How the Avexitide Phase 3 Trial Could Transform GLP-1 Antagonist Therapies
Amylyx Pharmaceuticals, Inc. has unveiled the design for its crucial Phase 3 LUCIDITY clinical trial, focusing on avexitide, a pioneering glucagon-like peptide-1 (GLP-1) receptor antagonist. This investigational drug aims to treat post-bariatric hypoglycemia (PBH). The trial’s primary goal, as agreed with the FDA, is to assess the reduction in hypoglycemic events. The study’s inclusion and exclusion criteria will closely mirror those of previous Phase 2 trials. Amylyx anticipates initiating the trial in early 2025, with participant recruitment expected to conclude later that year and preliminary results projected for 2026.
Joshua Cohen and Justin Klee, Co-CEOs of Amylyx, expressed their enthusiasm for advancing avexitide to Phase 3, highlighting its potential as the first approved therapy for PBH patients. They noted that data from five previous clinical trials consistently support avexitide’s efficacy in PBH treatment.
The LUCIDITY trial will be a comprehensive, multi-center study involving approximately 20 U.S. sites. It will randomly assign about 75 participants in a 3:2 ratio to receive either 90 mg of avexitide or a placebo, administered subcutaneously once daily. The study structure includes a three-week preparatory period followed by a 16-week double-blind treatment phase. Participants completing this phase will have the option to enter a 32-week open-label extension. The trial’s primary efficacy measure will evaluate the reduction in Level 2 and Level 3 hypoglycemic events over 16 weeks, along with safety and tolerability assessments.
Dr. Camille L. Bedrosian, Chief Medical Officer at Amylyx, explained that PBH is believed to stem from an excessive GLP-1 response, leading to persistent and debilitating hypoglycemic episodes. Avexitide is designed to counteract this by binding to GLP-1 receptors, thus mitigating hypoglycemia through decreased insulin secretion and blood glucose stabilization. The drug has received both FDA Breakthrough Therapy and Orphan Drug Designations. Dr. Bedrosian emphasized the alignment of the Phase 3 trial design with previous studies and expressed confidence in LUCIDITY’s ability to demonstrate a significant treatment effect.
The LUCIDITY trial design is based on data from five previous clinical trials of avexitide in PBH patients, which consistently showed dose-dependent effects. These trials included a Phase 1 study, single and multiple ascending dose trials, and two Phase 2 trials:
- The Phase 2 PREVENT trial, a 28-day randomized, placebo-controlled crossover study with 18 participants, demonstrated significant reductions in Level 2 and 3 hypoglycemic events in PBH patients post-RYGB surgery. The primary endpoint showed improved lowest glucose levels after meals, with 21% and 26% increases in mean plasma glucose nadir for 30 mg twice daily and 60 mg once daily dosing, respectively.
- A Phase 2b, 28-day, open-label, investigator-initiated crossover trial with 16 participants showed that 90 mg once daily and 45 mg twice daily of avexitide significantly reduced hypoglycemic events in post-RYGB and other upper-GI surgery patients. The 90 mg once-daily dose, planned for evaluation in LUCIDITY, resulted in a 53% reduction in Level 2 and a 66% reduction in Level 3 hypoglycemic events.
Across all clinical trials, avexitide demonstrated a favorable safety profile and was generally well-tolerated.
Amylyx plans to present the LUCIDITY trial design at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease (WCIRDC) in Los Angeles, December 12-14, 2024.
Commentary by YourDailyFit columnist Alice Winters:
Amylyx Pharmaceuticals’ announcement of the LUCIDITY Phase 3 trial for avexitide marks a significant milestone in the quest to address post-bariatric hypoglycemia (PBH), a condition that has long been overlooked in the broader conversation about bariatric surgery outcomes. As we dive into this development, several aspects warrant our attention and critical analysis.
Firstly, the innovative approach of using a GLP-1 receptor antagonist for PBH is noteworthy. While GLP-1 agonists have been making waves in the diabetes and weight loss markets, avexitide takes the opposite approach by blocking GLP-1 receptors. This counterintuitive strategy highlights the complex and sometimes paradoxical nature of metabolic disorders. It’s a reminder that in the realm of endocrinology, more is not always better, and balance is key.
The consistency of results across five clinical trials, including two Phase 2 studies, is encouraging. The reported 53% reduction in Level 2 and 66% reduction in Level 3 hypoglycemic events with the 90 mg once-daily dose are particularly impressive. However, we must approach these results with cautious optimism. Phase 2 trials, while promising, often show more dramatic effects than larger Phase 3 studies. The real test will be whether these results can be replicated in the larger, more diverse population of the LUCIDITY trial.
The trial design itself deserves scrutiny. The decision to use a 3:2 randomization ratio favoring the treatment group is interesting. While this may help with recruitment by increasing the chances of receiving the active treatment, it could potentially impact the statistical power of the study. The 16-week treatment period seems appropriate for assessing efficacy, but long-term safety data will be crucial for a condition that may require chronic treatment.
Speaking of safety, the “generally well-tolerated” profile reported so far is promising but vague. As we move into Phase 3, a more detailed safety profile will be essential. Given that avexitide is antagonizing a system (GLP-1) that plays multiple roles in metabolism, we should be vigilant for unexpected metabolic or gastrointestinal side effects.
The market potential for avexitide is intriguing. With the rising popularity of bariatric surgeries, particularly Roux-en-Y gastric bypass, the incidence of PBH is likely to increase. However, the exact prevalence of PBH is still debated, with estimates ranging widely. This uncertainty could pose challenges in defining the market size and, consequently, in pricing and reimbursement strategies.
From a broader perspective, avexitide represents a growing trend of developing therapies for the complications of obesity treatments, rather than just obesity itself. This reflects a maturing understanding of obesity as a complex, chronic condition with multifaceted treatment needs.
Lastly, while the focus on symptom reduction is crucial, future research should also explore whether long-term use of avexitide has any impact on the metabolic benefits of bariatric surgery. Does blocking GLP-1 signaling affect weight maintenance or glucose homeostasis in these patients over time?
In conclusion, the LUCIDITY trial for avexitide is a welcome advancement in addressing the unmet need of PBH patients. Its novel mechanism and promising early results make it a compound to watch closely. However, as with any new therapy, especially one targeting a complex metabolic pathway, we must balance enthusiasm with rigorous scrutiny of efficacy, safety, and long-term outcomes. The results of LUCIDITY will not only be crucial for avexitide’s future but may also provide valuable insights into the intricate metabolic changes following bariatric surgery.
