NeuroVoices: Justin Klee, Josh Cohen on Building AMX0035’s Case as the Next ALS Treatment

Following their data presentation on AMX0035 at AAN 2022, Justin Klee and Josh Cohen, the co-CEOs and co-founders of Amylyx Pharmaceuticals, shared their perspectives on the agent.

With only 2 FDA-approved medications, the treatment landscape for patients with amyotrophic lateral sclerosis (ALS) remains limited, though that could change soon. Currently under FDA review, AMX0035, Amylyx Pharmaceuticals’ orally administered fixed-dose coformulation of sodium phenylbutyrate and taurursodiol, has demonstrated the make-up of a promising agent thus far. Its new drug application, submitted in November 2021, was backed by phase 2/3 data from the CENTAUR study (NCT03127514) showing that the trial met its primary end point. After 24 weeks of treatment, AMX0035-treated patients demonstrated 2.32 points higher on ALS Functional Rating Scale-Revised (ALSFRS-R) than those on placebo.1,2

In March, at a public hearing, the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee (AdComm) voted that the current data on AMX0035 is not sufficient in demonstrating efficacy.3 The committee voted 6-4 (6 no; 4 yes; 0 abstain) that the data from that trial and its open-label extension did not adequately establish the agent as an effective medication for treatment of ALS. Now, Amylyx and the ALS community waits for the final decision from the FDA, which is expected to come by June 29, 2022.

In the meantime, at the 2022 American Academy of Neurology (AAN) Annual Meeting, April 2-7, in Seattle, Washington, the company presented additional safety data from CENTAUR, as well as from PEGASUS (NCT03533257), another clinical trial evaluating the agent in patients with Alzheimer disease (AD). Results showed that the majority of treatment-emergent adverse events (TEAEs) associated with AMX0035 were gastrointestinal and consistent with the observed individual safety profiles of the components of the treatment. Additionally, the findings in AD further elucidated the safety profile of AMX0035, as TEAEs in the CENTAUR trial appeared to be largely disease driven.4

To better understand the new data, as well as the initial thoughts following the FDA’s AdComm meeting, NeurologyLive® sat down with Justin Klee and Josh Cohen, cofounders and cochief operating offers of Amylyx. As part of a new iterations of NeuroVoices, the duo discussed the robust profile of AMX0035, whether the concerns of the AdComm panel were legitimate, and how the upcoming phase 3 PHOENIX study (NCT05021536) may address some of the lingering questions. They also provided a call-to-action and why they plan to publish the PHOENIX results even if AMX0035 is not approved.

NeurologyLive®: How does this data further boost AMX0035’s profile?

Josh Cohen, BSc: I think with any therapy, we want to learn more about the safety profile. That was one of the focuses here, to see that safety profile in a larger cohort of patients across two diseases. I think what we confirmed was that there appears to be a good safety profile, and the adverse events were seeing are consistent. These were generally things like diarrhea, which seems to resolve relatively quickly after initiation of therapy. In terms of increasing the profile of the therapy, I’d say we’re lucky that data for this therapy has already been published in the New England Journal of Medicine. We definitely plan to continue to analyze and publish, but I think it’s already quite a robust and rigorous study result.

What was your general reaction the FDA AdComm’s meeting? Did you feel that the concerns were addressable, or do the available data provide a clear enough picture?

Justin Klee, BSc: The first thing is, we’re proud of our team. I thought that they presented things in a clear manner, and we knew there were concerns from the FDA coming in. I thought the presentation did a great job of addressing those concerns, and also highlighting the strength of the data. The data, as Josh said, were first published in the New England Journal of Medicine, then in Nerve & Muscle, showing a benefit first on the ALS Functional Rating scale–the gold standard in the field of ALS–and then on overall survival in muscle and nerve, which is critical in any disease, but particularly in a rapidly fatal disease like ALS.

