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Islatravir (MK-8591) is a highly potent type 1 human immunodeficiency virus (HIV-1) nucleoside reverse transcriptase translocation inhibitor with a long intracellular half-life that is in development for the prevention and treatment of HIV-1. We conducted a randomized, double-blind, placebo-controlled, phase 1 trial in adults without HIV-1 infection. Participants received islatravir or placebo subdermal implants for 12 weeks and were monitored throughout this period and after implant removal. The co-primary end points were safety and tolerability of the islatravir implant and pharmacokinetics, including concentration at day 85, of islatravir triphosphate in peripheral blood mononuclear cells (PBMCs). Secondary end points included additional pharmacokinetic parameters for islatravir triphosphate in PBMCs and the plasma pharmacokinetic profile of islatravir. Based on preclinical data, two doses were assessed: 54 mg ( n  = 8, two placebo) and 62 mg ( n  = 8, two placebo). The most frequently reported adverse events were mild-to-moderate implant-site reactions (induration, hematoma, pain). Throughout the 12-week trial, geometric mean islatravir triphosphate concentrations were above a pharmacokinetic threshold of 0.05 pmol per 10 6 PBMCs, which was estimated to provide therapeutic reverse transcriptase inhibition (concentration at day 85 (percentage of geometric coefficient of variation): 54 mg, 0.135 pmol per 10 6 cells (27.3); 62 mg, 0.272 pmol per 10 6 cells (45.2)). Islatravir implants at both doses were safe and resulted in mean concentrations above the pharmacokinetic threshold through 12 weeks, warranting further investigation of islatravir implants as a potential HIV prevention strategy. A subdermal implant of the HIV-1 antiretroviral islatravir delivers sustained drug release over 12 weeks in humans.

Introduction Human respiratory syncytial virus (RSV) infections can result in hospitalization and/or death among vulnerable populations. Molnupiravir is a prodrug of ß-D-N4-hydroxycytidine, which has broad-spectrum preclinical activity against RNA viruses. We conducted a pilot trial evaluating molnupiravir for RSV infection. Methods Double-blind, placebo-controlled, phase 2a human challenge study in healthy adults (≥ 18 to ≤ 55 years old). Eligible participants were randomized 1:1:1 to molnupiravir prophylaxis (5 days, 800 mg twice daily; followed by placebo), molnupiravir treatment (5 days, 800 mg twice daily; started on day 5, unless triggered earlier by positive PCR test; preceded and followed by placebo), or placebo. Study intervention was administered for 11 days, from day −1 (evening), prior to inoculation with RSV on day 0 (morning). For 10 days, quarantined participants reported symptoms thrice daily and underwent nasal wash sample collection twice daily. Primary efficacy endpoints (assessed by quantitative viral culture on plaque assay) were peak viral load (PVL) in all participants (for prophylaxis) and area under the viral-load time curve (VL-AUC) in participants with confirmed infection (for treatment). Adverse events were assessed from day 0 to day 28. Results Forty participants each were randomized to prophylaxis and placebo and 36 to treatment. Molnupiravir was not statistically significant from placebo in either primary endpoint: with prophylaxis, the difference in mean log 10 PVL was − 0.29 plaque-forming units (PFU)/ml (90% CI − 1.16, 0.58; p  = 0.578), and with treatment, the difference in mean log 10 VL-AUC was − 2.69 day*PFU/ml (90% CI − 6.17, 0.79; p  = 0.201). Molnupiravir treatment resulted in significantly faster symptom resolution: 6.0 days versus 8.5 days with placebo (hazard ratio: 2.24 [95% CI: 0.99, 5.07]; p  = 0.0459). Adverse event rates were comparable between arms. Conclusions Although the primary endpoints were not met, modest, non-significant benefits with molnupiravir treatment were seen across virologic endpoints, along with significantly faster symptom resolution. Clinical Trial Registration ClinicalTrials.gov NCT05559905.

