Danuglipron was an investigational oral medication developed by Pfizer, intended to address obesity and type 2 diabetes. It aimed to provide a convenient, non-injectable treatment option for metabolic disorders. By targeting specific physiological pathways, danuglipron was studied for its potential to assist individuals in managing their body weight and achieving better control over their blood sugar levels. Its advancement through clinical trials was observed, highlighting the ongoing search for effective oral therapies.
How Danuglipron Works
Danuglipron functions as a glucagon-like peptide-1 (GLP-1) receptor agonist, mimicking the body’s natural GLP-1 hormone. This hormone is released from gut cells in response to food, playing a role in metabolic regulation. When danuglipron activates GLP-1 receptors, it initiates physiological responses to manage glucose levels and appetite.
One primary effect is stimulating insulin secretion from pancreatic beta cells. This glucose-dependent release occurs when blood sugar is elevated, helping to lower glucose concentrations. It also suppresses glucagon, a hormone that raises blood sugar by signaling the liver to release stored glucose. This reduction further contributes to improved glycemic control.
Beyond its effects on blood sugar, danuglipron also slows gastric emptying. This means food remains in the stomach longer, contributing to a prolonged feeling of fullness after meals. This extended satiety can lead to a reduction in overall food intake, which can contribute to weight loss over time. The combined actions on insulin, glucagon, and gastric emptying define its comprehensive approach to metabolic management.
Clinical Trial Performance
The Phase 2b clinical trial for danuglipron evaluated its twice-daily oral formulation in adults with obesity but without type 2 diabetes. This study achieved its primary endpoint, demonstrating significant reductions in participants’ body weight from baseline. Across the range of doses administered, individuals receiving danuglipron experienced mean body weight reductions ranging from -6.9% to -11.7% over a 32-week period, a considerable difference compared to the mean increase of 1.4% observed in the placebo group.
Placebo-adjusted mean body weight reductions ranged from -8% to -13% at 32 weeks, showcasing a clear impact on weight management. These results underscored the drug’s potential as a significant tool for individuals seeking to reduce their body mass.
Danuglipron had previously shown positive effects on glycemic parameters in earlier clinical investigations involving patients diagnosed with type 2 diabetes. A Phase 2a trial demonstrated notable improvements in blood sugar control, evidenced by dose-dependent, placebo-adjusted reductions in HbA1c of up to 1.16% at 16 weeks. HbA1c serves as a reliable indicator of average blood sugar levels over several months, making these reductions meaningful for diabetes management. This earlier study also reported mean reductions in body weight of 4.17 kg, reinforcing the drug’s potential to concurrently address both glycemic control and weight reduction in diabetic populations.
Side Effects and Development Challenges
Despite promising efficacy data from its clinical trials, danuglipron’s development faced challenges due to its tolerability profile, particularly with the twice-daily formulation. Participants in the Phase 2b study reported a high incidence of gastrointestinal adverse events, consistent with the known mechanism of action for GLP-1 receptor agonists. The most frequently observed side effects included nausea (up to 73%), vomiting (up to 47%), and diarrhea (up to 25%).
These significant adverse events led to exceptionally high rates of patient discontinuation from the study. Across dosing regimens, more than 50% of participants chose to withdraw from the trial, a rate notably higher than the approximately 40% observed in the placebo group. This elevated attrition rate, attributable to the burden of side effects, prompted Pfizer’s decision to discontinue the twice-daily formulation’s advancement into Phase 3 clinical trials. The company concluded that the observed tolerability issues rendered the twice-daily version unsuitable for further development.
Current Status and Future Direction
After discontinuing the twice-daily formulation due to tolerability challenges, Pfizer initially pivoted to developing a once-daily, modified-release version of danuglipron. This adjustment aimed for a more favorable side effect profile and enhanced patient convenience, improving its viability. The company aimed to gather further data to optimize its development pathway.
However, Pfizer later decided to completely discontinue danuglipron’s development. This halt followed a comprehensive review of all clinical data, including a potential case of drug-induced liver injury. While liver enzyme elevations were generally consistent with other approved therapies in its class, this review led to the conclusion that further investment was no longer warranted.