In terms of the panel, I think it’s important that we have open discussions on critical therapies like AMX0035. We were encouraged at first, similar to the presentation here at AAN. The FDA agreed that the safety profile appears quite good. Secondly, we were encouraged that in a very heavily biostatical discussion, Dean Follman, PhD, the biostatistician on the panel, thought that the way we handled things was done in an appropriate manner, and that it would support the efficacy of the treatment. Overall, there’s more to come. Of course, the ultimate decision is up to the FDA, but we’re proud of our team and the data.

Josh Cohen, BSc: To add to what Justin said, there was some important scientific discussion on the statistical handling, questions about blinding and things like that. It’s important to say, firstly, the statistical model that we designed was pre-specified, and was designed prior to seeing any of the data. It was designed with David Schoenfeld, who’s one of the top statisticians. I think he’s the most cited statistician in the ALS field. We stand by all the modeling choices and assumptions. Similarly, as Justin mentioned, Dr Follman, the only biostatistician on the panel, was similarly supportive of the choices we made. Additionally, we were a little puzzled by the discussion on blinding. Considering that in this study, there was no evidence that we know of, of unblinding. We consider the study quite well-blinded. That was surprising and a little puzzling to us as well.

Some felt as though they wanted to see data from PHOENIX, what types of goals are you looking to achieve in that study?

Josh Cohen, BSc: We’re thrilled about the PHOENIX study. It’s a global collaboration between many of the top researchers in the US and Europe. Sabrina Paganoni, MD, PhD, and Leonard Vanderburgh are cochairing the study. The study is actively recruiting. We announced at the AdComm meeting that we’ve already recruited 150 patients. We’re certainly trying to recruit as fast as possible. Ultimately, the prospect for a person with ALS is rapid disease progression and mortality. It’s likely that by the time PHOENIX reads out, much of a generation of ALS will have passed away. We feel that there’s a path to balance urgency and data.

We made the point at the advisory committee hearing that regardless of what happens in our process, we intend to complete the study. We think it’s critical data. Everybody wants more data. More data is always good. Everybody wants more data, but we have to balance that with the needs of patients today. None of these decisions are easy. Especially with current data published in the New England Journal of Medicine demonstrating survival benefit, it seems like we’re trying to find some balance where patients can get access as quickly as possible.

Do you have any call-to-actions before the FDA makes its decision this summer?

Justin Klee, BSc: We’re so inspired by all the people who wrote testimonies, people with ALS, their families, as well as the people who spoke in the open public hearing and who shared what their lives with ALS are like, and what these potential benefits would mean to their lives or their family’s lives. As well as hearing from the experts, ALS doctors who run clinical trials and see people with ALS. It’s critical that the key stakeholders, people with ALS, their doctors, the nurses, therapists who helped with their care and treatment, their voices are at the table.

In terms of our involvement as a company, we have always tried to stick as close to the science and data as possible. That’s what we’re published in the places we mentioned because the peer review process is an important factor in how the medical community knows what to trust. What we will continue to do is be transparent about the data, be as robust as possible in the way we conduct things, and in every opportunity, present at such wonderful conferences like AAN. We feel honored there’s a wonderful community and we know that many people have placed their trust in us. We take that incredibly seriously.

Transcript edited for clarity. Click here for more iterations of NeuroVoices.

REFERENCES
1. Amylyx Pharmaceuticals submits new drug application (NDA) for AMX0035 for the treatment of ALS. News release. Amylyx Pharmaceuticals. November 2, 2021. Accessed April 12, 2022. https://www.businesswire.com/news/home/20211102005320/en/Amylyx-Pharmaceuticals-Submits-New-Drug-Application-NDA-for-AMX0035-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. March 30, 2022. Accessed April 12, 2022.
4. Amylyx Pharmaceuticals announces oral presentation of safety and tolerability data on AMX0035 from clinical trials at 2022 American Academy of Neurology Annual Meeting. News release. Amylyx Pharmaceuticals. April 2, 2022. Accessed April 12, 2022. https://www.amylyx.com/media/amylyx-pharmaceuticals-announces-oral-presentation-of-safety-and-tolerability-data-on-amx0035-from-clinical-trials-at-2022-american-academy-of-neurology-annual-meeting