Avexitide reduced severe hypoglycemia after gastric bypass in Phase 3 trial

What happened

Amylyx Pharmaceuticals reported on August 18 that avexitide reduced clinically significant and severe hypoglycemic events in a Phase 3 trial involving adults who developed recurrent low blood glucose after Roux-en-Y gastric bypass surgery.

The company said the investigational peptide produced a 55% relative reduction versus placebo in the trial’s primary endpoint: the combined rate of Level 2 and Level 3 hypoglycemic events through 16 weeks. The reported p-value was 0.000003. Amylyx also said the study met secondary endpoints based on glucose-meter readings, continuous glucose monitoring and independently adjudicated severe events.

The result could advance the first drug developed specifically for post-bariatric hypoglycemia, a potentially disabling complication for which no therapy is currently approved by the Food and Drug Administration. Amylyx plans to submit a New Drug Application by the end of 2026, but avexitide remains investigational.

What the trial tested

LUCIDITY was a multicenter, randomized, double-blind, placebo-controlled Phase 3 trial conducted at 21 U.S. sites. It enrolled 78 adults with post-bariatric hypoglycemia following Roux-en-Y gastric bypass. Participants were assigned in a 3:2 ratio to receive avexitide or placebo during the 16-week controlled period.

The registry specified a selected population with persistent disease despite dietary management. Participants had undergone surgery at least one year earlier and needed to experience at least three discrete hypoglycemic episodes during a three-week run-in period. These criteria concentrated the trial on people with recurrent, clinically evident disease rather than everyone who has had bariatric surgery.

Avexitide, also called exendin 9-39, is a 31-amino-acid peptide that blocks the GLP-1 receptor. That mechanism runs opposite to GLP-1 receptor agonists used for diabetes and obesity. After gastric bypass, an exaggerated meal-triggered GLP-1 response can drive excessive insulin secretion in susceptible people, causing blood glucose to fall rapidly. Avexitide is intended to interrupt that pathway.

How to interpret the result

The primary endpoint combined Level 2 events—clinically significant low glucose documented by self-monitoring—with Level 3 events, which involve severe impairment requiring help from another person. Measuring events over several months is more clinically informative than relying only on a laboratory meal challenge or an average glucose value.

However, the 55% figure is a relative reduction. Amylyx’s topline announcement did not disclose the absolute event rates in the two groups, confidence intervals, discontinuations or results for individual secondary endpoints. Those details are important for estimating the magnitude and consistency of benefit. No Phase 3 results were posted in the ClinicalTrials.gov record available during reporting, and the complete dataset has not yet undergone peer review.

Earlier human evidence supports the biological rationale but was substantially smaller. A peer-reviewed Phase 2 crossover trial enrolled 18 women with post-bariatric hypoglycemia and found that avexitide raised glucose nadirs, reduced insulin peaks and lowered recorded hypoglycemic-event rates during short treatment periods. LUCIDITY provides a stronger controlled test, although independent assessment of the Phase 3 analysis remains necessary.

Safety and remaining questions

Amylyx said most adverse events were mild or moderate and that no serious adverse event was considered related to avexitide during the double-blind period. The most frequently reported events were diarrhea, injection-site redness and injection-site bruising. Body weight reportedly did not change in either group.

Those topline statements do not establish uncommon or long-term risks in a 78-person, 16-week comparison. A 32-week open-label extension is continuing, which may add durability and safety information but lacks the same placebo-controlled design.

The findings also apply directly to patients with recurrent hypoglycemia after Roux-en-Y gastric bypass, not automatically to people after sleeve gastrectomy, those with occasional symptoms or other causes of low glucose. FDA review, fuller reporting and longer follow-up will determine whether the reported reduction supports approval and how broadly the evidence can be applied.