126: Effect of a Moderate CYP3A4 Inducer on the Pharmacokinetics of Omaveloxolone in Healthy Subjects

Statement of Purpose, Innovation or Hypothesis: Omaveloxolone, a nuclear factor (erythroid-derived 2)-like 2 activator, is approved in the US and EU for the treatment of patients with Friedreich ataxia aged ≥16 years. CYP3A4 is the main enzyme involved in omaveloxolone metabolism in vitro. Coadministration of a strong CYP3A4 inhibitor itraconazole significantly increased omaveloxolone peak plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC) by 3- and 4-fold, respectively (Study 408-C-1806). This drug-drug interaction study aimed to determine the effect of a moderate CYP3A4 inducer, efavirenz, on the pharmacokinetic and safety profiles of omaveloxolone.
Description of Methods and Materials: This phase 1, open-label, single-sequence, 2-period crossover study (NCT05909644) enrolled healthy adults. In Period 1 (Days 1–15), subjects received a single dose of omaveloxolone 150 mg on Day 1 (after >10 hours of overnight fasting). In Period 2 (Days 15–43), subjects received efavirenz 600 mg once daily from Days 15–42 and a single dose of omaveloxolone 150 mg on Day 29. Pharmacokinetic plasma sampling for omaveloxolone was performed predose and at specified time points postdose over 336 hours per period; efavirenz trough sampling was performed predose on Days 28, 29 and 30. Primary pharmacokinetic endpoints included Cmax, AUC from time 0 to time of the last measurable concentration (AUC0-tlast) and AUC from time 0 extrapolated to infinity (AUC0-∞); secondary pharmacokinetic endpoints included time to Cmax (tmax), half-life (t1/2), clearance (CL/F) and volume of distribution (Vz/F). Safety was a secondary endpoint. Exposure parameters for Period 2 (Test) vs Period 1 (Reference) were compared using geometric mean ratios with 90% CIs calculated from an analysis of variance.
Data and

Results: Twenty subjects were enrolled and 18 completed both study periods. Subjects who completed Periods 1 (n=20) and 2 (n=18) were included in the pharmacokinetic analysis; all subjects were assessed for safety. Coadministration with efavirenz decreased Cmax, AUC and AUC0-∞ of omaveloxolone by 38.0%, 48.0% and 48.5%, respectively, compared with omaveloxolone administered alone. The 90% CIs of the geometric mean ratios were below the lower bound of the reference interval (80–125%) (Table 1). Coadministration with efavirenz also resulted in an earlier median tmax and shorter mean t1/2, and corresponding higher mean CL/F and Vz/F for plasma omaveloxolone. Efavirenz trough steady-state concentrations (2695–2825 ng/mL) were adequate for CYP3A4 induction. Overall, 14 subjects (70%) reported 44 treatment-emergent adverse events (TEAEs), the most frequent being dizziness (12 events in 10 subjects [50%]). Most TEAEs occurred prior to omaveloxolone administration in Period 2 (33 events in 11 subjects [58%]), including for dizziness (11/12 events). Nine events were considered at least possibly related to omaveloxolone; all were mild and occurred in Period 2. One subject discontinued due asymptomatic blood creatine kinase increased (unrelated to either treatment). Seven subjects had a TEAE of weight loss (≥5% decrease from baseline). No deaths or serious AEs were reported.
Interpretation, Conclusion or Significance: Coadministration with a moderate CYP3A4 inducer significantly reduced omaveloxolone systemic exposure. Omaveloxolone alone or when coadministered with efavirenz was generally well tolerated. These findings inform concomitant medication precautions and dosing recommendations for omaveloxolone when coadministered with a moderate CYP3A4 inducer.
Disclosures: Hamim Zahir, Masako Murai, Lucy Wu and Scott Hynes are employees of and hold stock in Biogen. Michelle Valentine is an employee of Celerion Inc, which was commissioned by Reata Pharmaceuticals to conduct the study; Reata was acquired by Biogen in 2023.