This was a randomized, placebo-controlled, double-blind, single-site, multiperiod, phase 1, first-in-human study. Healthy men and women of non–child-bearing potential aged between 18 and 45 years with a body mass index of  ≤ 32 kg/m2 and normal renal function (creatinine clearance > 80 mL/min based on the Cockcroft-Gault equation) were eligible for enrollment. Participants with a history of any malignancy, positivity for hepatitis B, hepatitis C, or HIV, or who require any prescription or nonprescription medications were ineligible.

Participants were enrolled in two panels (A and B). Four single-dose escalations of MK-1088 over five treatment periods were planned in each panel (Online Resource 1). Participants received study interventions in all periods under fasted conditions except for panel A, period 5, in which participants received MK-1088 or placebo with a high-fat meal. Specifically, participants in panel A received single ascending doses of MK-1088 at 1 mg, 10 mg, 50 mg, and 150 mg or placebo orally in a fasted state in periods 1–4 and 50 mg or placebo orally with a high-fat meal in period 5. Participants in panel B received single ascending doses of MK-1088 at 3 mg, 25 mg, 100 mg, and 224 mg or placebo orally in a fasted state in periods 1–4. Within each panel, participants were randomly assigned to receive MK-1088 or placebo in each of the periods. The assigned treatment for periods 3 and 5 (fasted/fed) in panel A were the same for each participant, such that the same participants received the active drug (MK-1088 50 mg) or matching placebo in both treatment periods. There was an interval of ≥ 3 days before dose escalation between panels and a washout period of ≥ 7 days between doses within each panel. A pharmacokinetic break for all participants occurred after completion of the 25-mg dose in panel B (period 2) and the 100-mg dose in panel B (period 3) to support dose escalation decisions.

The primary objectives of this study were to evaluate the safety, tolerability, and pharmacokinetic properties of single ascending doses of MK-1088. The primary pharmacokinetic hypothesis was that the true geometric mean concentration of MK-1088 at 12 h post dose (C12h) was > 0.3 µM at one or more well-tolerated fasted dose levels, based on predicted target engagement levels > 98% for A2A receptors and > 80% for A2B receptors. The aspirational target C12h was 1 µM based on predicted target engagement levels > 99.5% for A2A and > 90.0% for A2B. The secondary objective was to evaluate the effect of a high-fat meal on plasma pharmacokinetics compared with the fasted state.

Safety and tolerability were assessed by vital signs, 12-lead electrocardiogram (ECG), laboratory safety tests, and physical/neurological examinations as well as by reported adverse events (AEs), serious AEs, and other reportable safety events collected using open-ended, nonleading verbal questions. Safety was monitored from treatment allocation through 14 days after the last dose of study treatment. AE terms were taken from the Medical Dictionary for Regulatory Activities (MedDRA) version 24.0. Blood samples for pharmacokinetic analyses were collected before dosing and at 0.5 h, 1 h, 2 h, 4 h, 8 h, 10 h, 12 h, 24 h, 48 h, and 72 h post dose. The pharmacokinetic parameters analyzed were MK-1088 plasma concentration, area under the concentration-time curve (AUC) extrapolated to infinity (AUC0–inf), AUC from 0 to 24 h (AUC024h), time to maximum plasma concentration (Tmax), maximum plasma concentration (Cmax), concentration at 12 and 24 h post-dose (C12h and C24h, respectively), clearance or apparent total clearance after oral administration (CL/F), apparent volume of distribution after oral administration (Vz/F), and apparent terminal half-life (t½).

Safety and tolerability were reported as summary statistics and were assessed in all participants who received ≥ 1 dose of study drug. Pharmacokinetic analyses were performed in all participants who completed treatment per protocol. The primary hypothesis that the geometric mean C12h of MK-1088 exceeds 0.3 µM at one or more well-tolerated fasted doses was tested using a linear mixed effects model. Bayesian methodology was used for decision making, and posterior probability was calculated using model-based estimates. The posterior probability that the true geometric mean C12h is > 0.3 µM was calculated for each dose level, assuming normality and a noninformative prior. The pharmacokinetic hypothesis would be satisfied by posterior probability of ≥ 60% for at least one dose level that also demonstrates an acceptable safety and tolerability profile. Assuming the true coefficient of variance is 30%, there was a 93% probability to yield ≥ 80% posterior probability that the geometric mean of C12h was > 0.3 µM when the true geometric mean of C12h was 0.4 µM (n = 6) under the univariate normal likelihood model with a noninformative prior.

Pharmacokinetic parameters were calculated by noncompartmental analysis using Phoenix WinNonlin® Professional version 8.1 (Certara, Inc., New Jersey, NJ, USA). Model-based estimates for individual values of AUC0–inf, AUC0–24h, Cmax, C12h, C24h, CL/F, and Vz/F at each fasted and fed dose level were natural log-transformed and evaluated with a linear mixed effects model containing fixed effects for treatment and a random effect for participants. An unstructured covariance matrix was used to allow for unequal treatment variances and to model the correlation between the treatment measurements for each participant (SAS v9.4, Cary, NC, USA). The Kenward and Roger method was used to calculate the denominator degrees of freedom for the fixed effects. 95% confidence intervals for the least squares means for each factor level were constructed on the natural logarithmic scale and referenced the t-distribution. Exponentiating the least squares means and lower and upper limits of these confidence intervals yielded estimates for the population geometric means and confidence intervals about the geometric means on the original scale. Dose proportionality of MK-1088 AUC0–inf, AUC0–24h, and Cmax in the fasted stated was explored using a linear mixed effect model with natural logarithm of the dose, panel, and natural logarithm of dose by panel interaction as fixed effects and participants within panel as a random effect. The effect of food on MK-1088 pharmacokinetics was estimated using a geometric mean ratio of the fed state over the fasted state and 90% confidence intervals using the same linear mixed effects model.