Months after pulling its only approved product from the market, Amylyx Pharmaceuticals appears to be plotting a comeback—this time targeting the red-hot GLP-1 space. But rather than chasing obesity indications, the company has picked up a mid-stage candidate it says could become a first-in-class therapy for other diseases tied to blood sugar balance.

Earlier this month, the company announced it had paid $35 million inthe bankruptcy auction of Eiger BioPharmaceuticalsto acquire avexitide, a Phase III-ready candidate.

The candidate targets the GLP-1 hormone, but unlike the blockbuster weight-loss drugs that act as GLP-1 agonists, avexitide is an antagonist that raises blood sugar and lowers insulin levels. To date, the drug has shown promise in two diseases with a "double-hit" profile: post-bariatric surgery hypoglycemia and congenital hyperinsulinism. Based on the drug's performance in the clinic, Amylyx plans to launch a late-stage trial in the first quarter of 2025, hoping for a data readout in 2026 and a launch the following year.

"We want to balance normal glucose control and response, and [avexitide] has the potential to be a first-in-class drug for managing related diseases."

—Justin Klee, Co-CEO of Amylyx Pharmaceuticals

Although the company has not yet provided guidance on the market potential for these two indications, Amylyx's co-CEOs Josh Cohen and Justin Klee say post-bariatric surgery hypoglycemia affects about 160,000 people in the U.S.

"This is a truly debilitating disease," Klee said. "Many patients don't leave their homes and need round-the-clock care because they don't know when it will strike, such as unexpected seizures or fainting."

If approved, avexitide could bring much-needed new options for both indications.

"We think avexitide has enormous potential," Klee said. "The data also has our team very excited."

Moving into endocrine diseases marks another major pivot for Amylyx.

In 2022, the FDA approved the company's Relyvrio for ALS based on mid-stage data suggesting the drug could slow disease progression. But this spring, confirmatory trial results showed it was no better than placebo. After the disappointing results, Amylyx pulled Relyvrio from the market and cut about70% of its workforce。

Despite its roots in neurodegenerative disease, Amylyx's research on the compound continues. The drug, known as AMX0035 in clinical trials, is currently inmid-stage development for Wolfram syndrome, a rare genetic disease that can be fatal.

Amylyx also has another new ALS drug, AMX0114, in early-stage development targeting calpain-2, which research haslinked to neuronal death。

Here, Cohen and Klee reflect on the lessons learned from the Relyvrio experience and how they are applying them to other candidates in the pipeline.

This interview has been edited for length and style.

PHARMAVOICE: What are the most important takeaways from the Relyvrio failure in ALS?

JUSTIN KLEE:What I'm proud of is the research we conducted, and I believe the team is too. The team executed a large, multinational, complex Phase III study with a patient-centric design, efficiently.

The challenge is that these are difficult areas to develop in, and although the results did not meet expectations, the trial ran well. The most important takeaway is that we have the team, resources, and operational capability to advance these promising treatments to the development stage, and if effective, they could benefit thousands of people.

JOSH COHEN:As we move into future trials, another thing that excites us is the use of biomarkers. This is inherently more challenging in ALS, but great progress has been made. When we enter the next ALS trial, we will leverage many of the latest biomarker insights to enhance confidence as data comes in.

We are equally focused on biomarkers in Wolfram syndrome, and for avexitide, we benefit from objective measures like hemoglobin A1C (for blood sugar levels), which is one of the oldest biomarkers.

Did the Relyvrio setback make you rethink the science behind the drug or your approach to ALS?

KLEE:We still firmly believe that targeting neurodegenerative pathways is crucial for these diseases. What has changed is our understanding of these pathways, and our ability to target them has improved.

Our treatment (AMX0114 in ALS) has been studied as a target for decades. But it's difficult to target calpain-2 specifically and get adequate exposure in the brain and spinal cord. Now we have an antisense oligonucleotide that can be administered, we know we only act on calpain-2, and we know we achieve brain and spinal cord exposure at therapeutic doses. The approach to targeting neurodegeneration in a meaningful way has advanced by leaps and bounds.

COHEN:There is continuous excellent work in the ALS field, we have improved how we measure outcomes, how we look at biomarkers, there is much thought and debate about how to discern signal from noise, and a lot of publications on basic biology like genetics. ALS truly benefits from considerable research, especially for a rare disease, and we strive to keep up with the literature. We continuously document the targets we are most interested in, and calpain-2 has been one of the targets we are most excited about. It's a target that feels regrettable because it hasn't been studied in the right way.

For avexitide, you are developing it for post-bariatric surgery hypoglycemia. But there is some evidence that the need for bariatric surgery is declining due to the effectiveness of GLP-1 agonists. What is the long-term market outlook for avexitide?

KLEE:We have seen that agonists of this receptor are powerful in many different diseases and conditions because GLP-1 is one of the main regulators of glucose-insulin balance. So in these diseases, agonism of the GLP-1 receptor is beneficial. But that's only half the equation... We haven't done well enough in hypoglycemia and hyperinsulinemia. We want to balance normal glucose control and response, and this has the potential to be a first-in-class drug for managing related diseases.

Bariatric surgery is used for many reasons beyond weight loss. In the past 10 years, there have been at least 2 million of the most common bariatric surgeries in the U.S.—more than 200,000 per year. With the advent of GLP-1 agonists, this number may decline, but even if it drops by 10%, the number of surgeries remains substantial.

We also hear some of the opposite, because weight loss is becoming more mainstream and discussed, and in some clinics, some doctors see obesity surgery numbers rising with this awareness.

Last time I interviewed the two of you, we discussed theco-CEO modeland why it fits well in the pharmaceutical industry. How has this model performed during the crisis period of the past few months?

KLEE:It has been a blessing again. Making very important decisions in a limited time, when you have someone you can talk to and trust, and feel you can share the burden of what needs to be handled, it's much better. But more broadly, we are fortunate to have a great team that quickly rallied together. There was no arguing or disagreement—it was just about how to best accomplish what we needed to do. It was a difficult time, but I am proud of how we handled the results transparently, while providing the drug free of charge to ALS patients who wished to continue taking it.

COHEN:The advantages of the co-CEO model are amplified in a crisis because time is scarce and things can be emotionally draining. Having more than one leader at such times helps address all the issues.