Amycretin — a novel experimental molecular targeting both the glucagon-like peptide 1 (GLP-1) and the amylin receptor — has shown promise for weight management in early-phase clinical trials.

Administered as a once-weekly injection or daily oral pill, Amycretin was generally well tolerated and led to weight loss at the highest doses tested in adults without diabetes and with overweight or obesity.

Because amycretin activates the GLP-1 and amylin receptors simultaneously, it has the potential to better manage obesity than medicines that target just one receptor, researchers said.

Results of both studies were presented at the American Diabetes Association (ADA) 85th Scientific Sessions and simultaneously published in The Lancet.

Study Details

Amycretin is being developed by Novo Nordisk, which funded both trials.

In the phase 1b/2a trial, 125 adults with overweight or obesity (BMI, 27.0-39.9) were randomly allocated to amycretin or placebo administered subcutaneously as single and once-weekly multiple ascending doses for up to 36 weeks.

Treatment-emergent adverse events (TEAEs), the primary endpoint, which were mild or moderate in severity, increased in a dose-dependent manner and resolved by the end of the study.

The most common TEAEs were gastrointestinal (nausea, vomiting, and diarrhea) and decreased appetite (as expected). One third of participants withdrew from the study; 59% of these discontinuations were for reasons unrelated to side effects, largely the withdrawal of consent or recreational drug use. There were no unexpected safety concerns and no deaths.

For the secondary outcome of change in bodyweight from baseline, compared to placebo, amycretin led to greater weight loss across all doses. After 36 weeks, those who received the highest dose (60 mg once weekly) had a 24% reduction in body weight compared with a 1% reduction with placebo.

“Although other endpoints were exploratory in nature, observations suggest that amycretin might also provide benefits beyond weight reduction, with changes observed in fasting plasma glucose and glycated hemoglobin, compared with placebo,” the investigators reported.

In a separate phase 1 trial, amycretin also appeared safe and tolerable with weight-lowering effects when administered as a once-daily oral formulation over 12 weeks in 144 adults with overweight or obesity.

Once again, the most common TEAEs were related to gastrointestinal symptoms (mainly nausea and vomiting) and decreased appetite, and these were more frequent with the higher doses.

Participants taking the highest dose (50 mg twice daily) of oral amycretin lost an average of 13.1% of their body weight. Although the endpoint is exploratory and direct comparisons with other oral treatments have not been done, this level of weight loss is greater than that observed with any other oral obesity pharmacotherapy to date over the same timeframe, the investigators said.

Amycretin therapy was also associated with reductions in fasting blood glucose and improvements in other metabolic and glycemic parameters, suggesting the potential benefits of GLP-1 and amylin receptor agonism go beyond weight loss.

“We are pleased with the promising results of amycretin and the feedback from regulatory authorities and are excited to advance both subcutaneous and oral versions of this molecule into phase 3 development for weight management,” Martin Holst Lange, executive vice president for development at Novo Nordisk, said in a news release.

Caveats and Cautionary Notes

The UK-based authors of a Lancet Comment said these early studies show that amycretin, whether given orally or subcutaneously, is “generally well tolerated, is associated with promising weight loss, and shows some favorable changes in glycemia and lipid profiles in the context of nondiabetic overweight and obesity.”

Tricia Tan, MBChB, PhD, Imperial College London, and Bernard Khoo, PhD, University College London, both in London, England, cautioned, however, that these were “phase 1/2, they used small populations and tested widely varying dose regimens, so the headline weight losses and the frequency of adverse events might not be eventually realized in finalized dose schedules. Additionally, the subcutaneous study results might be subject to bias due to a high rate of participant discontinuation.”

“Head-to-head outcome studies comparing GLP-1 receptor monoagonists with GLP-1 plus amylin receptor multiagonists are required to definitively establish their added value and, hence, their place in obesity management,” Tan and Khoo said.

This research was funded by Novo Nordisk. Several authors declared being employees of the company. Tan declared receiving research funding from Leadiant Pharmaceuticals and being a founder of, former consultant for, and former shareholder in Zihipp. Khoo had no disclosures.