028: A Phase 1, Open-Label, 4-Part, Drug-Drug Interaction Study With Omaveloxolone in Healthy Subjects

Statement of Purpose: Omaveloxolone (SKYCLARYS™) is an activator of nuclear factor erythroid- derived 2-related factor 2 approved for Friedreich’s ataxia treatment in the United States. A 4-part drug-drug interaction (DDI) study was conducted to determine the perpetrator and the victim DDI potential of omaveloxolone.

Description of Methods & Materials: Sixty-one healthy subjects were enrolled in this 4-part, open-label, fixed-sequence, DDI study. In Part 1, the effects of multiple doses of omaveloxolone on the pharmacokinetics (PK) of single dose of midazolam (CYP3A4 substrate), repaglinide (CYP2C8 substrate), digoxin (P-gp substrate), metformin (OCT1 substrate) and rosuvastatin (BCRP substrate) were assessed. In Parts 2, 3, and 4, the effects of multiple oral doses of gemfibrozil, itraconazole, or verapamil, respectively, on the single oral dose PK of omaveloxolone were investigated. The primary PK endpoints included area under the concentration-time curve from time zero to infinity (AUC_0-∞) and maximum observed concentration (C_max); ANOVA analyses were conducted to assess the DDI effects.

Data & Results: The results from the DDI study are presented in Table 1. On co-administration of 2 mg midazolam with multiple doses of 150 mg omaveloxolone, midazolam C_max and AUC_0-∞ decreased by 34% and 45% respectively. On co-administration of 1 mg repaglinide with multiple doses of 150 mg omaveloxolone, repaglinide C_max and AUC_0-∞ decreased by 23% and 35% respectively. Following co-administration of 500 mg metformin with multiple doses of 150 mg omaveloxolone, AUCs were similar. Following co-administration of 10 mg rosuvastatin/0.25 mg digoxin cocktail with multiple doses of 150 mg omaveloxolone, rosuvastatin C_max and AUC_0-∞ decreased by 40% and 30% respectively, and there was a 15% decrease in digoxin C_max but AUCs were similar. The geometric mean apparent plasma terminal elimination half-life (t_1/2) of midazolam, repaglinide, metformin, rosuvastatin and digoxin were similar when administered alone and when co-administered with omaveloxolone. The systemic exposure to omaveloxolone was similar when administered alone compared to co-administration with gemfibrozil (strong CYP2C8 inhibitor). When coadministered with itraconazole (strong CYP3A4 inhibitor), there was approximately a 3- and 4-fold increase in C_max and AUC_0-∞, respectively of omaveloxolone. Omaveloxolone exposure increased by approximately 24% to 28%, following co-administration with verapamil (P-gp inhibitor). The geometric mean t_1/2 of omaveloxolone were similar when administered alone and when co- administered with probe drugs. There were no deaths or serious AEs during the study.

Interpretation, Conclusion or Significance: Co-administration of omaveloxolone significantly decreased the exposure of CYP3A4 and CYP2C8 substrates via enzyme induction. Omaveloxolone does not have any clinically meaningful effect on P-gp, OCT1, and BCRP substrates. Omaveloxolone exposure was not affected by either CYP2C8 or P-gp inhibitors. However, omaveloxolone exposure was increased by 3 to 4 times when coadministered with a strong CYP3A4 inhibitor. The results from this study were utilized to provide guidance when omaveloxolone is to be coadministered with strong and moderate CYP3A4 inhibitors and inducers and CYP3A4 or CYP2C8 substrates. Overall, there were no safety concerns when omaveloxolone was administered alone and when co-administered with probe drugs.

Disclosures: Joel Proksch is a consultant to Reata and have stock holdings in Reata. Aparna Shinde, Scott Hynes, Colin Meyer, and Hamim Zahir are employees of Reata Pharmaceuticals. Sarabjit Gahir is an employee of Bellus Health Inc., and a former employee of Reata Pharmaceuticals.