The first Phase 1 study was a randomized, double-blind, placebo-controlled, multiple ascending dose-escalation study of the pharmacokinetics, safety and tolerability of two formulations of XP23829 in healthy adult subjects. Five separate cohorts (12 active and three placebo subjects per cohort) were enrolled sequentially and received one of two formulations of XP23829 dosed with or without food. Following up-titration of up to five days, dosing for each cohort ranged from 400 to 1,000 mg XP23829 per day, administered either once a day (QD) or twice a day (BID), with dosing for an additional six days. On the seventh day of target dose administration, pharmacokinetic (PK) evaluations were conducted following the morning dose. Similarly, a sixth cohort of healthy subjects received 240 mg BID TECFIDERA® (dimethyl fumarate), which is also a prodrug of MMF. As a consequence of its higher molecular weight, 400 mg of XP23829 is approximately equimolar to 240 mg of dimethyl fumarate (DMF), i.e., these amounts of each compound can potentially be enzymatically converted to approximately the same amount of MMF.
The preliminary results of the first Phase 1 study showed that both formulations of XP23829 produced MMF in the plasma but with different PK profiles. The 400 mg BID XP23829 Formulation 1 dosed without food provided an MMF PK profile that was nearly identical to that of 240 mg BID TECFIDERA dosed without food. As expected, XP23829 Formulation 2, administered as 800 mg QD and 500 mg BID dosed with food, provided more extended exposure to MMF. These cohorts had a lower mean maximal plasma concentration (Cmax) of MMF, while providing a mean daily area under the concentration versus time curve (AUC) of MMF that was approximately 25% less than that seen after dosing 240 mg BID TECFIDERA. XP23829 was generally well tolerated in the study. The most common adverse events were flushing and gastrointestinal-related events, which were generally mild to moderate in severity.
The second Phase 1 study was an open-label, pharmacokinetic and mass balance study in healthy male subjects. One group of six subjects received a single dose of XP23829 that incorporated a radiolabel in the fumarate portion of the molecule and a separate group of six subjects received XP23829 with the radiolabel in the promoiety portion of the molecule. As expected, the metabolism and disposition of radioactivity from the fumarate-labeled version of XP23829 was similar to what has been publicly reported for dosing healthy subjects with DMF labeled in the same position. For the promoiety-labeled version of XP23829, 98% of the recovered radioactivity was in urine. The major metabolites of the promoiety found in humans were the same as those observed in animal studies.
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