Amylyx Pharmaceuticals has acquired avexitide from Eiger BioPharmaceuticals, an investigational, first-in-class glucagon-like peptide-1 (GLP-1) receptor antagonist that has been evaluated in five clinical trials for post-bariatric hypoglycaemia (PBH) and has also been studied in congenital hyperinsulinism (HI), two indications characterised by hyperinsulinemic hypoglycaemia.
The FDA has granted avexitide Breakthrough Therapy Designation for both indications, Rare Pediatric Disease Designation in congenital HI, and Orphan Drug Designation for the treatment of hyperinsulinemic hypoglycaemia (which includes PBH and congenital HI).
Avexitide is designed to bind to the GLP-1 receptor on pancreatic islet beta cells and block the effect of GLP-1 to mitigate hypoglycaemia by decreasing insulin secretion and stabilizing glucose levels. In PBH, excessive GLP-1 can lead to the hypersecretion of insulin and subsequent severe hypoglycaemic events, including autonomic and neuroglycopenic symptoms if left unaddressed.
In previous Phase 2 and Phase 2b studies in PBH, avexitide showed statistically significant reductions in hypoglycaemic events characterized by low blood glucose, including severe hypoglycaemic events with altered mental and/or physical function requiring assistance. FDA guidance for industry combined with initial FDA feedback specific to the pivotal Phase 3 program of avexitide for PBH suggest that reduction in hypoglycaemia events could be an endpoint to support approval following positive results from a pivotal Phase 3 clinical trial.
Amylyx expects to begin the Phase 3 program for avexitide in PBH in Q1 2025. Furthermore, Amylyx is actively engaging in discussions with the broader congenital HI community, including experts in the field, to develop a path forward based on promising Phase 2 study results conducted at Children's Hospital of Philadelphia.
Avexitide will be added to Amylyx’ current pipeline programs that have been in research and development for several years: AMX0035 for the treatment of Wolfram syndrome, AMX0035 for the treatment of progressive supranuclear palsy, and AMX0114, the Company’s antisense oligonucleotide targeting calpain-2 for the treatment of amyotrophic lateral sclerosis (ALS).
The following table shows key results from the Phase 2, randomized, placebo-controlled crossover study (PREVENT) that evaluated efficacy and safety of avexitide for treatment of PBH following Roux-en-Y gastric bypass surgery. The results showed that, compared with placebo, avexitide 30 mg twice daily (BID) and 60 mg once daily (QD) significantly increased mean plasma glucose nadir (prespecified primary endpoint) and lowered insulin peak, corresponding to 50% and 75% fewer participants requiring rescue during mixed meal tolerance testing, respectively. Significant reductions in rates of Levels 1, 2, and 3 hypoglycaemia were observed. Continuous glucose monitoring (CGM) demonstrated reductions in time in hypoglycaemia without induction of clinically relevant hyperglycaemia.
Avexitide was generally well tolerated. The most common adverse events were injection site bruising, headache, and nausea; these occurred more often with placebo than either avexitide dose. No participants withdrew due to adverse events.
A Phase 2b open-label, investigator-initiated, cross-over study of higher dose avexitide (45 mg BID and 90 mg QD) was completed in a broader eligible population of 16 participants with PBH following Roux-en-Y gastric bypass surgery, vertical sleeve gastrectomy, esophagectomy, Nissen fundoplication, or gastrectomy. This trial met both its primary endpoint of number of diurnal Level 2 hypoglycaemia events (glucose <54mg/dL) as measured by CGM as well as its secondary endpoints, which includes the rate of Level 2 hypoglycaemia, rate of Level 3 hypoglycaemia, percent diurnal time <70 mg/dL as measured by CGM, and percent diurnal time <54 mg/dL as measured by CGM.
Avexitide was successful in reducing the frequency of hypoglycaemia up to 65% and the amount of time in hypoglycaemia up to 64%. The below table shows results of avexitide at both doses of 45 mg BID and 90 mg QD compared to medical nutrition therapy alone.
There were no reported serious adverse events, and adverse events were mostly mild to moderate and resolved without medical treatment. The most common adverse events included diarrhoea, headache, bloating, and injection site reaction/bruising. No participant withdrew due to adverse events.
“PBH is a debilitating condition with no approved treatment options, and we look forward to advancing this critical work with avexitide into Phase 3 for individuals with PBH based on the totality of data from five clinical trials, and informed by our ongoing work to address endocrine and metabolic aspects of Wolfram syndrome. We also are continuing our conversations with the congenital HI community regarding the clinical development of avexitide in congenital HI to develop a path forward,” said Dr Camille L Bedrosian, Chief Medical Officer of Amylyx. “While we are excited to study this new scientific pathway in hyperinsulinemic hypoglycaemia, our research in ALS and other neurodegenerative diseases continues through our AMX0035 and AMX0114 programs, guided by the understanding that people living with these devastating diseases have no time to wait – we must continue to research and collaborate with urgency.”
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