Once well-known as an ALS-focused company, Amylyx is now developing therapies for a kaleidoscope of rare diseases—the only requirement being that the indication have a very high unmet need.
“We only work in areas where there are either no treatments or substantially inadequate treatments,” co-CEO Justin Klee told BioSpace.
Founded in 2013 when Klee and co-CEO Josh Cohen were still undergrads at Brown University, Amylyx initially set out to treat neurodegenerative diseases such as ALS. These are “debilitating, devastating diseases and we thought perhaps we can be a real partner there,” Klee said.
Less than ten years later, the Cambridge, Mass.–based company appeared to have succeeded when the FDA granted approval to Relyvrio as only the third drug to treat ALS.
But the fairytale ending was not to be. In March 2024, Amylyx announced that Relyvrio failed the Phase 3 PHOENIX trial, generating no significant difference compared to placebo on a key ALS measurement scale’s change from baseline at 48 weeks. Less than a month later, Klee and Cohen pulled the drug from U.S. and Canadian markets, honoring a pledge they’d made to a 2022 FDA advisory committee.
Now, Amylyx is back with a refreshed pipeline consisting of therapeutic candidates for post-bariatric hypoglycemia (PBH) and Wolfram syndrome plus a new contender for ALS—rare diseases all. One drug, a GLP-1 receptor antagonist named avexitide, is nearing the regulatory finish line in PBH.
A partial pivot
Pivoting is hardly new to Amylyx. ALS wasn’t the original target for the biotech, Rudolph “Rudy” Tanzi, founding chair of Amylyx’s scientific advisory board, told BioSpace in 2024. Rather, the company’s original target was Alzheimer’s disease and the amyloid cascade specifically, hence the name.
But a serendipitous meeting with renowned ALS investigator Merit Cudkowicz—who noted that the drug may also work for ALS where a Phase 2 trial could be enough for FDA approval—prompted the young entrepreneurs to change course and begin studying their lead asset in the intractable neurodegenerative disease.
Ultimately, the FDA approved Relyvrio in September 2022 after posthoc analysis of data from the Phase 2 CENTAUR trial showed the drug slowed progression of ALS, extending the lives of patients by several months.
Since then, Amylyx has been through the ringer. The company’s stock crashed more than 80% after the Phase 3 failure of its only marketed product, and Relyvrio’s market withdrawal cost the company approximately 70% of its workforce.
Fast-forward two years, and the biotech is again getting ready to approach regulators with a new product. Amylyx acquired the Phase 3–ready avexitide from Eiger BioPharmaceuticals in July 2024.
A late complication of bariatric surgery, PBH is “a really debilitating” endocrine condition involving bouts of severe low blood sugar, Klee explained. “People get these episodes at quite frequent times where their blood sugar goes so low that the brain stops functioning properly,” potentially leading to sudden loss of consciousness, severe confusion and seizures. Many patients are afraid to be alone because they never know when these episodes will strike, he said.
PBH affects around 160,000 people in the U.S., or 8% of those who undergo bariatric surgery, per Amylyx’s estimates, and there are currently no treatments. The condition is thought to be caused by an excessive GLP-1 response. Enter avexitide, which binds to the GLP-1 receptor on pancreatic islet beta cells and inhibits this response, thereby decreasing insulin secretion and stabilizing blood glucose levels.
Cohen said Amylyx “gets compassionate use requests all the time” for avexitide, reflecting the unmet need in this space.
And the opportunity is not limited to PBH. “It appears that virtually any gastric surgery has the potential to cause this. Anything that alters the food transit has the potential to cause this debilitating condition,” Klee said. This includes surgery for gastric or esophageal cancer and for hepatic ulcer disease, Cohen added.
Amylyx is expecting topline results from a pivotal study of avexitide in the third quarter. If positive, the company “will work to submit the NDA as soon as possible,” the executives said, and expects to launch the drug in PBH next year, per its first quarter earnings report in May.
Next up, Amylyx is targeting a rare, monogenic neurodegenerative disease called Wolfram syndrome with the same asset it once marketed as Relyvrio.
Cohen described Wolfram as being “half neuro, half endocrine.” The disease initially manifests as type 1 diabetes, he said, but as it progresses, people suffer from vision loss, hearing loss and swallowing and breathing difficulties, “which usually lead to death.”
In May 2025, Amylyx announced positive long term data from 12 patients in a Phase 2 trial showing “sustained stabilization or improvement in multiple outcomes related to disease progression, including pancreatic function, glycemic control, vision, and overall symptom burden” after 48 weeks of treatment with the company’s drug, known as AMX0035.
Always ALS
The executives emphasized that “debilitating, devastating” neurodegenerative diseases, including ALS, are still a primary focus for Amylyx.
“That’s still what drives us today,” Klee said. “That’s still what drives our work in ALS. We’re very proud that we have our next drug candidate for ALS in a clinical trial.”
That candidate, AMX0114, is an investigational antisense oligonucleotide (ASO) targeting calpain-2 (CAPN2), a protein that plays an essential role in axonal degeneration and is elevated in people with ALS, according to Amylyx’s website.
One of the hallmarks of ALS is the degeneration of the long processes that connect the nervous system to the muscles, Klee explained. “While we don’t totally know why that occurs, the mechanism by which that degeneration happens has been quite extensively studied, and one of the key actors in that process is calpain-2.”
There are two challenges with targeting this pathway, however, Klee continued. One is that there are multiple calpains, and two, “you need to get adequate exposure of the treatment into the central nervous system.” Amylyx hypothesized that both challenges could be addressed with an ASO administered intrathecally, or injected direct into the cerebrospinal fluid of the spinal canal.
“With an ASO, you can be very certain that you’re targeting only calpain-2 and not any of the other calpains, and with intrathecal administration you can be certain that you’re getting exposure into the central nervous system,” Klee said.
In December, the biotech announced that AMX0114 was “was generally well-tolerated, with no treatment-related serious adverse events” in 12 patients in the first cohort of the Phase 1 LUMINA trial.
“The unmet need in ALS is just as high today as when we started,” Klee said, “but we think if we can combine . . . new technology with ASOs, then we hope we can make a really big difference in people’s lives.”
https://www.biospace.com/business/consummate-chameleon-amylyx-nears-regulatory-run-in-obesity-surgery-complication
