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Pfizer’s twice-daily danuglipron formulation to be discontinued after high rates of GI complaints

Topline data from Pfizer’s Phase 2b clinical trial investigating its oral Glucagon-like peptide-1 receptor agonist (GLP-1RA) candidate, danuglipron, in adults with obesity and without type 2 diabetes has revealed the study met its primary endpoint demonstrating statistically significant change in body weight from baseline. However, the twice-daily danuglipron formulation resulted in high rates of gastrointestinal complaints (73% nausea; 47% vomiting; 25% diarrhoea). High discontinuation rates, greater than 50%, were seen across all doses compared to approximately 40% with placebo.

Although the most common adverse events were mild and gastrointestinal in nature consistent with the mechanism, at this time twice-daily danuglipron formulation will not advance into Phase 3 studies. Future development of danuglipron will be focused on a once-daily formulation, with pharmacokinetic data anticipated in the first half of 2024.

“We believe an improved once-daily formulation of danuglipron could play an important role in the obesity treatment paradigm, and we will focus our efforts on gathering the data to understand its potential profile,” said Dr Mikael Dolsten, Chief Scientific Officer & President, Pfizer Research and Development. “Results from ongoing and future studies of the once-daily danuglipron modified release formulation will inform a potential path forward with an aim to improve the tolerability profile and optimize both study design and execution.”

Nevertheless, twice-daily dosing of danuglipron showed statistically significant reductions from baseline in body weight for all doses, with mean reductions ranging from -6.9% to -11.7%, compared to +1.4% for placebo at 32 weeks, and -4.8% to -9.4%, compared to +0.17% for placebo at 26 weeks. Placebo-adjusted reductions in mean body weight ranged from -8% to -13% at 32 weeks and -5% to -9.5% at 26 weeks. Depending on titration schedule, participants were at target dose levels for 6 to 24 weeks.

No new safety signals were reported and treatment with danuglipron was not associated with increased incidence of liver enzyme elevation compared to placebo. Data from this study will be presented at a future scientific conference or published in a peer-reviewed journal.

Results previously published in the Journal of the American Medical Association Network Open from the Phase 2 study of danuglipron in type 2 diabetes showed dose-dependent placebo-adjusted reductions in HbA1c of up to -1.16%; fasting plasma glucose of -33.24 mg/dL; and body weight of -4.17 kg over 16 weeks. Additionally, the Phase 2a study (NCT04617275) of danuglipron in patients with type 2 diabetes who are treated with metformin and in non-diabetic adults with obesity showed robust declines in HbA1c, fasting plasma glucose (FPG) and body weight. In both populations, danuglipron demonstrated a safety and tolerability profile consistent with the mechanism of action.

The Phase 2b randomized, double-blind, placebo-controlled, parallel group, dose-ranging study evaluated the efficacy and safety of danuglipron administration in adults with obesity and without type 2 diabetes. The study evaluated three cohorts across different fixed titration schedules and target doses. Cohorts 1 and 2 (n=497) evaluated one-week and two-week titration steps over 26 weeks with target doses at 40mg, 80mg, 120mg, 160mg and 200mg twice-daily. Cohort 3 (n=129) evaluated four-week titration steps over 32 weeks with target doses at 80mg, 140mg and 200mg twice-daily. The study utilised a titration protocol where participants were required to follow a fixed titration scheme, according to their randomised treatment group.

Danuglipron is an experimental medicine that is taken as a tablet by mouth and is not approved for use by health authorities at this time.


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