Amylyx Pharmaceuticals has announced the design of its pivotal Phase 3 LUCIDITY clinical trial for avexitide, a first-in-class glucagon-like peptide-1 (GLP-1) receptor antagonist, aimed at treating post-bariatric hypoglycemia (PBH). The trial's primary objective is to evaluate the reduction in hypoglycemia events, with the first participant expected to be dosed in Q1 2025 and topline results anticipated in 2026.
Trial Design and Objectives
The LUCIDITY trial will be a multicenter, randomized, double-blind, placebo-controlled study conducted at approximately 20 sites in the U.S. It will involve around 75 participants who have undergone Roux-en-Y gastric bypass (RYGB) surgery and are experiencing PBH. Participants will be randomized in a 3:2 ratio to receive either 90 mg of avexitide subcutaneously once daily or a placebo.
The trial includes a three-week run-in period followed by a 16-week double-blind treatment period. Participants completing the double-blind phase will be eligible for a 32-week open-label extension (OLE) period. The primary efficacy endpoint is the reduction in the composite of Level 2 and Level 3 hypoglycemia events through Week 16. Safety and tolerability will also be assessed.
Avexitide: A Novel GLP-1 Receptor Antagonist
Avexitide is an investigational, first-in-class GLP-1 receptor antagonist. It is designed to bind to the GLP-1 receptor on pancreatic islet beta cells, inhibiting the effects of excessive GLP-1, which is believed to cause PBH. By decreasing insulin secretion and stabilizing blood glucose levels, avexitide aims to mitigate hypoglycemia in PBH patients.
Prior Clinical Data
The LUCIDITY trial design is informed by data from five previous clinical trials of avexitide in PBH patients. Notable findings from Phase 2 trials include:
- PREVENT Trial: A 28-day, randomized, placebo-controlled crossover trial (N=18) showed a significant reduction in Level 2 and 3 hypoglycemia events with avexitide (30 mg twice daily and 60 mg once daily) compared to placebo. The trial met its primary endpoint, demonstrating improved lowest glucose levels (nadir) after a meal, with mean plasma glucose nadir increased by 21% (p=0.001) and 26% (p=0.0002) following avexitide dosing, respectively.
- Phase 2b Trial: A 28-day, open-label, investigator-initiated, crossover trial (N=16) showed that 90 mg once daily of avexitide resulted in a statistically significant 53% reduction in Level 2 hypoglycemia events (p=0.004) and a 66% reduction in Level 3 hypoglycemia events (p=0.0003).
Regulatory Status and Market Need
Avexitide has been granted Breakthrough Therapy Designation and Orphan Drug Designation by the FDA for the treatment of post-bariatric hypoglycemia. PBH affects approximately 8% of individuals who undergo bariatric surgery in the U.S., resulting in significant disruptions to their quality of life. Currently, there are no approved therapies for PBH, highlighting the unmet medical need that avexitide aims to address.
Expert Commentary
"PBH is believed to result from an excessive GLP-1 response leading to persistent, recurrent, and debilitating hypoglycemia events that take a profound toll on someone’s quality of life," said Camille L. Bedrosian, MD, Chief Medical Officer of Amylyx. "Our goal in Phase 3 is to align the trial design as closely as possible with the prior studies. Importantly, we believe LUCIDITY is well powered to detect a treatment effect."
Amylyx plans to present the LUCIDITY trial design at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease (WCIRDC) in Los Angeles on December 12-14, 2024.
