Why FDA’s omaveloxolone approval for Friedreich’s ataxia matters

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.

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.

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.