Once-weekly eloralintide leads to 20% weight loss in Phase II trial

A multicenter team including Endeavor Health and Eli Lilly found that once-weekly eloralintide produced dose-dependent weight loss up to 20% over 48 weeks in adults with obesity or overweight without type 2 diabetes.

Despite a rise in availability, many patients seeking medical weight loss do not tolerate incretin receptor agonists like semaglutide (Ozempic, Wegovy, Rybelsus) or do not reach goals with them.

Previous studies have examined amylin biology as a satiety pathway and have evaluated selective and non-selective amylin or calcitonin receptor agonists for appetite control. Unmet need remains for additional agents that reduce bodyweight while maintaining acceptable tolerability.

Amylin is co-secreted with insulin in response to nutrients and slows stomach emptying, lowers glucagon, and helps people feel full. Previous studies examined how amylin helps people feel full and tested drugs that act on amylin and calcitonin receptors to curb appetite, with investigators proposing potential benefits for weight management that might complement other approaches.

In the study, “Eloralintide, a selective amylin receptor agonist for the treatment of obesity: a 48-week phase 2, multicentre, double-blind, randomised, placebo-controlled trial,” published in The Lancet, researchers conducted a Phase II trial to evaluate the efficacy and safety of multiple once-per-week eloralintide doses and dose-escalation schemes.

Design and measures

A total of 263 participants were enrolled across 46 research centers in the U.S. Ages ranged from 18 to 75 years, with a mean age of 49.0 years and a mean BMI of 39.1 kg/m² at baseline.

Random assignment directed use of placebo or eloralintide regimens at 1 mg, 3 mg, 6 mg, 9 mg, 6–9 mg, or 3–9 mg for 48 weeks of treatment followed by a 10-week follow-up.

Participants received weekly subcutaneous injections under double-blind masking with matched placebo injection volumes. Lifestyle and dietary counseling accompanied pharmacotherapy, with sites implementing local programs or a centrally provided plan.

Analyses used an efficacy estimand for pharmacologic effect and mixed models for repeated measures that included data before permanent discontinuation of study treatment. A treatment-regimen estimand was prespecified as supportive.

The primary endpoint was percent weight change at week 48, with secondary and exploratory endpoints including absolute weight change, BMI, waist circumference, glycemia, lipids, high-sensitivity C-reactive protein, and adverse events.

Results by dose

All eloralintide groups reduced bodyweight more than placebo at 48 weeks. Mean percentage change in bodyweight was −9% at 1 mg, −12% at 3 mg, −18% at 6 mg, −20% at 9 mg, −20% with a 6–9 mg escalation, and −16% with a 3–9 mg escalation, compared with −0.4% with placebo.

Dose groups at or reaching 9 mg produced the largest effects with an absolute mean kg change up to –21.3 kg. Waist circumference fell by up to 17.1 cm, and BMI decreased by up to 7.8 kg/m² across groups. A greater share of participants on eloralintide achieved at least 5%, 10%, 15%, and 20% weight loss versus placebo, with 9 mg and 6–9 mg groups most likely to reach 25% or 30%.

Safety signals and tolerability

Adverse events occurred in 81% of eloralintide recipients and 71% on placebo. Nausea and fatigue were the most common events with eloralintide, with group-specific nausea rates ranging from 11% to 64% and fatigue from 0% to 46%. Dose escalation from 3 mg reduced gastrointestinal symptoms and fatigue compared with starting at 6 mg or 9 mg.

Serious adverse events were reported in 14 participants overall, with investigators and sponsor reporting no events related to study treatment. No pancreatitis, no cholecystitis, and no deaths were reported; 10% of participants discontinued treatment due to adverse events across groups.

At a glance

Authors report clinically meaningful, dose-dependent weight loss over 48 weeks with generally acceptable tolerability, supporting eloralintide’s potential as a treatment for obesity.

Findings suggest a role for a selective amylin receptor agonist as monotherapy for weight management in adults without diabetes, with future studies planned to define use across populations and in combination regimens.

Eli Lilly designed and oversaw the trial, with site investigators responsible for data collection.

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