Amycretin, a novel, unimolecular GLP-1 and amylin receptor agonist has a safety and tolerability profile similar with other GLP-1 and amylin agonists in both oral and subcutaneous formulations, according to two studies published in The Lancet.

In a first-in-human, phase 1 trial of daily oral amycretin, Agnes Gasiorek, PhD, et al., randomized 144 participants to a multipart regimen of oral amycretin or placebo of up to twelve weeks. Their mean age was 39, 40% were women, 58% were White and 37% were Black, and they had a BMI between 25.0-34.9 kg/m2.

Results showed that treatment-emergent adverse events, the primary endpoint, were reported in 89 (62%) participants, with gastrointestinal (GI) being most common (180 [49%] of 364 events), including nausea, vomiting and decreased appetite. All events were mild or moderate and increased in frequency in a dose-dependent manner. No deaths were reported.

Additionally, amycretin reduced body weight, with a mean percentage loss of 13% after 12 weeks with the highest daily amycretin dose of two tablets of 50 mg vs. 1% in placebo. "To date, no other oral drug has shown the same level of effectiveness in reducing body weight as observed with amycretin in individuals with overweight or obesity over a 12-week timeframe" write the authors. "Importantly, there were no apparent signs of weight loss plateauing in our study."

In a placebo-controlled phase 1b/2a study of weekly subcutaneous amycretin, Kristen Dahl, PhD, et al., randomized 125 participants aged 18-55 years with a BMI of 25.0-34.9 kg/m2 to either amycretin (n=101) or placebo (n=24) up to twelve weeks. The study was conducted in five parts: single ascending doses designed to identify a tolerable starting dose in Part A and multiple ascending doses up to 60 mg in Part B, 20 mg in Part C, 5 mg in Part D and 1.25 mg in Part E. In the dose response total (n=79) of parts C-E, the mean age was 37 years, 53% of participants were women, and 66% were White, 28% Black and 51% Hispanic or Latino.

Results showed that in groups B-E, 80 of 83 participants across treatment arms experienced a treatment-emergent adverse event (496 in total) compared to 18 of 18 participants in the placebo arms (72 in total), which investigators partially attribute to a nocebo effect and low sample size.

The most common adverse events were GI, with most mild or moderate and resolved by the end of the study. Of note, 33% of participants withdrew from the study; 59% of these were for reasons unrelated to adverse events, many due to withdrawal of consent or recreational drug use.

Subcutaneous administration of single doses up to 1.0 mg and weekly doses up to 60 mg with dose escalation appeared safe and tolerable. Similar with oral amycretin, estimated mean body weight change from baseline was significantly higher in the treatment group vs. placebo, with no plateau observed. At 36 weeks, once-weekly subcutaneous amycretin up to 60 mg reduced body weight by 24% compared with a 1% reduction in placebo.

"The rapid loss of body weight seen in such clinical trials might not result in the beneficial effects observed following a more gradual reduction, and further research is required to better understand the optimal rate to improve overall health," write the authors.

"Although additional weight loss is welcome and helpful, our evolving concept of obesity management has now shifted towards an emphasis on the reduction of the risks and burdens of cardiovascular disease and other comorbidities," write Bernard Khoo, PhD, and Tricia M-M Tan, PhD, in an accompanying editorial comment, adding that several GLP-1 receptor monoagonists have positive cardiovascular effects. "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."