Molnupiravir is an orally administered prodrug of β‐D‐N4‐hydroxycytidine (NHC) that is conditionally approved in China for the treatment of mild to moderate COVID‐19 in nonhospitalized adults at high risk of disease progression. Molnupiravir is rapidly absorbed and hydrolyzed to deliver NHC into systemic circulation. An open‐label, fixed‐sequence, Phase 1 study was conducted to evaluate the tolerability, safety, and pharmacokinetics (PK) following single and multiple (every 12 h for 5.5 days) oral dosing of molnupiravir 800 mg in 16 healthy, male Chinese participants. After multiple doses of molnupiravir, the median time to maximum concentration was 2.0 h for plasma NHC. NHC concentrations generally decreased in a biphasic manner, with a terminal half‐life of 21.9 h, and NHC exposures (i.e., area under the curve and maximum plasma concentration) were similar following single and multiple doses of molnupiravir. No accumulation of NHC in plasma was observed. When compared with historical data from published clinical trials of similar study design, NHC exposure in Chinese participants was marginally higher than that in non‐Asian participants but remained within established clinical bounds. Overall, molnupiravir was generally well‐tolerated. Ten participants (63.5%) experienced at least one adverse event throughout the study, the severity of which was mild or moderate, and none led to treatment discontinuation. There were no clinically meaningful findings in other safety evaluations. These data support use of the standard 5‐day regimen of molnupiravir 800 mg every 12 h without dose adjustment for the treatment of COVID‐19 in the Chinese population. Study Highlights What is the current knowledge on the topic? ○Molnupiravir is an orally administered prodrug of β‐D‐N4‐hydroxycytidine (NHC) with potent, broad‐spectrum preclinical activity against RNA viruses, including SARS‐CoV‐2, and a high barrier to the development of resistance. ○Molnupiravir is conditionally approved in China for the treatment of mild to moderate COVID‐19 in nonhospitalized adults at high risk of disease progression. ○The safety and pharmacokinetics (PK) of molnupiravir have been extensively studied in clinical trials in which healthy volunteers and patients with COVID‐19 were enrolled. ○Tolerability and PK data in Asian populations are limited. What question did this study address? ○An open‐label, fixed‐sequence, Phase 1 study was conducted to evaluate the tolerability, safety, and PK following single and multiple (every 12 h for 5.5 days) oral dosing of molnupiravir 800 mg in 16 healthy, male Chinese participants. What does this study add to our knowledge? ○Molnupiravir was generally well tolerated in healthy Chinese participants; all adverse events were mild or moderate in severity, and none resulted in treatment discontinuation. ○NHC concentrations generally decreased in a biphasic manner and NHC exposures were similar following single and multiple doses of molnupiravir in healthy Chinese participants; no accumulation of NHC in plasma was observed. ○The NHC exposure observed in Chinese participants was marginally higher than the exposure previously reported in non‐Asian individuals but remained within the established clinical bounds for NHC. How might this change clinical pharmacology or translational science? ○These results support the use of the standard regimen of molnupiravir for the treatment of COVID‐19 (i.e., 800 mg every 12 h for 5 days) in the Chinese population without the need for dose adjustment.

Omarigliptin (MK-3102) is a potent, oral, long-acting dipeptidyl peptidase (DPP)-4 inhibitor approved in Japan and in global development as a once-weekly treatment for type 2 diabetes mellitus (T2DM). The aim of this study was to investigate the pharmacokinetic (PK) and pharmacodynamic (PD) effects of omarigliptin in obese participants with and without T2DM. This was a Phase I, randomized, double-blind, placebo-controlled, multiple-dose study of 50-mg omarigliptin administered once weekly for 4 weeks. Participants included 24 obese but otherwise healthy subjects (panel A; omarigliptin, n = 18; placebo, n = 6) and 8 obese patients with T2DM (treatment naive, hemoglobin A1c ≥6.5% and ≤10.0% [panel B]; omarigliptin, n = 6; placebo, n = 2). Participants were 45 to 65 years of age with a body mass index of ≥30 and ≤40 kg/m2. Blood sampling occurred at select time points, depending on the study panel, to evaluate the PK properties of omarigliptin, DPP-4 activity, active glucagon-like peptide 1 levels, and plasma glucose concentrations. Body weight was an exploratory end point. Due to sparse sampling in panel A, a thorough PK analysis was performed in obese patients with T2DM (panel B) only. PD analyses were performed in the overall study population (pooled panels A and B). PK profiles in obese participants with and without T2DM were similar to those observed in nonobese reference subjects (historical data). Steady state was achieved after 1 or 2 weekly doses in obese participants with and without T2DM. In obese patients with T2DM, omarigliptin was rapidly absorbed, with a median Tmax of 1 to 2.5 hours (days 1 and 22). Compared with those in reference subjects, the geometric mean ratios (95% CI) (Obese T2DM/reference) for steady-state plasma AUC0–168h, Cmax, and C168h were 0.80 (0.65–0.98), 0.86 (0.53–1.41), and 1.08 (0.88–1.33), respectively. Trough DPP-4 activity was inhibited by ~90%; postprandial (PP) 4-hour weighted mean active GLP-1 concentrations were increased ~2-fold; and PP glucose was significantly reduced with omarigliptin versus placebo in the pooled population. Omarigliptin was generally well-tolerated in the pooled population, and there were no hypoglycemic events. Consistent with other DPP-4 inhibitors, omarigliptin had no effect on body weight in this short-duration study. The administration of omarigliptin was generally well-tolerated in obese participants with and without T2DM, and the favorable PK and PD profiles support once-weekly dosing. Omarigliptin may provide an important once-weekly treatment option for patients with T2DM. ClinicalTrials.gov identifier: NCT01088711.

