danuglipron immediate release (PF-06882961 IR) / Pfizer - LARVOL DELTA

Pfizer drops obesity pill development after liver injury report (Yahoo Finance) - P1 | N=82 | NCT06567327 | N=23 | NCT06568731 | Sponsor: Pfizer | "Pfizer has terminated the development of its oral obesity candidate danuglipron after a patient on a clinical trial with the drug suffered a liver injury...Two Phase I studies (NCT06567327 and NCT06568731) met pharmacokinetic (PK) endpoints and determined a formulation and dose for danuglipron. In one of these studies, an asymptomatic patient experienced a potential drug-induced liver injury. The injury resolved after drug discontinuation; however, Pfizer has decided, based on this event, available clinical data, and recent input from regulators to discontinue the development of the drug. The therapy has been investigated in a total of 1,400 patients."

Discontinued • P1 data • Obesity

A Study to Evaluate the Efficacy and Safety of PF-06882961 in Adults With Obesity (clinicaltrials.gov) - P2 | N=628 | Completed | Sponsor: Pfizer | Phase classification: P2b ➔ P2

Phase classification • Genetic Disorders • Obesity

Study to Learn How Different Forms of The Study Medicine Called Danuglipron Are Taken up Into the Blood In Healthy Adults (clinicaltrials.gov) - P1 | N=20 | Recruiting | Sponsor: Pfizer | Trial completion date: Jan 2024 ➔ May 2024 | Trial primary completion date: Jan 2024 ➔ May 2024

Trial completion date • Trial primary completion date

Pfizer (PFE) plans to announce Danuglipron Phase 2b clinical trial results at the end of the year… expected to secure at least a high single-digit market share [Google translation] (Infostock Daily) - "Danuglipron (PF-07081532), Pfizer's only clinical-stage obesity treatment candidate, is scheduled to announce the results of phase 2b clinical trials at the end of the year. The final patient intervention for weight loss rate, the primary efficacy evaluation indicator, is expected to have already been completed in mid-September."

P2b data • Trial status • Metabolic Disorders • Obesity

Study to Learn How Different Forms of The Study Medicine Called Danuglipron Are Taken up Into the Blood In Healthy Adults (clinicaltrials.gov) - P1 | N=20 | Recruiting | Sponsor: Pfizer | Not yet recruiting ➔ Recruiting

Enrollment open

Pfizer Announces Topline Phase 2b Results of Oral GLP-1R Agonist, Danuglipron, in Adults with Obesity (Businesswire) - P2b | N=630 | NCT04707313 | Sponsor: Pfizer | "Pfizer Inc...today announced topline data from the Phase 2b clinical trial (NCT04707313) investigating...danuglipron (PF-06882961), in adults with obesity and without type 2 diabetes. The study met its primary endpoint demonstrating statistically significant change in body weight from baseline. 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....Future development of danuglipron will be focused on a once-daily formulation, with pharmacokinetic data anticipated in the first half of 2024."

P2b data • PK/PD data • Metabolic Disorders • Obesity

Study to Learn How Different Forms of The Study Medicine Called Danuglipron Are Taken up Into the Blood In Healthy Adults (clinicaltrials.gov) - P1 | N=20 | Not yet recruiting | Sponsor: Pfizer

New P1 trial

Safety and efficacy of the new, oral, small-molecule, GLP-1 receptor agonists orforglipron and danuglipron for the treatment of type 2 diabetes and obesity: systematic review and meta-analysis of randomized controlled trials. (PubMed, Metabolism) - "Preliminary evidence supports that orforglipron and danuglipron are efficient in glycemic control and weight reduction in T2DM, obesity or both. More longitudinal research is warranted in order to provide deeper insights into their efficacy, safety and tolerability before their potential incorporation in the pharmacological arsenal against T2DM or obesity."

Journal • Retrospective data • Review • Diabetes • Gastrointestinal Disorder • Genetic Disorders • Metabolic Disorders • Obesity • Severe Hypoglycemia • Type 2 Diabetes Mellitus

Evaluating Glycemic Control Efficacy and Safety of the Oral Small Molecule Glucagon-Like Peptide 1 Receptor Agonist Danuglipron in Type 2 Diabetes Patients: A Systemic Review and Meta-Analysis. (PubMed, Diabetes Metab Syndr Obes) - "Adverse outcomes include diarrhea, nausea, vomiting, and decreased appetite, with dose-related effects. Clinicians must weigh benefits against side effects when considering Danuglipron for T2DM management."

