A twin gut-hormone drug from Novo cut weight up to 24% in an early trial

The next wave of obesity drugs is trying to hit more than one hormone receptor with a single molecule. Amycretin is one of those candidates: it activates both the GLP-1 receptor, the target of semaglutide, and the amylin receptor, a separate appetite pathway. An early trial reported weight loss large enough to draw attention — with the caveats that always attach to early trials.

The Lancet published on June 20, 2025 the results of a phase 1b/2a randomised, placebo-controlled study of subcutaneous amycretin in people with overweight or obesity [s1]. A companion phase 1 first-in-human trial of the same molecule was published alongside it [s2].

What the drug is

Amycretin is described by its investigators as a novel, unimolecular GLP-1 and amylin receptor agonist [s1]. "Unimolecular" is the point of interest: rather than combining two drugs, it is one molecule engineered to engage two receptors that both suppress appetite. Amylin-based drugs are a distinct line of obesity research from the GLP-1 drugs already on the market, and combining the two mechanisms in a single agent is the design bet being tested.

The trial

The study took place at a single clinical research centre in San Antonio, Texas, and enrolled participants aged 18 to 55 years with overweight or obesity, defined as a body-mass index of 27.0 to 39.9 kg/m² [s1]. Between September 15, 2023 and April 24, 2024, 125 participants were randomly allocated to amycretin (n=101) or placebo (n=24) [s1].

It was structured in five parts. Part B escalated once-weekly amycretin from 0.3 mg to 60 mg over a 36-week treatment period, while Parts C, D, and E escalated to maintenance doses of 20 mg over 36 weeks, 5 mg over 28 weeks, or 1.25 mg over 20 weeks [s1]. Crucially, the primary endpoint was the number of treatment-emergent adverse events, not weight — weight change was a secondary endpoint [s1]. This was a safety-and-dose-finding study, and it should be read as one.

The weight numbers

Against placebo, the estimated mean bodyweight change from baseline was significantly greater with amycretin at every dose tested [s1]:

• 60 mg (Part B, week 36): −24.3% versus −1.1% with placebo
• 20 mg (Part C, week 36): −22.0% versus 1.9%
• 5 mg (Part D, week 28): −16.2% versus 2.3%
• 1.25 mg (Part E, week 20): −9.7% versus 2.0%

The differences were significant across Parts A–D (P<0.0001) and in Part E (P=0.0003) [s1]. Mean baseline bodyweight ranged from 88.3 to 99.1 kg across Parts B–E [s1]. A −24.3% figure at 36 weeks is larger than the average seen with the older single-mechanism drugs over similar spans — but a cross-trial comparison like that is exactly the kind this study cannot support.

Why the enthusiasm needs restraint

The doses were tested in different, small groups over different lengths of time. The 60 mg result comes from Part B; the 1.25 mg result from Part E, a 20-week arm. These are not four arms of one large randomised comparison, and the numbers per group are small [s1].

Dropout was high. The report notes that a large number of participants withdrew from the study, with a high proportion of discontinuations occurring for reasons unrelated to adverse events [s1]. When many people leave a small trial, the weight estimates in those who remain become harder to trust.

Side effects followed the class pattern. The most common treatment-emergent adverse events were gastrointestinal, and the majority were mild to moderate and resolved by the end of the study [s1]. The investigators note the rates were similar to those seen in early studies of other GLP-1 and amylin agents [s1].

The population was narrow and young. Adults aged 18 to 55 with a BMI capped at 39.9, at a single centre [s1]. That is not the population that will ultimately take an approved drug.

The funder makes the drug. The study was funded by Novo Nordisk, and the disclosure statement lists most authors as employees and shareholders of the company [s1].

What to watch

This is a first look, and the investigators frame it as supporting "further investigation" rather than as establishing efficacy [s1]. The meaningful evidence will come from larger, longer, adequately powered phase 2 and phase 3 trials with weight loss as a primary endpoint and lower dropout — the stage at which early obesity-drug numbers routinely shrink.

This article describes early trial results, including doses and adverse events, for informational purposes only. It is not medical advice and not a recommendation about any medication.

Sources

• [s1] Dahl K, Toubro S, Dey S, et al. Amycretin, a novel, unimolecular GLP-1 and amylin receptor agonist administered subcutaneously: results from a phase 1b/2a randomised controlled study. The Lancet, published online 2025-06-20.
• [s2] Gasiorek A, Heydorn A, Gabery S, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of the first-in-class GLP-1 and amylin receptor agonist, amycretin: a first-in-human, phase 1, double-blind, randomised, placebo-controlled trial. The Lancet, published online 2025-06-20.