Reactions, Ramifications, and Forward Progress of Newly Approved AMX0035 for ALS

Justin Klee

On September 29, 2022, the FDA made a groundbreaking decision, as it approved AMX0035 (Relyvrio; Amylyx Pharmaceuticals) for the treatment of amyotrophic lateral sclerosis (ALS), making it the third approved therapy to help slow disease progression or mortality.¹ It joined riluzole (Rilutek; Sanofi) and edaravone (Radicava; MT Pharma)—which received approvals in 1995 and 2017, respectively—as the only other approved medications. AMX0035, a coformulation of sodium phenylbutytrate-taurursodiol, was approved based on findings from the phase 2 CENTAUR trial (NCT03127514).

In CENTAUR, the drug met its primary end point, with treated patients reporting an ALS Functional Rating Scale-Revised (ALSFRS-R) scores of 2.32 points higher than those on placebo (P = .03) after 24 weeks of treatment.² Additionally, the new drug application was supported by survival data, which showed that AMX0035 reduced the risk of death by 44% relative to placebo. Despite the positive findings, the drug was first met with some resistance, as a first meeting by the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee voted to not recommend the therapy for approval.

Josh Cohen, MSc

After the original PDUFA date was pushed back for additional review, the AdComm panel agreed to reconvene again for a second meeting, in early September 2022, weeks ahead of the new scheduled date. There, the script flipped, and the panel voted 7–2 (7 yes; 2 no) in favor of recommending the therapy for FDA approval.³ Shortly after the approval, NeurologyLive® sat down with Justin Klee and Josh Cohen, MSc, cofounders and cochief operating officers of Amylyx. They sat down to discuss their original reaction to the decision, the biggest learning experiences from AMX0035’s pathway to approval, and the ongoing questions that remain as the drug enters the market. Additionally, the gave an update for the ongoing phase 3 PHOENIX trial (NCT05021536), which is being used as supplemental evidence to confirm the therapy’s effectiveness.

NeurologyLive®: What was your initial reaction to the approval and message to the ALS community?

Justin Klee: When we first got the news, we just felt so humbled and grateful. This is a community we deeply care about, and the opportunity to have a new treatment option that could help people is so exciting. But it’s also just the start for us. We’re proud of the results, but we need to keep going until we cure this disease.

Josh Cohen, MSc: To echo Justin, gratitude was the main feeling. We started this company when I was a junior in college and Justin was a senior. Most investigators aren’t too thrilled about going after a disease that generally has resulted in treatment failures with the management team who have not done it before. It was a lot of special people who took a lot of chances on us, who spent time with us, mentored us. Among them include Merit Cudkowicz, MD, MSc, and Sabrina Paganoni, MD, PhD. In moments like that, you reflect on the people who have made it possible. The other emotion was excitement, just to finally get it [AMX0035] to patients and deliver the benefit to them.

What remaining questions do we have concerning insurance, access, and dosing?

Justin Klee: Our of our first mentors was Henry Trameer, who was the longtime CEO of a company called Genzyme. Henry always would say there’s a point where a treatment moves from being an opportunity for the company to being a responsibility, and we’re very much in that place now. We have a responsibility to deliver this to the community in the right way. We know how precious time is for people with ALS. We know that clinics work day and night to try to help these people, and so it’s our responsibility to be a good partner to them.

First, our teams have been preparing for this all year. We’ve talked with every major insurance company, talked with pharmacies, gotten our supply ready, and checked our quality many times. Our ACT team, or Amylyx Care Team, is ready to help individuals navigate the complex US healthcare system, and I could go on in terms of the specific details. The product will be available within the next 4 to 6 weeks; however, our Amylyx Care Team is up and running. When people are enrolled, it’s a prescription plus enrollment into the team, who can then start the work on the insurance coverage, assistance with financing, and all that stuff. Our goal is to get this to people as quickly and efficiently as we can.

Josh Cohen: The only thing I’d add is that one of our main focuses as we planned and built our commercial organization and process was access and affordability. We’re trying to make it so that most, if not all, patients and physicians can connect through for their prescription through the Amylyx Care Team. These people liaison directly with the healthcare professional as well as the patient, and many of them have direct connections to ALS or rare disease. It’s personal for them. We’ve built it so that for people with commercial insurance that you might get through your employer, we’re able to bring the co-pay down to $0 in most cases. For government insurance, it’s a bit more complicated, there are a lot of different plans, but we’ve set it up so that the team can provide various financial assistance options to those with government pay insurance as well. If all else fails and we can’t find a good financial assistance path, we’re fully ready and willing to provide free drug. Obviously, we can’t run a business if we’re trading everything for free, but for those patients who’ve exhausted options and there’s no good path, that’s the route we’ll take.

Where do we currently stand with PHOENIX?

Justin Klee: Firstly, we were very happy that at the FDA Advisory Committee meeting, we were given the opportunity to share our perspective on the PHOENIX trial. It may have seemed contentious, but to us it was very simple. We’re going to do what’s right for patients and what’s right for the community. That means running the study, getting the results, and making our decisions based off those results. PHOENIX is ongoing, it’s going very well. We don’t expect results until 2024, so it was an important discussion between experts and the FDA Advisory Committee for people living with ALS today. The FDA’s decision was that, based on the data they’ve seen, the impact on function, the impact on survival, that this meets their bar for substantial evidence of effectiveness needed for approval. In the meantime, we’ll continue with PHONEIX, and we, and the global ALS community, are excited about those [future] results as well.

What was your biggest takeaway from this entire process?

Josh Cohen: I try to live life not looking too much at hindsight because you can always do things better. That being said, the one thing I wish is that we could have done it faster. There are several people with ALS, including some people who we’re very close to, who passed away recently before the approval. What would it have meant if we did this 6 months quicker? A year quicker? 2 years quicker? That’s something we want to take as we move forward and hopefully develop additional drugs.

In terms of lessons learned, the main thing that has always been key and core to Amylyx is listening. We were lucky to get to connect early with the NEALS network, get to know a number of clinicians and clinical researchers, many of whom have been thinking critically about ALS trials for decades, and thinking about all the past trials and what worked and what didn’t. So much of our success is attributable to all the people who took the time and taught us, frankly. As we go forward into the next stage, similarly, the important thing is to partner with the community, with the experts, and bring people together. It took us about 10 years for this drug, so my hope is that the next one will be a lot quicker.

Justin Klee: I don’t have much to add, but just to put some metrics to it, we announced our topline results from the CENTAUR trial in late 2019. We’re almost 3 years later. In that time, in the United States alone, about 18,000 people with ALS have died. As excited as we are, there’s a lot more we have to do.

Transcript edited for clarity.

REFERENCES
1. Amylyx Pharmaceuticals announces FDA approval of Relyvrio for the treatment of ALS. News release. Amylyx Pharmaceuticals. September 29, 2022. Accessed September 30, 2022. https://www.amylyx.com/media/amylyx-pharmaceuticals-announces-fda-approval-of-relyvriotm-for-the-treatment-of-als
2. Paganoni S, Macklin EA, Hendrix S, et al. Trial of Sodium Phenylbutyrate–Taurursodiol for Amyotrophic Lateral Sclerosis. N Engl J Med. 2020;383:919-930. doi:10.1056/NEJMoa1916945
3. FDA. Peripheral and Central Nervous System Drugs Advisory Committee Meeting. September 7, 2022. Accessed September 29, 2022. https://www.fda.gov/advisory-committees/advisory-committee-calendar/september-7-2022-meeting-peripheral-and-central-nervous-system-drugs-advisory-committee-meeting