Novo Nordisk announced new clinical data from the positive phase 2 trial of investigational zenagamtide, also known as amycretin. Zenagamtide is the first of its class, being a unimolecular peptide agonist of GLP-1 and amylin receptors. Results from the phase 2 dose finding study included the evaluation of six subcutaneous doses of zenagamtide (ranging from 0.4 mg to 40 mg) versus matched placebo in 262 adults with type 2 diabetes inadequately controlled (A1C 7.0?10.0%) on metformin, with or without an SGLT2 inhibitor.

The study met its primary endpoint of change in A1C across all doses and also key supportive secondary endpoint of change in body weight (with doses 1.5 mg and greater) with zenagamtide versus placebo after 36 weeks. The phase 2 study showed a dose-dependent and statistically significant change in A1C from baseline to week 36 with all doses vs placebo. From a baseline of 7.8%, the estimated mean change in A1C at week 36 was up to -1.71% with zenagamtide 40 mg (estimated treatment difference [ETD] vs placebo: -1.56% [95% confidence interval (CI): -2.05, -1.07]; p70% across all zenagamtide doses investigated (up to 91.5% with zenagamtide 40 mg).

These results suggest strong glycemic efficacy, considering that the higher zenagamtide dose treatment groups were only exposed to the maintenance dose for a short period of time (ie 20 mg for 8 weeks and 40 mg for 4 weeks). As a key supportive secondary endpoint, trial participants taking zenagamtide also saw a mean body weight reduction of up to 14.6% (baseline body weight ~219 lbs) with the 40 mg dose compared with 2.1% with placebo. No apparent weight loss plateau was seen at week 36 with the higher doses of zenagamtide.

Table. Endpoints: once-weekly subcutaneous zenagamtide vs placebo: Once-weekly subcutaneous zenagamtide n=225, placebo n=37, 0.4 mg -0.91, 1.5 mg -1.31, 5 mg -1.00, 10 mg -1.41, 20 mg -1.64, 40 mg -1.71, placebo -0.14. Key supportive secondary endpoint: Change at week 36, % body weight (baseline body weight = 99.2 kg (218.7 lbs)): 0.4 mg -4.35, 1.5 mg -7.62, 5 mg -8.19, 10 mg -12.92, 20 mg -13.13, 40 mg -14.60, placebo -2.10.

Participant (N=262) baseline characteristics: Male 66%; mean age 57.1 yrs; A1C 7.8%; body weight 99.2 kg (218.7 lbs); 40% on SGLT2i. All patients on a stable dose of metformin with or without SGLT2 inhibitor. Each endpoint was analyzed using an ANCOVA model.

The analyses were based on data from the on-treatment without rescue medication observation period. Using the dose?response model for analysis, the estimated mean change in A1C from baseline to week 36 was up to ?1.8% (ETD vs placebo [95% CI]: ?1.58 [?2.08, ?1.08]; p. This trial used a fixed-dose-escalation trial design; if the planned treatment dose was not tolerated, treatment was permanently discontinued. In the trial, the most common adverse events were gastrointestinal, and the majority were mild to moderate in severity.

The safety and tolerability profile in this phase 2b trial was consistent with other incretin and amylin-based therapies. These results support further investigation of zenagamtide in phase 3 trials. Based on the results, Novo Nordisk is planning to initiate a phase 3 development program with zenagamtide for adults with type 2 diabetes in H2 2026.

Zenagamtide, also known as amycretin, is a unimolecular peptide agonist of glucagon-like peptide-1 (GLP-1) and amylin receptors under clinical trial development by Novo Nordisk with separate programs to investigate treatment for adults with type 2 diabetes and for adults with overweight or obesity. Zenagamtide is under investigation for oral and subcutaneous administration. This trial was a 36-week, randomized, double-blind, placebo-controlled, dose-finding, phase 2 trial which assessed the dose-response relationship and the effect on glycemic control and body weight of once-weekly subcutaneous zenagamtide vs placebo in adults with type 2 diabetes.

The primary endpoint was change in A1C from baseline to week 36. Key supportive secondary endpoints included changes from baseline to week 36 in: time in range; body weight; systolic blood pressure; high-sensitivity C-reactive protein; lipids; and the number of adverse events (AEs) from baseline to end of trial (week 40).