025: Safety, Tolerability & Pharmacokinetics of Single-dose INCB000928 & Food Effect on INCB000928 in Healthy Adult Participants

INCB000928 is a selective equipotent inhibitor of wild-type and mutant ALK2, which has shown the ability to prevent injury-induced heterotopic ossification in nonclinical models and therefore is evaluated in the treatment of patients with fibrodysplasia ossificans progressiva. This Phase I clinical study is to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of escalating oral doses of INCB000928 in healthy adult participants.

Description of Methods & Materials: The clinical study is a first-in-human, single-center, randomized, double-blind, placebo‑controlled, sponsor-unblinded, single-dose Phase 1 study. A total of 79 healthy adult participants were enrolled at doses ranging from 10 mg to 500 mg and randomized to receive either INCB000928 tablets or placebo. Additionally, 12 healthy adult participants were studied for the effect of high-fat meal using a 2-way crossover design. Plasma, saliva and urine samples were collected up to 144 hours after drug administration. Standard NCA methods were used to analyze the INCB000928 pharmacokinetic data. Safety data was tabulated using descriptive statistics.
 

Data & Results:

INCB000928 was rapidly absorbed with an observed median t_max of 2.0 to 4.1 hours postdose. The terminal t_½ in plasma was consistent across the 7 doses evaluated (approximately 27 hours). INCB000928 exposure was approximately dose-proportional over the range of 10 to 500 mg. A high-fat meal delayed INCB000928 median t_max by 1 hour, but did not significantly change C_max or AUC. The INCB000928 saliva concentrations were well correlated with those of plasma. There was no dose-limiting toxicity and the maximum tolerated exposure following a single dose has not been established in this study.

Interpretation, Conclusion or Significance:

INCB000928 was generally well tolerated and no unexpected safety signals were observed. Approximate dose proportionality was observed over the range of 10 mg to 500 mg in healthy participants and the terminal half-life would allow QD dosing. INCB000928 can be administered without regard to food. Saliva can be used as an alternative to plasma to determine drug exposure.