MADRID — Amycretin, a dual-pathway, oral weight loss drug, led to up to 13% body weight loss in participants with overweight or obesity according to phase 1, first-in-human study data presented at the European Association for the Study of Diabetes (EASD) 2024 annual meeting.
Body weight loss was “remarkable for an orally delivered biologic,” said Agnes Gasiorek, PhD, senior clinical pharmacology specialist at Novo Nordisk, Måløv, Denmark, who presented the results. And “there was no plateauing of weight loss in the treatment period.”
With respect to the primary endpoint, stepwise dose escalation demonstrated that all tested dose levels up to and including 2 × 50 mg over a 12-week escalation period were safe and tolerable, Dr. Gasiorek reported.
The adverse events were in line with what was expected from targeting these receptors, and no new safety signals appeared during the study, she added.
Dual Pathways
Amycretin is a novel protein-based unimolecular amylin combined with a glucagon-like peptide 1 receptor agonist (GLP-1 RA) and is the first oral formulation of this combination under development.
The two components are both known to reduce appetite and energy intake and increase satiety, said Dr. Gasiorek, but amylin is considered to potentially increase leptin sensitivity and GLP-1 RAs are known to increase insulin secretion and biosynthesis. Together, the two components improve insulin sensitivity, decrease glucagon secretion, and lead to acute delay in gastric emptying.
The single-center, placebo-controlled, double-blind phase 1 study enrolled men and women aged 18-55 years (mean, 38-42 years across groups) with a body mass index of 25.0-39.9, without diabetes, and considered otherwise healthy.
Participants were randomly assigned to receive to receive oral amycretin (n = 95) or placebo (n = 29) once a day for up to 12 weeks. Study arms comprised single-ascending dosing (increasing from 1 mg/d to 25 mg), and multiple-ascending dosing. The latter consisted of multiple ascending doses (from 3 to 12 mg) over 10 days and multiple ascending doses (stepwise dose escalation, from 3 mg up to a final dose of 2 × 50 mg) over 12 weeks.
In her presentation at the EASD meeting, Dr. Gasiorek focused on results of the 12-week multiple ascending dose schedule with amycretin 50 mg (n = 16), amycretin 2 × 50 mg (n = 16), and placebo (n = 12).
The primary endpoint of the study was the number of treatment-emergent adverse events, while the area under the amycretin plasma concentration time curve and the maximum plasma concentration of amycretin were secondary endpoints.
The researchers also added percentage change in body weight after 12 weeks of treatment as an exploratory endpoint.
Safety Findings of Multiple Dosing
A total of 242 treatment-emergent adverse events were reported in the combined active and placebo groups and were of mild to moderate severity.
Treatment-emergent adverse events were found in 75% of the amycretin 50 mg group, 93.8% of the amycretin 2 × 50 mg group, and 33.3% of placebo recipients.
“Most adverse events reported were mild to moderate in severity and related to gastrointestinal discomfort (nausea and vomiting) and occurred in a dose-proportional manner,” reported Dr. Gasiorek.
Gastrointestinal events were experienced by 50%, 87.5%, and 16.7% of participants receiving amycretin 50 mg, amycretin 2 × 50 mg, and placebo, respectively (112 in total).
Decreased appetite was also found in 56.3%, 81.3%, and 16.7% of the amycretin 50 mg, amycretin 2 × 50 mg, and placebo groups, respectively.
Two serious adverse events occurred, one of which was acute cholecystitis and the other diabetic ketoacidosis; “however, the [latter] participant was found to have autoantibodies for beta cells before treatment and was later diagnosed with type 1 diabetes,” Dr. Gasiorek said.