Pharmacokinetics of Zilurgisertib With and Without Food from Single and Multiple Ascending Dose Phase 1 Studies in Healthy Adults.

Background and objectives: The oral, potent, and highly selective activin receptor-like kinase 2 (ALK2) inhibitor zilurgisertib (INCB000928) is in development as a treatment for fibrodysplasia ossificans progressiva (FOP), and for anemia due to myelofibrosis, myelodysplastic syndromes, and multiple myeloma. Saliva is an attractive alternative to blood for drug monitoring and pharmacokinetic analysis, as it is non-invasive to retrieve. This is beneficial for patients, such as those with FOP, for whom blood draws can be challenging due to soft tissue damage susceptibility that can cause progressive heterotopic ossification, and for whom tourniquet time and blood draws must be minimized. The objectives of these studies were to evaluate zilurgisertib pharmacokinetics, safety, tolerability, and the effect of food in healthy participants from phase 1 single ascending dose (SAD) and multiple ascending dose (MAD) studies.

Methods: Both the SAD and MAD studies were double-blind, randomized, placebo-controlled dose escalation studies. In the SAD study, healthy participants received a single oral dose of zilurgisertib (10, 25, 50, 100, 175, 250, or 500 mg) or placebo in the fasted state. A further group of healthy participants were enrolled into an additional "food effect" cohort and randomized to receive a single oral dose of zilurgisertib (100 mg) after either an overnight fast or a high-fat meal in a 2-way crossover manner. In the MAD study, healthy participants received oral zilurgisertib at 50, 100, 150, 200, or 400 mg once daily or 300 mg twice daily in the fasted state. Blood, saliva, and urine samples were collected for zilurgisertib pharmacokinetic analysis. Safety was assessed throughout both studies.

Results: Overall, 91 participants (70 active, 21 placebo) were enrolled and randomized to the SAD study and 79 participants (59 active, 20 placebo) were enrolled and randomized to the MAD study. Zilurgisertib was generally well tolerated, and adverse events were generally of mild-to-moderate severity. Zilurgisertib was rapidly absorbed, with median time to maximum plasma drug concentration (C_max) of 2.0-4.1 h post-dose. Zilurgisertib exposure was more than dose proportional after single and multiple doses over the dose range tested, suggesting non-linear pharmacokinetics. Plasma half-life values ranged from 22.8 to 31.4 h, supporting once-daily dosing. There was a strong correlation between zilurgisertib concentrations in saliva and plasma. No food effect was observed on zilurgisertib pharmacokinetics, with geometric mean ratio (90% confidence interval) C_max and area under the plasma concentration-time curve values of 0.98 (0.91 to1.06) and 1.03 (0.97 to 1.10). Renal excretion under fasted conditions was 16% and 27% of total drug clearance with single and multiple doses, respectively; therefore, it was not the predominant pathway for zilurgisertib elimination.

Conclusions: Zilurgisertib exhibited a favorable pharmacokinetic profile amenable to once-daily dosing that can be administered without regard to food. Study results support further clinical development of zilurgisertib in patients.