Phase I trials inform on the initial safety profile of a new molecule and impact whether further development is pursued or not. Understanding the effect of non‐pharmacological factors on the variability of routine safety parameters could improve decision making in these early clinical trials, helping to separate signals related to the new molecule from background “noise.” To understand the impact of non‐pharmacological factors on routine safety parameters, we evaluated pooled safety data from over 1000 healthy participants treated with placebo in phase I trials between 2009 and 2018. The phase I participants were predominantly men, less than or equal to 50 years, White, and non‐Hispanic; and approximately an equal proportion had body mass index in the normal and overweight/obese range. Following administration of placebo, vital signs, electrocardiogram, and laboratory parameters remained near predose baseline values. Large changes from baseline were observed for many safety parameters, but these occurred in a relatively small number of participants. At least one adverse event (AE) occurred in 49.7% of participants receiving placebo in single ascending dose (SAD) studies and in 72.4% of participants receiving placebo in multiple ascending dose (MAD) studies, with headache being the most commonly reported AE (18.7% in SAD and 28.3% in MAD studies). Overall, these analyses are consistent with non‐pharmacological factors having a small impact on routine safety parameters in a phase I trial. The provided supplemental data may be used to contextualize the magnitude and frequency of abnormal safety values and AEs observed in phase I trials.

MK‐8527 is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) in clinical development. Two Phase 1 trials evaluated single (trial A) and multiple (trial B) ascending doses of MK‐8527 in adults without HIV. In trial A, 34 participants were assigned to 1 of 4 panels and randomized to receive single oral doses of MK‐8527 (0.5–200 mg) or placebo after fasting, over 3 dosing periods; 25 mg was assessed after a high‐fat meal. In trial B, 32 participants were randomized to receive 3 once‐weekly (QW) oral doses of MK‐8527 (between 5 and 40 mg) or placebo. Safety and pharmacokinetics (PK) of MK‐8527 and MK‐8527‐triphosphate (TP) were assessed. MK‐8527 was generally well tolerated with no serious adverse events. Plasma exposure of MK‐8527 increased approximately dose‐proportionally, and intracellular exposure of MK‐8527‐TP was slightly less than dose‐proportional over administered doses between 5 and 200 mg. Participants who received MK‐8527 with a meal showed a 41% decrease in Cmax with no effect on AUC0–168, and a 20%, 22%, and 58% increase in intracellular MK‐8527‐TP Cmax, C168, and AUC0–168, respectively. Across QW doses, plasma MK‐8527 median Tmax ranged from 0.5 to 1 h, and t1/2 was 24–81 h; MK‐8527‐TP median Tmax ranged from 10 to 24 h on Day 15, and geometric mean apparent t1/2 was 216–291 h. Accumulation of intracellular MK‐8527‐TP was modest (accumulation ratios [Day 15/Day 1] for Cmax and AUC0–168 ranged from 1.1 to 1.6; C168 from 1.2 to 2.4). Single and multiple QW doses of MK‐8527 were generally well tolerated in adults without HIV. The safety and PK profiles of MK‐8527 support continued clinical development. Trial Registration: EudraCT numbers: 2016‐004647‐36 (trial A); 2018‐000846‐20 (trial B)

Molnupiravir is an orally administered, small‐molecule ribonucleoside prodrug of β‐D‐N4‐hydroxycytidine (NHC) that has demonstrated potent, broad‐spectrum preclinical activity against RNA viruses and has a high barrier to the development of resistance. A double‐blind, placebo‐controlled, phase I trial was conducted to evaluate the pharmacokinetics (PKs), safety, and tolerability of 10.5‐day administration of multiple doses of molnupiravir and its metabolites in healthy, adult participants. Participants were randomly assigned (3:1) to receive molnupiravir (400 mg [ n  = 6], 600 mg [ n  = 6], and 800 mg [ n  = 12]) or matching placebo ( n  = 8) every 12 h (q12h) for 10.5 days. Blood was collected to evaluate the PKs of NHC in plasma and of its active metabolite, NHC‐triphosphate (NHC‐TP), in peripheral blood mononuclear cells (PBMCs). Molnupiravir was generally well‐tolerated. All adverse events were mild or moderate in severity and none led to treatment discontinuation. No clinically meaningful dose‐related safety findings were observed. Mean time to maximal concentration was ~1.50 to 1.98 h for plasma NHC and ~4.00 to 8.06 h for PBMC NHC‐TP. Accumulation was minimal (<1.2) for NHC and ~2‐ to 2.5‐fold for NHC‐TP. Plasma NHC PKs was generally dose proportional, and PBMC NHC‐TP PKs was less than dose proportional over the dose range studied. NHC and NHC‐TP PK support twice‐daily administration. Overall, molnupiravir administered at up to 800 mg q12h for 10.5 days was generally well‐tolerated in healthy participants with dose‐linear PKs, supporting the evaluation of longer molnupiravir dosing up to 10 days in future clinical trials.