Journal • Retrospective data • Review • Diabetes • Dyspepsia • Metabolic Disorders • Pain • Type 2 Diabetes Mellitus

Newer Pharmacological Interventions Directed at Gut Hormones for Obesity. (PubMed, Br J Pharmacol) - "There are several approved single or dual incretin agonists which are administered subcutaneously daily (e.g., liraglutide) or weekly (e.g., semaglutide, dulaglutide, and exenatide QW), and experimental dual or triple incretin agonists...Oral semaglutide (administered daily) is approved for type 2 diabetes and is on track for regulatory review for obesity...In the future, it is anticipated that small molecule GLP-1 receptor agonists (e.g., oral danuglipron) will be developed. These pharmacological agents are having significant impact on glycemic control and obesity and their co-morbidities."

Journal • Review • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

A Study to Evaluate the Efficacy and Safety of PF-06882961 in Adults With Obesity (clinicaltrials.gov) - P2b | N=630 | Completed | Sponsor: Pfizer | Active, not recruiting ➔ Completed

Trial completion • Genetic Disorders • Obesity

Effect of Renal Impairment on The Pharmacokinetics of A Single Oral Dose of Danuglipron In Participants With Type 2 Diabetes. (PubMed, J Clin Pharmacol) - "A single 20-mg oral dose of danuglipron was generally safe and well tolerated in all participant groups. In participants with T2D, renal impairment had no clinically meaningful effect on the pharmacokinetic, safety, and tolerability profiles of danuglipron, indicating that dose adjustment of danuglipron will not be required when administered to patients with T2D and reduced renal function."

Journal • PK/PD data • Chronic Kidney Disease • Diabetes • Genetic Disorders • Metabolic Disorders • Nephrology • Obesity • Renal Disease • Type 2 Diabetes Mellitus

Efficacy of novel small molecule GLP-1 receptor agonist AZD0186 on glucose stimulated insulin secretion in obese, male non-human primates (EASD 2023) - "AZD0186 was evaluated in 3 dose groups 0.1, 0.25 and 0.7 mg/kg, positive control Danuglipron at 1 mg/kg and one group was treated with placebo. In response to the ivGTT, all three doses of AZD0186 induced an increase in the insulin AUC, Kg and decreased the glucose AUC in obese, dysmetabolic NHPs. The efficacy of AZD0186 achieved in this study supports further evaluation in human."

Clinical • Diabetes • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

6-Azaspiro[2.5]octanes as Small Molecule Agonists of the Human Glucagon-Like Peptide-1 Receptor. (PubMed, Bioorg Med Chem Lett) - "Herein, we describe an SAR investigation leading to small-molecule GLP-1 receptor agonists that represent a series that parallels the recently reported clinical candidate danuglipron...A new series of 6-azaspiro[2.5]octane molecules were optimized into potent GLP-1 agonists. Information gleaned from cryogenic electron microscope structures was used to rationalize the SAR of the optimized compounds."

Journal • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

Sosei Heptares Operational Highlights and Consolidated Results for the Second Quarter and First Half of 2023 (Yahoo Finance) - "Pfizer announced its decision to prioritize the development of danuglipron over lotiglipron for the treatment of diabetes and obesity...as a result, Pfizer discontinued the development of lotiglipron, a novel and orally available GLP-1 receptor agonist discovered and developed by Pfizer during a multi-target research collaboration with Sosei Heptares. Sosei Heptares will explore next steps with Pfizer for the future development of lotiglipron."

Discontinued • Pipeline update • Diabetes • Fibrosis • Immunology • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Obesity • Type 2 Diabetes Mellitus

Tolerability, safety and pharmacodynamics of oral, small-molecule glucagon-like peptide-1 receptor agonist danuglipron for type 2 diabetes: A 12-week, randomized, placebo-controlled, Phase 2 study comparing different dose-escalation schemes. (PubMed, Diabetes Obes Metab) - P2a | "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."

Journal • P2 data • PK/PD data • Diabetes • Gastrointestinal Disorder • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

Discovery of Novel 5,6-Dihydro-1,2,4-triazine Derivatives as Efficacious Glucagon-Like Peptide-1 Receptor Agonists. (PubMed, J Med Chem) - "Furthermore, 42 significantly reduces glucose excursion and inhibits food intake of hGLP-1R Knock-In mice. These effects are longer-lasting than that shown by danuglipron, demonstrating feasibility in the treatment of T2DM and obesity."

