Once-daily aleniglipron, an oral small-molecule glucagon-like peptide-1 receptor agonist, reduced body weight by an estimated 9% to 12% at 36 weeks, compared with approximately 1% with placebo, in a randomized phase 2b trial of adults with obesity or overweight without diabetes. The weight-loss curves had not shown an apparent plateau by the end of the double-blind period, according to the researchers.

Researchers conducted the double-blind, placebo-controlled ACCESS trial at 38 US sites. Between October 2024 and February 2025, they screened 406 adults and randomly assigned 230 patients to aleniglipron maintenance doses of 45 mg, 90 mg, or 120 mg or to placebo.

Eligible patients were aged 18 to 79 years and had obesity, defined as a body mass index of at least 30 kg/m², or overweight, defined as a body mass index of at least 27 kg/m², with at least one weight-related comorbidity. Patients were required to have a hemoglobin A1c below 6.5% and no diagnosed diabetes. Those weighing 80 kg or less, those whose weight had changed by more than 5% during the previous 3 months, and those with prior or planned surgical treatment for obesity were excluded.

At baseline, the mean age was 50 years, mean body mass index was 39.5 kg/m², and mean body weight was 114.8 kg. Women accounted for 54% of the study population, and 84% of patients were White.

Patients assigned to aleniglipron began treatment at 5 mg once daily and underwent dose escalation every 4 weeks until reaching their assigned maintenance dose. Randomization was stratified by sex and baseline body mass index. Placebo patients from the three dose cohorts were pooled for analysis.

The primary endpoint was percentage change in body weight from baseline to week 36 under an efficacy estimand. Under this prespecified approach, measurements obtained more than 2 days following permanent treatment discontinuation, initiation of another antiobesity medication, or bariatric surgery were considered missing. The outcome was analyzed with a mixed model for repeated measures that included treatment group, baseline weight, visit, treatment-by-visit interaction, sex, and baseline body mass index stratum.

At week 36, estimated mean body weight declined by 9% with 45 mg, 11% with 90 mg, and 12% with 120 mg, compared with 1% with placebo. The corresponding placebo-adjusted reductions were 8%, 10%, and 11%.

A prespecified treatment-regimen estimand, which included outcomes regardless of treatment adherence, produced similar results. Estimated body-weight reductions were approximately 9%, 10%, and 11% in the 45-mg, 90-mg, and 120-mg groups, respectively.

In model-estimated categorical analyses, 86% of patients assigned to 120 mg achieved at least 5% weight loss, compared with 23% of patients assigned to placebo. At least 10% weight loss occurred in 70% vs 7%, and at least 15% weight loss occurred in 38% vs 1%. These response rates were calculated using multiple imputation and logistic regression rather than representing unadjusted observed proportions.

Secondary analyses also favored aleniglipron for absolute body weight, waist circumference, and body mass index. No adjustment for multiple comparisons was made.

In prespecified exploratory analyses, hemoglobin A1c declined by 0.27 to 0.36 percentage points in the aleniglipron groups, compared with a 0.01-percentage-point increase with placebo. The researchers also reported reductions in systolic and diastolic blood pressure and high-sensitivity C-reactive protein, whereas lipid profiles did not change meaningfully.

Gastrointestinal adverse events were common. Any gastrointestinal treatment-emergent adverse event occurred in 79% to 89% of aleniglipron-treated patients, compared with 55% of patients receiving placebo. Nausea occurred in 65% to 71% of the aleniglipron groups, vomiting in 32% to 45%, diarrhea in 22% to 42%, and constipation in 30% to 40%. Most gastrointestinal events were mild to moderate, occurred during dose escalation, and became less frequent later in treatment.

Adverse events led to discontinuation of study treatment in approximately 10% of aleniglipron-treated patients overall, compared with 5% of patients receiving placebo. Approximately 73% to 78% of patients in each group completed assigned treatment through week 36.

Serious adverse events occurred in 2% of patients receiving 45 mg, no patients receiving 90 mg, 6% receiving 120 mg, and 5% receiving placebo. No deaths or cases of drug-induced liver injury were reported.

Among adverse events of special interest, three patients in the 120-mg group experienced syncope and three experienced acute kidney injury. One patient in that group reported a depressive symptom and one reported suicidal ideation. Depression was reported in one patient receiving 90 mg and one patient receiving placebo. Because these were small numbers from individual event categories, the study did not establish whether their occurrence differed by treatment.

The researchers also reported a prespecified interim analysis of the ongoing open-label extension among patients who completed the double-blind period and elected to continue. At week 56, observed mean weight loss from the original baseline was 13.3%, 16.2%, and 15.3% among patients initially assigned to 45 mg, 90 mg, and 120 mg, respectively.

The researchers described the extension as exploratory and did not plan an estimand or model-based analysis; results were summarized descriptively from observed data. Patients initially assigned to aleniglipron were titrated toward 120 mg, while placebo patients crossed over to aleniglipron, and not all participants had reached week 56 at the interim analysis.

The researchers identified several limitations, including prospective electronic-diary collection that may have increased gastrointestinal adverse-event reporting, enrollment exclusively at US sites, and a predominantly White population. They also noted that female participation was lower than in other obesity trials of glucagon-like peptide-1 receptor agonists, which may have attenuated the observed mean weight reduction because women have generally experienced greater weight loss than men in previous studies.

Disclosures: Structure Therapeutics funded the study, designed the trial, collected and analyzed the data, and participated in manuscript preparation. The first manuscript draft was written by the first researcher and researchers employed by the sponsor. Several researchers were Structure Therapeutics employees, and other researchers reported consulting, research, advisory, speaking, or other financial relationships with Structure Therapeutics and multiple pharmaceutical

Source: Nature Medicine