Amylyx Pharmaceuticals (NASDAQ:AMLX) executives outlined a slate of milestones they expect to shape the company’s near-term trajectory during TD Cowen’s 46th Annual Healthcare Conference, with co-CEOs Josh Cohen and Justin Klee emphasizing that 2026 could be “transformative” primarily due to a pivotal readout for avexitide in post-bariatric hypoglycemia (PBH).
Avexitide Phase 3 timeline and near-term catalysts
The company’s lead program is avexitide, a GLP-1 receptor antagonist being developed for PBH. Management said the company initiated the LUCIDITY Phase 3 trial in 2025, describing it as the sixth clinical study of avexitide in PBH. The prior five PBH studies, the executives said, showed “very statistically significant, clinically meaningful reductions” in hypoglycemia and supported FDA Breakthrough Therapy designation.
PBH: diagnosis, prevalence, and unmet need
Management described PBH as emerging after bariatric surgery, typically one to three years post-procedure on average, though they noted patients may present five to eight years after surgery in some cases. The executives described symptoms ranging from sweating, dizziness, and shakiness to more severe outcomes including loss of consciousness, seizures, and coma in particularly severe cases.
The co-CEOs reiterated their estimate that there are about 160,000 people with PBH in the U.S. today. They said PBH occurs in roughly 8% of people who have bariatric surgery, and pointed to over 2 million U.S. bariatric procedures over the past decade as a basis for their prevalence estimate. They also said the estimate is supported by claims database analyses and cited work from a Stanford team that arrived at a similar figure (they referenced approximately 167,000).
They framed PBH as a major unmet need, emphasizing that hypoglycemic events can be medical emergencies and may prevent patients from driving, make it difficult to hold a job, and create reliance on caregivers. They also said efforts are underway in the medical community to potentially establish an ICD-10 code for PBH this year, and noted growing physician awareness, including PBH being on the Endocrinology Board Exam.
Current management and the company’s mechanistic view
Amylyx said there are no approved treatments for PBH, with the primary intervention being medical nutrition therapy. Executives described that approach as avoiding simple carbohydrates, eating small meals frequently, and attempting to maintain glycemic control. They argued PBH is characterized by ongoing severe hypoglycemic events even with dietary intervention, which they attribute to an “exaggerated GLP-1 response,” stating patients may produce 10 to 20 times normal GLP-1 levels.
Asked about the impact of GLP-1 agonist weight-loss drugs on bariatric procedure volumes, management said bariatric surgery numbers have remained “quite robust” and have net increased since Wegovy’s approval. They described bariatric surgery as the “gold standard” for substantial weight loss in severe obesity and noted patients may pursue surgery for broader health concerns such as hypertension and high cholesterol. They also emphasized PBH is lifelong because the altered gut anatomy does not revert, citing interactions with patients living with PBH for 10 to 20 years.
Prior data and LUCIDITY study design
Management reviewed a development package that included three Phase 1 studies and two Phase 2 studies in PBH, which they said supported Breakthrough Therapy designation. They highlighted an early Stanford Phase 1 experiment in which PBH patients received a glucose challenge (“Glucola”) and, with avexitide dosed intravenously in that initial trial, the drug “prevented 100% of the hypoglycemia” observed in the clinic setting.
In Phase 2 studies using subcutaneous dosing, the company said it observed statistically significant reductions in level 2 and level 3 hypoglycemic events. They defined level 2 events as finger-stick blood glucose below 54 mg/dL and level 3 events as severe symptomatic episodes requiring independent rescue, adjudicated by an independent committee. In the Phase 2b study using the dose being advanced into Phase 3, Amylyx said avexitide achieved a 52% reduction in level 2 events and a 66% reduction in level 3 events.
For LUCIDITY, management said the company tried to change as little as possible relative to the Phase 2 program. Key differences include a longer treatment period—16 weeks in Phase 3 versus 4 weeks previously—and a parallel-group design rather than crossover. They also described a run-in period requiring at least one event per week during a three-week run-in, and said Amylyx centrally signs off on each participant entering the study. Executives said they are pleased with the patients being enrolled, but had not decided whether to release baseline characteristics ahead of data given the study’s timeline.
On powering, the company said LUCIDITY is designed with approximately 90% power to detect a 35% treatment effect versus placebo, describing the assumptions as conservative relative to prior results.
Pipeline updates: Wolfram syndrome, ALS, and long-acting GLP-1 antagonism
Beyond avexitide, management provided brief updates on multiple programs:
- Wolfram syndrome (AMX0035): Executives said the company remains in discussions with the FDA regarding what an appropriate Phase 3 trial could look like, emphasizing feasibility and efficiency. They estimated about 3,000 people with Wolfram syndrome in the U.S., with more internationally.
- ALS (AMX0114): The company is running a multiple ascending dose, placebo-controlled study in people living with ALS targeting calpain-2, which management linked to axonal degeneration and Wallerian degeneration pathways. They said safety data from the first cohort showed the drug was “quite safe and well-tolerated.” They expect to share biomarker data in the first half of the year at a medical meeting and expect to complete enrollment of the second cohort in March. Biomarkers discussed included calpain activity signatures such as spectrin breakdown products and measures related to neurofilaments.
- Long-acting GLP-1 receptor antagonist: Amylyx said it is pursuing a next-generation, potentially long-acting antagonist through a collaboration with Gubra. The company announced a lead candidate earlier in the year and said it is currently in IND-enabling studies, aiming for dosing potentially once weekly or better, though management noted the program remains early.
When asked about additional business development, executives said the company maintains an active process and would be interested in opportunities comparable to avexitide, while emphasizing current focus on the LUCIDITY readout, NDA work, and a potential launch thereafter. They also said the company has cash runway into 2028 and continues to plan for potential avexitide commercialization in 2027.
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.