Journal • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

Efficacy and Safety of Oral Small Molecule Glucagon-Like Peptide 1 Receptor Agonist Danuglipron for Glycemic Control Among Patients With Type 2 Diabetes: A Randomized Clinical Trial. (PubMed, JAMA Netw Open) - P2b | "Adults with T2D inadequately controlled by diet and exercise, with or without metformin treatment, were enrolled from 97 clinical research sites in 8 countries or regions. In adults with T2D, danuglipron reduced HbA1c, FPG, and body weight at week 16 compared with placebo, with a tolerability profile consistent with the mechanism of action. ClinicalTrials.gov Identifier: NCT03985293."

Clinical • Journal • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

Discovery and synthesis of danuglipron (PF-06882961): A small molecule GLP-1 receptor agonist– from lead to clinical candidate (ACS-Sp 2023) - "This presentation will discuss the synthetic strategy toward PF-06882961 from mg scale parallel medicinal chemistry to kg scale for pre-clinical safety studies. Large scale amenable routes to the three key fragments (amino-oxetane, 4-pyridyl-piperdine and benzimidazole) will be highlighted with a focus on the discovery of a novel hydrolysis transformation utilizing an organic base in the penultimate step."

Clinical • Diabetes • Genetic Disorders • Hepatology • Metabolic Disorders • Non-alcoholic Steatohepatitis • Obesity

A Study to Evaluate the Efficacy and Safety of PF-06882961 in Adults With Obesity (clinicaltrials.gov) - P2b | N=497 | Active, not recruiting | Sponsor: Pfizer | Recruiting ➔ Active, not recruiting

Enrollment closed • Genetic Disorders • Obesity

A Study to Evaluate the Efficacy and Safety of PF-06882961 in Adults With Obesity (clinicaltrials.gov) - P2b | N=581 | Recruiting | Sponsor: Pfizer | Active, not recruiting ➔ Recruiting

Enrollment open • Genetic Disorders • Obesity

A phase 1 study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of danuglipron (PF-06882961), an oral small-molecule glucagon-like peptide-1 receptor agonist, in Japanese adults with type 2 diabetes mellitus. (PubMed, Diabetes Obes Metab) - "In Japanese adults with T2DM, danuglipron exhibited dose-proportional increases in plasma exposure at steady state and robustly reduced glycaemic parameters and body weight after 8 weeks of dosing, with a safety profile consistent with the mechanism of action."

Journal • P1 data • PK/PD data • Diabetes • Metabolic Disorders • Pain • Type 2 Diabetes Mellitus

Person-centered choice of anti-obesity pharmacotherapy. (PubMed, J Pak Med Assoc) - "It lists drugs as calorie restrictors (appetite suppressants), calorie restriction mimetics (absorption inhibitors), calorie substitutes (medical nutrition therapy), and calorie utilizers (energy expenditure enhancers). This novel classification will help provide a patient centered pharmacotherapy in the management of obesity."

Journal • Genetic Disorders • Obesity

Oral small molecule GLP-1 receptor agonist danuglipron (PF-06882961) results in glucose lowering and body weight loss over 16 weeks in adults with type 2 diabetes (EASD 2022) - P2b | "Materials and A total of 411 participants with T2DM (91% on metformin background therapy) were randomised and dosed across 6 arms (placebo or 1 of 5 dose levels of danuglipron); 316 (77%) completed double-blind treatment. In adults with T2DM, danuglipron robustly reduced HbA 1c , FPG and body weight over 16 weeks, and was safe, with a tolerability profile consistent with the mechanism of action."

Clinical • Diabetes • Metabolic Disorders • Severe Hypoglycemia • Type 2 Diabetes Mellitus

Efficacy, safety and tolerability of danuglipron (PF-06882961) over 12 weeks in adults with type 2 diabetes (EASD 2022) - P2a | "This Phase 2a, randomised, double-blind, placebo-controlled, parallel-group study assessed the tolerability, safety and pharmacodynamic effects over 12 weeks of different titration schemes of danuglipron in adults with type 2 diabetes mellitus (T2DM) treated with metformin. In adults with T2DM, danuglipron robustly reduced HbA 1c , FPG and body weight over 12 weeks. In adults with obesity without T2DM, treatment with danuglipron resulted in greater reductions in body weight vs placebo. In both populations, danuglipron was safe, with a tolerability profile of danuglipron consistent with the mechanism of action."

Clinical • Diabetes • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus