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Aim: To investigate the effects of lotiglipron (PF‐07081532), a once‐daily, oral small‐molecule glucagon‐like peptide‐1 receptor agonist, in participants with type 2 diabetes (T2D) and/or obesity. Materials and Methods: Two Phase 1 randomized, double‐blind, placebo‐controlled, multiple‐ascending‐dose studies were conducted to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of lotiglipron. Results: Across the studies, 74 participants with T2D were treated for 28 or 42 days, and 26 participants with obesity without diabetes were treated for 42 days, following randomization to placebo or lotiglipron (target doses 10–180 mg/day, with dose titration to higher target doses). Most adverse events were mild (89.6%), with nausea the most frequently reported in both studies. There were no clinically meaningful adverse trends noted in safety laboratory tests, vital signs, or electrocardiogram parameters. In participants with T2D, lotiglipron resulted in dose‐dependent reductions in mean daily glucose. The 180‐mg dose was associated with least squares mean decreases from baseline in glycated haemoglobin (−1.61% [90% confidence interval {CI} –2.08, −1.14] vs. −0.61% [−1.56, 0.34] for placebo) and body weight (−5.10 kg [90% CI –6.62, −3.58] vs. −2.06 kg [90% CI –4.47, 0.36] for placebo) after 42 days; a similar magnitude of weight loss was seen in participants with obesity. The observed pharmacokinetic profile supported once‐daily dosing. Conclusions: The profile of once‐daily lotiglipron with doses up to 180 mg, as observed in these two Phase 1 studies, indicated a safety and tolerability profile consistent with the mechanism of action, with dose‐dependent reductions in glycaemic indices (T2D) and body weight (both populations) after multiple doses. Clinicaltrials.gov identifier: NCT04305587, NCT05158244. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the tolerability, safety and pharmacodynamics of different dose‐escalation schemes of the oral small‐molecule glucagon‐like peptide‐1 receptor (GLP‐1R) agonist danuglipron. Materials and Methods: This Phase 2a, double‐blind, placebo‐controlled, parallel‐group study randomly assigned adults with type 2 diabetes (T2D) treated with metformin to placebo or danuglipron (low [5‐mg] or high [10‐mg] starting dose, with 1‐ or 2‐week dose‐escalation steps, to target doses of 80, 120 or 200 mg twice daily [BID]) and adults with obesity without diabetes to placebo or danuglipron 200 mg BID. Results: Participants with T2D (n = 123, mean glycated haemoglobin [HbA1c] 8.19%) or obesity without diabetes (n = 28, mean body mass index 37.3 kg/m2) were randomly assigned and treated. Discontinuation from study medication occurred in 27.3% to 72.7% of participants across danuglipron groups versus 16.7% to 18.8% for placebo, most often due to adverse events. Nausea (20.0%‐47.6% of participants across danuglipron groups vs. 12.5% for placebo) and vomiting (18.2%‐40.9% danuglipron vs. 12.5% placebo, respectively) were most commonly reported in participants with T2D. Gastrointestinal adverse events were generally related to danuglipron target dose and were not substantially affected by starting dose. In participants with T2D, least squares mean changes from baseline in HbA1c (−1.04% to −1.57% across danuglipron groups vs. −0.32% for placebo), fasting plasma glucose (−23.34 mg/dL to −53.94 mg/dL danuglipron vs. −13.09 mg/dL placebo) and body weight (−1.93 to −5.38 kg danuglipron vs. −0.42 kg placebo) at Week 12 were generally statistically significant for danuglipron compared with placebo (P < 0.05). Conclusions: Danuglipron resulted in statistically significant reductions in HbA1c, FPG and body weight over 12 weeks, in the setting of higher discontinuation rates and incidence of gastrointestinal adverse events with higher target doses. Clinicaltrials.gov identifier: NCT04617275. [ABSTRACT FROM AUTHOR]