticMEPmotor evoked potentialsOCToptical coherence tomographyMRSmagnetic resonance spectroscopyLFTliver function tests

Additional information

Funding

This paper was not funded.