Steady State Pharmacokinetics of Formulations of XP23829, a Novel Prodrug of Monomethyl Fumarate (MMF), in Healthy Subjects (P1.188)

OBJECTIVE: To assess the pharmacokinetics of XP23829 formulations after repeated daily dosing. BACKGROUND: XP23829 is a novel prodrug of MMF that has shown efficacy in the mouse Experimental Autoimmune Encephalomyelitis (EAE) model of Multiple Sclerosis (MS). Based on a single dose Phase 1 study, two XP23829 formulations were selected for further evaluation. DESIGN/METHODS: This was a randomized, double-blind, placebo-controlled, multiple ascending, oral-dose study of Formulations 1 (delayed release) and 2 (extended release) of XP23829 in healthy adults in five sequential cohorts of 12 active and 3 placebo. Each cohort received 7 days at target dose after titration: Formulation 1 at 200 mg BID or 400 mg BID (fasted); Formulation 2 at 800 mg QD (fed or fasted) and 500 mg BID (fed). Each 200 mg of XP23829 contains 107 mg-eq MMF. A sixth cohort received Tecfidera ® (dimethyl fumarate, BG-12) 240 mg BID (fasted; fed on Day 7). Pharmacokinetics of MMF in blood and plasma were determined on Day 7 (Days 6 and 7 for Tecfidera ® ). RESULTS: The average ratio of MMF in plasma vs whole blood was 1.6. Mean maximum MMF concentration (C max,ss ) in plasma was 1490 and 2200 ng/mL for 200 and 400 mg BID Formulation 1, respectively; mean area under the curve over 24 hours (AUC 24,ss ) was 3670 and 6910 ng*hr/mL. Mean C max,ss in plasma for Formulation 2 was 1370, 1830, and 1170 ng/mL at 800 mg QD (fasted), 800 mg QD (fed) and 500 mg BID, respectively; AUC 24,ss was 4490, 5080, and 5510 ng*hr/mL. XP23829 levels were below quantitation limits. Tecfidera ® (fasted) mean C max,ss and AUC 24,ss were 2170 ng/mL and 7010 ng*hr/mL. Intersubject AUC variability (%CV) was 14% for Formulation 1 compared to 27% for Tecfidera ® . CONCLUSIONS: XP23829 formulations provide similar or more sustained MMF exposure compared to Tecfidera ® . Results support evaluation of XP23829 for potential once- and twice-a-day dosing in MS. Study Supported by: XenoPort, Inc. Disclosure: Dr. Lissin has received personal compensation for activities with XenoPort Inc. as an employee. Dr. Lissin holds stock and/or stock options in XenoPort Inc. Dr. Lissin has received research support from XenoPort Inc. Dr. Luo has received personal compensation for activities with XenoPort, Inc. as an employee. Dr. Luo has received research support from XenoPort, Inc. Dr. Tai has received personal compensation for activities with XenoPort, Inc. as an employee. Dr. Tai has received research support from XenoPort, Inc. Dr. Zomorodi has received personal compensation for activities with XenoPort, Inc. Dr. Zomorodi holds stock and/or stock options in Johnson and Johnson Pharmaceuticals. Dr. Zomorodi has received research support from XenoPort, Inc. Dr. Chen has received personal compensation for activities with XenoPort Inc. as an employee. Dr. Chen holds stock and/or stock options in XenoPort Inc. Dr. Chen has received research support from XenoPort Inc. Dr. Nguyen has received personal compensation for activities with XenoPort, Inc. as an employee. Dr. Nguyen has received research support from XenoPort, Inc. Dr. Yao has received personal compensation for activities with XenoPort, Inc. Dr. Yao has received research support from XenoPort, Inc. Dr. Kim has received personal compensation for activities with XenoPort, Inc. as an employee. Dr. Kim has received research support from XenoPort, Inc. Dr. Zou has received personal compensation for activities with XenoPort, Inc. as an employee. Dr. Zou has received research support from XenoPort, Inc. Dr. Cundy has received personal compensation for activities with Xenoport, Inc. as an employee. Dr. Cundy has received research support from Xenoport, Inc.