Amylyx Pharmaceuticals (NASDAQ:AMLX) co-CEO Justin Klee discussed the company’s lead endocrine program, avexitide, and provided updates on its pivotal LUCIDITY trial during a conversation at day two of the Leerink Partners Conference.
Avexitide mechanism and the unmet need in post-bariatric hypoglycemia
Klee described avexitide as a “first-in-class GLP-1 receptor antagonist” that competes with endogenous GLP-1. By blocking the GLP-1 receptor, avexitide lowers insulin and raises blood glucose, a mechanism the company believes is well-suited to conditions where the body overproduces GLP-1 and triggers hyperinsulinemic hypoglycemia.
According to Klee, there are currently no approved treatments for PBH. The current mainstay is medical nutrition therapy, where patients attempt to manage triggers by eating small, frequent meals and avoiding simple carbohydrates, though he said many factors—including exercise, stress, and lack of sleep—can still precipitate events. He also noted that off-label approaches are tried, but “nothing works” reliably in his characterization of the treatment landscape.
Prior clinical evidence and Breakthrough Therapy designation
Klee said five prior trials of avexitide in PBH showed significant reductions in hypoglycemia and supported the FDA’s Breakthrough Therapy designation for the program. He emphasized consistency across studies and described an early proof-of-concept trial conducted by Stanford investigators in eight PBH patients. In that study, participants were given a liquid sugar drink (Glucola), which led to severe hypoglycemia; after receiving avexitide, he said the drug prevented hypoglycemia in all participants in that controlled setting.
He also referenced phase I dose-ranging work that moved to a subcutaneous formulation and two phase II studies. In one of the phase II trials, he cited a 64% reduction in a composite of level II and level III hypoglycemic events at the highest daily dose tested (90 mg once daily), with a p-value of 0.003.
LUCIDITY phase III: endpoints, enrollment, and placebo expectations
Turning to the ongoing pivotal trial, Klee said the LUCIDITY study is the sixth avexitide trial in PBH and is designed as a 16-week randomized, placebo-controlled study with an open-label extension. He said the company expects top-line results in the third quarter and noted the trial had finished screening and was “just about fully enrolled.”
He detailed how the trial defines and captures severe events:
- Level II hypoglycemia: blood glucose less than 54 mg/dL, measured by fingerstick self-monitored blood glucose, which Klee described as the gold standard. A blinded continuous glucose monitor is also used as a secondary outcome.
- Level III hypoglycemia: events requiring independent rescue because the patient is too impaired to help themselves. These are recorded via an electronic diary and adjudicated by an independent committee of expert endocrinologists.
Klee said the trial includes a run-in period to identify patients experiencing at least one qualifying event per week over three weeks prior to randomization. He also discussed placebo response, saying that historically PBH trials have not shown a placebo effect, referencing both the PREVENT study (an earlier avexitide phase II trial) and a trial of dasiglucagon in PBH, where he said event rates did not differ between run-in and placebo periods.
On the patient experience, Klee said blood glucose can drop within minutes, while recovery can take hours because rescuing too quickly may trigger another spike and “put you right back on the roller coaster.”
Potential labeling considerations and addressable population
Asked about a potential label in a positive trial scenario, Klee said the company’s current thinking would be for treatment of post-bariatric hypoglycemia, while noting there may be a nod to continued medical nutrition therapy. He also raised a key design-driven consideration: LUCIDITY is enrolling only patients with PBH following Roux-en-Y gastric bypass, which he said was chosen because the company has the most data in that subgroup. He added that phase II data suggested avexitide’s effect was similar regardless of the surgery type that led to PBH, though he acknowledged the FDA could initially limit labeling to the Roux-en-Y population.
Klee cited estimates shared by a Stanford group suggesting roughly 120,000 of the 160,000 U.S. PBH patients had Roux-en-Y gastric bypass, and he characterized this as a substantial orphan population even if labeling were initially narrower. He also said the company’s internal claims work suggested “line of sight” to approximately 160,000 patients, and that the Stanford group independently reported a similar estimate of about 167,000.
On care delivery, Klee said PBH patients are largely managed in adult endocrinology centers, with some major centers treating several hundred patients and many clinics managing smaller cohorts.
Pipeline expansion plans: long-acting antagonist and Wolfram syndrome
Klee said avexitide is currently administered as a daily subcutaneous injection. He added that Amylyx is pursuing a long-acting GLP-1 receptor antagonist through a collaboration with Gubra, and identified the lead candidate as AMX0318, which is in IND-enabling studies. He said the company is working to bring that candidate into the clinic next year.
He also discussed potential expansion into other surgery-induced hypoglycemia settings, including gastrectomy and esophagectomy procedures, noting that the company has phase II-B data suggesting avexitide may work in other upper GI surgery-induced hypoglycemias. Klee pointed to the prevalence of gastrectomy procedures in Japan as an example and said there are no treatments for those hypoglycemia conditions.
Separately, Klee briefly updated investors on Amylyx’s program in Wolfram syndrome. He described Wolfram syndrome as a monogenic neuroendocrine disease caused by mutations in WFS1 that lead to endoplasmic reticulum stress and downstream cell dysfunction and death, with early-onset diabetes followed by neurodegeneration and early mortality. He said the company’s ongoing study in 12 patients showed an increase in C-peptide, which he characterized as a direct measure of insulin production and beta-cell function, and that other measures including visual acuity and bladder functioning have “gone in the right direction.” He added that the company is still working on alignment with the FDA on a phase III trial design intended to support approval.
About Amylyx Pharmaceuticals (NASDAQ:AMLX)
Amylyx Pharmaceuticals, Inc is a biopharmaceutical company dedicated to developing treatments for rare and debilitating neurological diseases. Founded in 2013 and headquartered in Cambridge, Massachusetts, the company focuses on leveraging novel approaches to target cellular pathways implicated in neurodegeneration. Amylyx’s research platform centers on small-molecule therapies designed to protect neurons and support cellular health in patients with conditions that currently have limited or no disease-modifying treatment options.
The company’s lead product, AMX0035, is marketed under the trade name Relyvrio following U.S.
