Oral Aleniglipron Shows Dose-Dependent Weight Loss in Phase 2b Trial

Once-daily oral aleniglipron produced up to 11.3% greater placebo-adjusted weight loss than placebo at 36 weeks in adults with overweight or obesity. The oral small-molecule GLP-1 receptor agonist was evaluated for obesity treatment in the randomized, double-blind, placebo-controlled 36-week ACCESS phase 2b trial in Nature Medicine. Weight reduction increased across the 45-mg, 90-mg, and 120-mg groups over the randomized treatment period.

Key Takeaways

• Placebo-adjusted body-weight reduction was observed across all active doses, ranging from 8.2% to 11.3% at week 36.
• In the 120-mg arm, 86%, 70%, and 38% reached at least 5%, 10%, and 15% weight loss, versus 23%, 7%, and 1% with placebo.
• Gastrointestinal events were most common, treatment-related discontinuations were 10.4% across aleniglipron arms, no drug-induced liver injury was observed, and interim follow-up indicated additional weight loss beyond 36 weeks.

ACCESS randomized 230 adults across 38 US sites in a parallel-group design. Eligible participants were 18 to younger than 80 years and had obesity, or overweight with at least one weight-related comorbidity, stable weight for 3 months, and screening HbA1c below 6.5%. Participants received once-daily aleniglipron starting at 5 mg, with dose escalation every 4 weeks to maintenance doses of 45 mg, 90 mg, or 120 mg, or placebo. Mean baseline age was 49.8 years, mean BMI was 39.5 kg/m2, mean body weight was 114.8 kg, mean waist circumference was 121.2 cm, and 54% were female. The primary endpoint was percentage change in body weight from baseline to week 36.

At week 36, placebo-adjusted least-squares mean body-weight change was -8.2% with 45 mg, -9.8% with 90 mg, and -11.3% with 120 mg, with P < 0.0001 for each dose. Least-squares mean changes from baseline were -9.0%, -10.7%, and -12.1% in the active groups, versus -0.8% with placebo. In the 120-mg group, 86%, 70%, and 38% reached at least 5%, 10%, and 15% weight loss, compared with 23%, 7%, and 1% with placebo. Absolute body weight, waist circumference, and BMI also declined significantly in the active groups, alongside HbA1c reductions from a 5.63% baseline and exploratory hsCRP declines. Weight loss followed a dose-dependent pattern during the randomized period, and investigators reported no apparent plateau by week 36.

Nausea, diarrhea, vomiting, and constipation were the most common treatment-emergent adverse events. Treatment-related discontinuations were 10.4% across aleniglipron arms. Treatment-emergent serious adverse events occurred in 1 participant at 45 mg, none at 90 mg, 4 at 120 mg, and 3 with placebo, and no deaths occurred. Gastrointestinal events generally lessened over time, vomiting rarely recurred after dose reintroduction, and heart rate increased modestly by 0.8, 2.2, and 2.1 beats per minute versus -1.2 with placebo. No drug-induced liver injury, persistent liver enzyme elevation, or QTc prolongation was reported, and liver and ECG findings did not reveal a clear signal.

A prespecified interim open-label extension analysis after a median follow-up of 20 weeks showed additional observed weight loss beyond week 36. Total mean weight loss from randomization to week 56 was 13.3%, 16.2%, and 15.3% in the 45-mg, 90-mg, and 120-mg groups. Participants who switched from placebo to aleniglipron, starting at 2.5 mg, had 6.4% weight loss at week 56. The authors noted limitations including prospective e-diary capture of gastrointestinal events, lower female representation, a high proportion of White participants, US-only sites, no multiplicity adjustments, and the exploratory open-label extension. Additional weight loss was observed during the extension, with longer-term effects still under open-label follow-up.