Amylyx CEOs look for a path forward following major setback
In 2020, a small clinical trial had a big impact. The study evaluated whether a drug from a young and relatively unknown biotechnology company could help people with amyotrophic lateral sclerosis, a disease so complex that almost every attempt at developing an effective therapy had ended in failure.
Surprisingly, the drug, from then-startup Amylyx Pharmaceuticals, appeared to slow the disease down a little and keep patients alive several months longer. In the years since those results were published in The New England Journal of Medicine, the drug has been approved in Canada and the U.S., where it’s sold under the brand name Relyvrio.
While far from a cure, Relyvrio has become a source of hope for patients and caregivers. Nearly 4,000 of the roughly 30,000 people living with ALS in the U.S. were taking it by the end of September. Relyvrio has also been transformative for Amylyx, which became profitable shortly after its launch. Some Wall Street analysts have estimated the drug could eventually generate more than $1 billion in annual sales.
But the view of Relyvrio dramatically changed late last week, when Amylyx disclosed results from an additional trial meant to confirm the results seen in that earlier “CENTAUR” study. This larger trial, codenamed PHOENIX, found the drug was no better than a placebo at slowing the functional decline associated with ALS.
Before securing approval from the Food and Drug Administration, Amylyx’s co-CEOs Justin Klee and Joshua Cohen had, at the request of a top agency official, pledged to pull Relyvrio from the market if it failed in confirmatory testing. The company said it will take up to eight weeks to disclose its next steps, but may choose to voluntarily withdraw Relyvrio. Already, Amylyx has paused promoting the drug.
The company’s share price has fallen more than 80% since Thursday, as investors question whether it can stay afloat without Relyvrio.
The Amylyx team still believes there’s a path forward, however. Klee and Cohen spoke to BioPharma Dive about the setback and lessons learned from the Relyvrio saga. This interview has been condensed and lightly edited for clarity.
BIOPHARMA DIVE: Do you have any best guess as to why these new results are so different from those seen in CENTAUR?
JUSTIN KLEE: Those are the key questions. We had the CENTAUR study — a clearly successful study that met its pre-specified primary outcome. A longer-term post-hoc analysis showed an overall survival benefit, and that supported the FDA approval. Then PHOENIX did not meet its primary outcome nor secondary outcomes. So it’s clearly not the same.
That’s why we said we want to take some time to meet with experts and go through the results. One thing it certainly speaks to is that in ALS, I think there’s still a lot that we have to learn. It’s a heterogeneous disease. That’s certainly something we’re interested in getting feedback on.
But we also wanted to be very candid in the results. We have a statistical analysis plan for a reason and we pre-specify things for reasons. The results are the results. Now, it’s important that we learn from them.
Amylyx plans to make marketing decisions over the next eight weeks. Is that the amount of time you think you’ll need to analyze results further and draw some conclusions about what happened?
JOSHUA COHEN: In short, yes. We said within eight weeks. Certainly we’ll try to move swiftly as we go through the process. But this is also a big trial with a lot of results and we want to do it right. That, of course, will be our focus.
You’ve already decided to stop promoting your drug. What factored into that decision, and what are you weighing as you consider possibly pulling the drug from market?
KLEE: We felt like, as we’re in this interim period, it didn’t feel proper to continue promotion at this time.
As far as withdrawal goes, that’s where it’s important for us to meet with regulatory authorities, to meet with the expert community. But we made a commitment, and it’s a commitment that I think anyone in the industry believes in, which is that if this is a medication that can benefit people, then our responsibility is to get it to people. If it’s not a medication that’s beneficial, it should not. Within eight weeks, we’ll share plans and next steps.
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Permission granted by Amylyx Pharmaceuticals
Most companies won’t even mention the idea of pulling a drug despite a failed trial. Why has Amylyx been so upfront about that being a possibility since even before Relyvrio was approved?
COHEN: I hopefully don’t mean this to sound any particular way, but we’ve always tried not to be most companies. At Amylyx we live by our values. We believe we have very high integrity. We’re here not for anything other than trying to serve patients and change these terrible diseases.
So that’s why, quite frankly, making the commitments we have has not been difficult. It’s been consistent with our values. It’s been what we built this company to do. With this data in hand, our intention is to follow the science. And if that means taking the drug off the market, we’re fully prepared to do so.
How does that approach square with investors? Have you been talking to them over the course of the last few days and, if so, how have those conversations gone?
KLEE: We tried to be very clear in our press release what our plans and intentions are. In terms of investors, we’re very thankful. We’ve had great supporters for a long time. We think it’s our responsibility to be as candid and transparent as possible, particularly when we’re in areas like ALS that are really challenging. In many ways we’re pioneering. There’s a lot we don’t know. I think it’s especially important that we’re candid.
Certainly the results are not what we hoped for, not what the ALS community hoped for, not what shareholders hoped for. But this was a possibility, especially in a disease like ALS.
The good part is we have cash, we have other programs, including the same treatment in Wolfram syndrome. We’re seeing early signs of clinical activity. We have another drug candidate, AMX0114, that we plan to have in the clinic for ALS by the end of this year. So we have a lot more going on. But obviously this is both a surprise and sad result.
What, if any, lessons have you taken from the Relyvrio saga?
KLEE: The best people to ask are the ALS community. Their perspectives are probably more valuable than ours.
But I would say that in diseases like ALS, it’s so important to remember what people and their families go through every day. ALS is currently a relentlessly progressive and universally fatal disease. So every stakeholder, we need to keep trying to push, trying to innovate and take on challenges.
That’s why for us, even with this challenging news, our commitment is unwavering. And we will continue our fight against ALS. It’s what the community deserves.
COHEN: I’m quite proud of what the team did. Through the whole process we’ve received wonderful notes from people. At every stage we followed the science. But one of the lessons certainly is that this is a tough disease. It’s not for lack of trying that this disease has not been significantly changed since it was first discovered over 100 years ago.
As these events happen, it’s all about perseverance. We’ve certainly not given up an ALS, [and] ‘114 may be applicable to other indications in addition to ALS.
The road is not always straight, but I think what we can do is continue to keep our values front and center and continue trying to help patients. The path forward will become clear through that.
Relyvrio gets brought up in conversations about regulatory flexibility from the FDA. What effect, if any, do you see Friday’s results having on the idea of regulatory flexibility?
COHEN: While this saga may be painful for us, in some way, this is one of the risks having these types of processes. It shows that they’re working as well. Had PHOENIX come out positive, we would have gotten a drug that clearly benefited patients to them much sooner. That is essential.
We should not take this event as an example that says, “Now, we should be extremely risk-averse in all cases.” Coming off a study with a positive pre-specified primary outcome, nine times out of 10 PHOENIX would have been positive. So I think it was the right path. In fact, I think the FDA should continue to lean into risks like this and understand that, when you lean in, sometimes it won’t pan out. But most of the time it will. And that’s worthwhile for patients and for these deadly diseases.
What do you think Amylyx will look like in a year?
KLEE: I really appreciate you asking. I’d say let’s connect weeks [from now] as we outline that further.