(T1130-10-65) A Phase 1, Randomized, Open-Label, Single-Dose, Crossover, Relative Bioavailability Study of Omaveloxolone Intact Capsules versus Capsule Contents Sprinkled on Applesauce in Healthy Adult Subjects

Purpose: Omaveloxolone (SKYCLARYS™) is an activator of nuclear factor erythroid-derived 2-related factor 2 and is approved for Friedreich ataxia treatment in the United States. Currently omaveloxolone is available only in capsule formulation (50 mg). However, as some patients may have difficulty in swallowing capsules, it is important to establish an alternate method of oral administration. Therefore, this study was conducted to assess the relative bioavailability of a single dose of omaveloxolone when administered via intact capsules versus capsule contents sprinkled on applesauce at a dose of 150 mg. The delivery of omaveloxolone sprinkled over applesauce could provide an alternate administration method for subjects who were unable to swallow capsules. The secondary objectives were to assess the safety and tolerability of a single 150-mg dose of omaveloxolone when administered as either an intact capsule or capsule contents sprinkled on applesauce in healthy subjects.

Methods: This was a randomized, phase 1, open-label, single-dose, crossover, relative bioavailability study in healthy subjects. The study was conducted in 2 periods with a washout of at least 14 days between omaveloxolone dosing. Subjects were randomized to treatment sequences to minimize assignment bias. A crossover design was used to control the variability between subjects. A 14-day washout between doses was considered sufficient to eliminate the carry-over effects of the treatments. Because the primary endpoints of this study were objective PK measurements, blinding was not necessary. Approximately 32 adult male or female subjects between the ages of 18 and 55 years (inclusive), in generally good health, and who met the study eligibility criteria were enrolled to ensure at least 26 subjects completed the study. Subjects were confined to the clinical unit and supervised for approximately 29 days. Serial blood samples were collected in each period before study drug administration (predose) and 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 288, and 336 hours after dosing. The 336-hour sample in Period 1 served as the predose sample in Period 2. The safety and tolerability of the study drug were assessed throughout the study. The PK parameters were calculated using non compartmental analysis (NCA) method and using the actual sampling time intervals (relative to omaveloxolone administration). All 32 subjects enrolled in the study had sufficient concentration-time data for NCA. Log-transformed maximum plasma concentration (C_max), area under the plasma concentration versus time curve from time 0 to t, the time of the last measurable concentration (AUC_0-tlast), and area under the plasma concentration versus time curve from time zero extrapolated to infinity (AUC_0-∞) of omaveloxolone were analyzed using a mixed effect analysis of variance model with treatment, period, and sequence as fixed effects and subject nested within sequence as a random effect.

Results: Of 32 subjects enrolled, 31 subjects completed the study. The majority of the enrolled subjects (25 out of 32) were white, with 18 of them being female subjects and an age range of 23 to 55 years. All 32 subjects who received at least one dose of study treatment were included in the safety analysis. max (t_max) of 6 hours and 10 hours when omaveloxolone administered as sprinkled over applesauce and when administered as intact capsules, respectively (Figure 1). Even though median t_max was earlier when omaveloxolone was administered as sprinkled over applesauce, there was considerable overlap in the range of t_max between both treatments. The mean (standard deviation) apparent plasma elimination half-life was similar whether omaveloxolone was administered as intact capsules versus sprinkled over applesauce 86.9 (17.2) hours versus 90.4 (19.7) hours, respectively. The statistical comparisons of the ln-transformed plasma omaveloxolone exposure parameters demonstrated the peak (based on C_max) and overall (based on (AUC_0-tlast and AUC_0-∞) exposures were similar following a single oral dose of 150 mg omaveloxolone sprinkled on applesauce versus intact capsules, with the 90% CIs of the GMRs falling entirely within the 80.00% to 125.00% reference interval (Table 1). Omaveloxolone administered sprinkled on applesauce had acceptable palatability, as assessed for taste, odor, swallowability, and texture by the subjects in this study.

Conclusion: The peak and overall exposure of omaveloxolone were similar when omaveloxolone was administered as intact capsules versus when sprinkled over applesauce. Even though the results suggest that absorption was faster following administration of omaveloxolone sprinkled on applesauce relative to omaveloxolone intact capsules, given that the exposure was similar irrespective of the mode of administration and omaveloxolone is approved for the treatment of Friedreich ataxia, the difference in t_max is not considered clinically relevant. Additionally, omaveloxolone (150 mg) administered as either an intact capsules or capsule contents sprinkled on applesauce appeared to be safe and well tolerated. Therefore, omaveloxolone sprinkled over applesauce may be considered as an alternative dosing method.

Acknowledgements: This study was conducted in compliance with the International Council for Harmonisation Harmonized Tripartite Guideline regarding Good Clinical Practice. Scott Hynes, Seemi Khan, Masako Murai, Aparna Shinde, and Hamim Zahir are employees of Reata Pharmaceuticals.

Mean Plasma Omaveloxolone Concentration Versus Time Profiles Following Administration of a 150 mg Dose of Omaveloxolone Intact Capsules and a 150 mg Dose of Omaveloxolone Sprinkled on Applesauce (A: Linear and B: Semi-Log Scale)

Summary of Statistical Comparisons of Plasma Omaveloxolone PK Parameters for a 150 mg Dose of Omaveloxolone Sprinkled on Applesauce (Treatment B) Versus a 150 mg Dose of Omaveloxolone Intact Capsules (Treatment A)