Amycretin provides unprecedented weight loss treatment for obesity in early study

Amycretin provides unprecedented weight loss treatment for obesity in early study

A new study shows that once-weekly amycretin injections help adults lose more than 20% of their body weight, marking a major leap in obesity treatment and metabolic health.

In a recently published study inThe LancetA group of investigators evaluated the safety, tolerability, pharmacokinetics, and weight reduction effects of once-weekly subcutaneous amycretin in adults who are overweight or obese.

background

Obesity affects more than a billion people worldwide. It promotes serious diseases such as cardiovascular disease, type 2 diabetes and sleep apnea. However, many individuals still fall short of their health goals despite using weight loss medications that mimic glucagon-like peptide 1 (GLP-1) or glucose-dependent insulinotropic polypeptide (GIP).

The gut hormone amylin, which suppresses appetite and slows gastric emptying, potentiates the effects of GLP-1-based therapies when used in combination. Amycretin is a single peptide that simultaneously activates GLP-1, amylin and calcitonin receptors, potentially delivering stronger and longer-lasting weight control.

The safety in regular use and effectiveness of this multi-pathway approach in humans remains unclear and highlights the need for further research.

About the study

Investigators conducted a five-part, randomized, placebo-controlled Phase 1B/2A study at a single site in the United States (San Antonio, Texas). Eligible adults (18 to 55 years of age) had a body mass index (BMI) of 27.0-39.9 kg/m² and no major medical conditions such as diabetes. Participants received either amycretin or placebo as a weekly subcutaneous injection.

Part A tested single ascending doses (0.3 mg, 0.6 mg, 1.0 mg). Parts B to E examined multiple doses in separate cohorts: Part B escalated doses up to 60 mg over 36 weeks; Part C Escalated to a 20 mg maintenance dose in the last 12 weeks of 36 weeks; Part D Escalated to a 5 mg maintenance dose in the last 12 weeks of 28 weeks; and Part E escalated to a maintenance dose of 1.25 mg for the last 12 weeks of 20 weeks.

The primary endpoint was the incidence of treatment-related adverse events. Secondary endpoints included changes in body weight, pharmacokinetic metrics (peak plasma concentration and area under the curve), and exploratory metabolic markers such as fasting plasma glucose and glycated hemoglobin (HBA1c).

Investigators monitored participants with laboratory tests, electrocardiograms, and safety visits and analyzed the results using statistical models adjusted for baseline weight.

Study results

Between September 2023 and April 2024, investigators enrolled and randomly assigned 125 adults to Amycretin and 101 and 24 at a single center in San Antonio, Texas. Participants were 18-55 years old, had baseline BMIs ranging from 30.0 to 33.1 kg/m² across groups (with an overall mean of 33.4 kg/m²), and weighed between 83.6 and 99.1 kg at baseline.

Part A evaluated single doses of 0.3 mg, 0.6 mg and 1.0 mg and confirmed acceptable tolerability. Parts B through E then evaluated different dosing regimens: Part B escalated weekly doses to 60 mg for 66 weeks; Part C up to a maintenance dose of 20 mg; Part D to a 5 mg maintenance dose; and Part E to 1.25 mg maintenance dose, each with a 12-week maintenance period in the final dose.

Thirty-eight amycretin recipients (37%) and four placebo recipients (17%) withdrew participation, most commonly for uncertain reasons (e.g., withdrawal of consent, recreational drug use). Importantly, most discontinuities in the placebo group were not consistent with treatment, supporting a likely nocebo effect.

Occurrences occurred in 92% of amycretin users compared to 100% of placebo participants in parts B-E reporting at least one event. Gastrointestinal symptoms predominated and were generally mild or moderate in intensity.

Nausea affected 82%, vomiting 53%, and diarrhea 41% of treated participants, peaking during upitration and decreasing thereafter. The incidence of dysaesthesia varied by dose: 18% in Part B (60 mg), 29% in Part C (20 mg), and 6% in Part D (5 mg), resolving in all but one case. A single case of mild gallstone pancreatitis occurred in a Part C participant during dose escalation (2.5 mg); This later resulted in a serious recurrent event but resolved without sequelae by the end of the study.

Weight reduction was rapid, dose-dependent and sustained. At their respective end-of-treatment time points, estimated average percentage losses from baseline were:

• 24,3% mit 60 mg (Woche 36)
• 22,0% mit 20 mg (Woche 36)
• 16,2% mit 5 mg (Woche 28)
• 9,7% mit 1,25 mg (Woche 20)

Placebo groups showed weight changes of -1.1% (Part B), +1.9% (Part C), +2.3% (Part D) and +2.0% (Part E). Superiority over placebo became evident at week 4 and was extended throughout the study, with no plateauing in weight loss observed during the 12-week maintenance periods in each cohort. Mixed model analyzes with repeated measures adjusting for baseline weight, weaning, and missing data produced virtually identical estimates, increasing precision.

Metabolic markers showed exploratory improvements parallel to weight. Fasting plasma glucose levels decreased by up to 0.8 mmol/L and HbA1c levels decreased by 0.6 percentage points in the highest dose cohort, although statistical significance versus placebo was inconsistent across doses. Lipid profiles and sitting blood pressure remained neutral.

Continuous electrocardiography revealed no clinically relevant QT prolongation and a transient increase in impulse of approximately 10 beats per minute after initial injections resolved spontaneously. Antidrug antibodies appeared in 29% (5/17) of participants Part B (60 mg), 21%

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