Friedreich’s Ataxia (FA) is a rare, genetic, and progressive neurodegenerative disorder. A defect in the Frataxin (FXN) gene causes FA. FXN is essential for the proper functioning of the mitochondria, and its deficiency leads to mitochondrial dysfunction, oxidative stress, and neuroinflammation.
Patients develop ataxia, balance issues, loss of motor skills, speech impairment, weakness, visual impairment, and sensory loss. Patients with FA also have diverse non-neurological features. These include cardiomyopathy, kyphoscoliosis, and foot deformities, such as pes cavus.
The FDA approved omaveloxolone in 2023 for the treatment of FA. Omaveloxolone activates the transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2), which regulates the cellular response to oxidative stress. It restores mitochondrial function, subsequently restoring redox balance and reducing inflammation. The dose is 150 mg orally.
The evidence for approval was a single, randomized, double-blind, placebo-controlled study and an open-label extension study. 82 FA patients without pes cavus participated in the trial. They showed statistically significant improvement in the modified Friedreich’s Ataxia Rating Scale (mFARS) at Week 48 in the omaveloxolone arm compared to placebo.
Omaveloxolone showed a dose-dependent increase in ferritin observed in a dose range-finding study. Patients taking omaveloxolone showed laboratory abnormalities likely due to Nrf2 activation, such as increases in liver enzymes, B-natriuretic peptide, and lipids. Thus, the sponsor will need to monitor patients for lab abnormalities in the post-marketing surveillance.
Clinical pharmacology considerations
A few interesting aspects can be discerned from the summary basis of approval.
Assessment of cardiac safety risk: Drug-induced QT prolongation can cause torsades de pointes, a potentially lethal cardiac arrhythmia. The agency indicated that the effect of omaveloxolone on prolonging the QTc interval was inadequately characterized. They also stated that the clinical ECG data were insufficient to exclude a 10-msec mean increase in the QTc interval. Hence, the FDA issued a post-marketing requirement of a thorough QT study.
QTc assessment in the Phase 1 program is critical. There are ways to avoid conducting expensive and time-consuming studies such as a TQT trial (or as a post-marketing requirement; PMR). These include performing PK/QTc sampling in the first-in-human (FIH) study. If you take this approach, be sure to follow the regulatory guidance on this topic.
Biomarkers: The company scientists reported on a translational PK/PD study to show that the exposures at which biomarker changes were seen could be attained in the clinic. Omaveloxolone is a potent activator of nuclear factor (erythroid-derived 2)-like-2 factor (Nrf2). Nrf2 regulates the expression of Nrf2 target gene NAD(P)H quinone:oxidoreductase 1 (Nqo1), thioredoxin reductase 1 (Txnrd1), the peroxiredoxin regulator sulfiredoxin 1 (Srxn1), genes involved in glutathione homeostasis [eg, glutamate–cysteine ligase catalytic subunit (Gclc) and glutathione reductase (Gsr)], aldoketo reductase 1c1 (Akr1c1), phosphogluconate dehydrogenase (Pgd) and proteins important in iron homeostasis (e.g., ferritin). The sponsor appeared to have focused on the role of ferritin as a biomarker of Nrf2 activation. Increases in ferritin levels in plasma are a specific pharmacodynamic biomarker for Nrf2 activation in humans.
In Figure 2, it was revealed that many of the Nrf2 target genes examined were observed to be increased in monkeys at omaveloxolone concentrations observed in the 80-, 160-, and 300-mg dose groups in patients with Friedreich’s ataxia (Reisman et al., 2019).
Drug-drug interaction (DDI) study: Omaveloxolone is a CYP3A4 substrate. Being a CYP3A4 substrate raises the threshold of potential interactions with CYP3A4 inhibitors and inducers. Therefore, it is not surprising that the agency also required a post-marketing study to examine the effect of concomitant administration of a moderate CYP3A4 inducer on the omaveloxolone pharmacokinetics. Several in-silico tools can be applied to understand the effects of potential CYP3A4 inhibitors and inducers as exemplified in the paper by Almond et al., 2016.
Clinical development considerations
The sponsor’s development program included a single, two-part clinical trial, Study 408-C-1402. The second part of this trial served as the primary basis for assessing drug effectiveness. An open-label extension provided additional supportive analyses and a comparison of the open-label extension study to a propensity-matched natural history cohort.
Why is this FDA drug approval significant?
Of course, FA is an unmet medical need, and this approval would mean a lot to patients with FA. The FDA used its 2019 draft guidance, Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products, in this approval framework.
This guidance allows the Agency to consider “data from one adequate and well-controlled clinical investigation and confirmatory evidence” to show substantial evidence of effectiveness. The FDA’s substantial evidence requirement for effectiveness, which had been generally interpreted as needing two adequate and well-controlled trials, has been since clarified in the 2019 guidance as being also met by a single trial plus confirmatory evidence. A single adequate and well-controlled study achieved its primary endpoint.
The development program used an outcome assessment (mFARS) that the agency considered acceptable. This outcome assessment also had a clinically meaningful observed change. The biomarker data strengthened evidence for the drug’s mechanism of action being Nrf2 activation. This approval underscores the importance of identifying a biomarker useful for demonstrating drug target engagement and mechanism of action, despite ferritin being a nonspecific marker.
Learn more about the opportunities and challenges in rare disease drug development in our white paper.
References
- FDA Summary Basis of Approval. URL: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216718Orig1s000SumR.pdf
- Reisman S et al. Pharmacokinetics and pharmacodynamics of the novel Nrf2 activator omaveloxolone in primates. Drug Des Devel Ther 2019 Apr 17;13:1259–1270.
- Almond L et al. Prediction of Drug-Drug Interactions Arising from CYP3A induction Using a Physiologically Based Dynamic Model. Drug Metab Dispos 44:821–832, June 2016.
