After withdrawing ALS drug, Amylyx CEOs take lessons to rebuild the pipeline

Amylyx’s co-CEOs Josh Cohen and Justin Klee have already had to make what may end up being the toughest decision of their careers: withdrawing Relyvrio from the market after a late-stage study showed it was not effective in amyotrophic lateral sclerosis (ALS).

With that behind them, it’s time for the small biotech’s next act: a GLP-antagonist the leadership team believes will set it apart.

And no, it’s not that kind of GLP-1. The company is tackling the other side of the equation, buying out a GLP-1 receptor antagonist from bankrupt Eiger BioPharmaceuticals for $35 million to tackle two rare metabolic diseases. Amylyx disclosed the asset purchase last month, after it won an auction for avexitide, which has been under development for post-bariatric hypoglycemia (PBH) and congenital hyperinsulinism (HI).

“It just met, I think, all of our criteria,” Klee told Fierce Biotech in an interview. “We've looked at hundreds of potential therapies to bring in, and this was really one of the first that checked all the boxes.”

Klee said the hunt for new assets would have happened regardless of the situation with Relyvrio, which has now reverted in the pipeline back to AMX0035 and is still being pursued in different neurodegenerative diseases including Wolfram syndrome.

The current GLP-1 frenzy focuses on agonism of the receptor—which regulates insulin and glucose—to address diseases like obesity and diabetes. Antagonism, meanwhile, can address diseases like PBH and HI where there’s too much glucose or not enough insulin.

PBH is a complication of bariatric surgery characterized by progressive low blood sugar after eating that can cause dizziness, loss of consciousness, slurred speech or heart palpitations. Avexitide already has breakthrough-therapy status, meaning Amylyx inherits a hall pass to the FDA for extra discussions on the med’s development.

Congential HI is a genetic disorder of the pancreas that causes excessive insulin production, which in turn lowers plasma sugar or blood sugar.

“There's compelling data, [avexitide] targets important biology, and I think it's an opportunity where we may be able to help many people potentially quickly given that this is a phase 3-ready asset,” Klee said.

Amylyx intends to move quickly to get that late-stage study underway. Cohen said the previous company had already conducted five trials with avexitide, the most recent of which were randomized and placebo controlled, that showed a normalization of glucose and insulin. In a phase 2 and phase 2b study, the therapy led to a statistically significant reduction in the rate of hypoglycemic events in patients with PBH.

That’s where the work stopped and where Amylyx will pick back up, Cohen said.

“Certainly we'll look a little bit at the protocol and everything and make sure we get the right input from experts in the field and otherwise as we plan to initiate the study, but our thought is that we'll have this in phase 3 by the first quarter of 2025,” Cohen said.

Avexitide will arrive at Amylyx with a smaller team to handle the work, as the company laid off about 70% of staff in April. Cohen said the dramatic cuts were meant to be one and done, so he doesn’t expect any more. The company moved quickly after obtaining the results of the PHOENIX trial that doomed AMX0035’s ALS market position.

“As we went through the process, we're really proud of the people that have joined our mission. Our team surely tried … to gracefully go about that process. And part of doing it gracefully is to ideally do it only once,” Cohen said.

Amylyx is now sitting at around 100 people who will handle avexitide, future work on AMX0035 in Alzheimer’s disease and progressive supranuclear palsy (PSP), plus the antisense oligonucleotide AMX0114 in ALS. The team is focused on clinical development.

“We are well staffed and well funded to pursue this opportunity,” Cohen said.

This next phase of Amylyx’s history will be guided by the tough lessons after the failure of AMX0035 in ALS. Klee and Cohen acknowledge that and say the decision to withdraw the drug from the market when the data didn’t go their way shows they remain focused on their mission.

“Faced with the scenario we had … we felt at that point that the benefit of the drug in ALS became uncertain,” Cohen said. “In that context, we did what seemed right and seemed in line with our values.”

The company also made sure to reach out to the ALS community and experts to consider all sides. Cohen continued: “For us, the decision was simple. It was: What is ultimately right and best for the ALS community? And that's where we landed with it.”

Now, Amylyx will fight on with four programs that are expected to be in the clinic “shortly,” according to Cohen. They'll be armed with plenty of experience on the FDA regulatory process thanks to the complex path AMX0035 took to market—and then back again.

Besides the plan to get avexitide into the clinic as soon as possible, Amylyx is expecting full data from the Wolfram program with AMX0035 by the end of the year and will be engaging with regulators to discuss the path forward for that indication. A phase 3 PSP trial is also running now with interim results expected in the middle of next year.

Amylyx’s new ALS program AMX0114 is taking a different approach to the neurodegenerative disease, and an early-stage trial is expected to see initial patients enrolled later this year. Avexitide results are expected in 2026.

“Our team has shown that we can run large-scale phase 3 trials, and then, if successful, we can get meaningful treatments to people very quickly,” Klee said. "We were able to get treatment to thousands of people with ALS in a very short period of time. And, if given the opportunity, that's what the team is prepared to do again.”