This phase 1 study (NCT04370873) evaluated safety and pharmacokinetics/pharmacodynamics (PK/PD) of MK-5475 in participants with pulmonary hypertension associated with COPD (PH-COPD). Eligible participants were 40-80 years old with COPD (FEV /FVC <0.7; FEV >30% predicted) and PH (mean pulmonary arterial pressure ≥25 mmHg). Participants were randomized 2:1 to MK-5475 or placebo via dry-powder inhaler once daily for 7 days in Part 1 (360 µg) or 28 days in Part 2 (380 µg). Safety was assessed by adverse events (AEs) and arterial blood oxygenation. Part-2 participants had pulmonary vascular resistance (PVR; primary PD endpoint) and pulmonary blood volume (PBV; secondary PD endpoint) measured at baseline and Day 28. A non-informative prior was used to calculate posterior probability (PP) that the between-group difference (MK-5475 - placebo) in mean percent reduction from baseline in PVR was less than -15%. Nine participants were randomized in Part 1, and 14 participants in Part 2. Median age of participants (86.4% male) was 68.5 years (41-77 years); 95.5% had moderate-to-severe COPD. Incidences of AEs were comparable between MK-5475 and placebo: overall (5/14 [36%] versus 5/8 [63%]), drug-related (1/14 [7%] versus 2/8 [25%]), and serious (1/14 [7%] versus 1/8 [13%]). MK-5475 caused no meaningful changes in arterial blood oxygenation or PBV. MK-5475 versus placebo led to numerical improvements from baseline in PVR (-21.2% [95% CI: -35.4, -7.0] versus -5.4% [95% CI: -83.7, 72.9]), with between-group difference in PVR less than -15% and calculated PP of 51%. The favorable safety profile and numerical reductions in PVR observed support further clinical development of inhaled MK-5475 for PH-COPD treatment.

Development and validation of digital measures require dedicated clinical studies, which can be conducted by a single study sponsor or a precompetitive collaboration. In this perspective, we propose an alternative model, data syndication, a curated collaboration, which foresees a technology provider being a founding member with biopharmaceutical sponsors and other stakeholders joining. Its main advantages are the speed of the study startup and the opportunity for real‐time data streaming.

[¹⁸F]MK-9470 is a selective, high-affinity, inverse agonist (human IC₅₀, 0.7 nM) for the cannabinoid CB1 receptor (CB1R) that has been developed for use in human brain imaging. Autoradiographic studies in rhesus monkey brain showed that [¹⁸F]MK-9470 binding is aligned with the reported distribution of CB1 receptors with high specific binding in the cerebral cortex, cerebellum, caudate/putamen, globus pallidus, substantia nigra, and hippocampus. Positron emission tomography (PET) imaging studies in rhesus monkeys showed high brain uptake and a distribution pattern generally consistent with that seen in the autoradiographic studies. Uptake was blocked by pretreatment with a potent CB1 inverse agonist, MK-0364. The ratio of total to nonspecific binding in putamen was 4-5:1, indicative of a strong specific signal that was confirmed to be reversible via displacement studies with MK-0364. Baseline PET imaging studies in human research subject demonstrated behavior of [¹⁸F]MK-9470 very similar to that seen in monkeys, with very good test-retest variability (7%). Proof of concept studies in healthy young male human subjects showed that MK-0364, given orally, produced a dose-related reduction in [¹⁸F]MK-9470 binding reflecting CB1R receptor occupancy by the drug. Thus, [¹⁸F]MK-9470 has the potential to be a valuable, noninvasive research tool for the in vivo study of CB1R biology and pharmacology in a variety of neuropsychiatric disorders in humans. In addition, it allows demonstration of target engagement and noninvasive dose-occupancy studies to aid in dose selection for clinical trials of CB1R inverse agonists.