NeuroVoices: Justin Klee and Josh Cohen on AMX0035 and Pending PHOENIX Data


The cofounders and cochief executive officers at Amylyx Pharmaceuticals provided commentary on the incorporation of AMX0035 for patients with ALS and the upcoming PHOENIX confirmatory trial.

Justin Klee

Justin Klee

In September 2022, the FDA approved Amylyx Pharmaceuticals’ AMX0035, a coformulation of sodium phenylbutyrate-taurursodiol, for the treatment of patients with amyotrophic lateral sclerosis (ALS).1 The drug, marketed as Relyvrio, became the 3rd approved therapy to help slow disease progression or mortality in ALS, following riluzole (Rilutek) in 1995 and edaravone (Radicava; MT Pharma) in 2017. To further the efficacy and safety profile of the agent, Amylyx initiated a subsequent phase 3 study, dubbed PHOENIX (NCT05021536).

PHOENIX, a 48-week trial assessing the agent in 664 individuals with ALS, is expected to have data read out in Q2 of 2024. The randomized, placebo-controlled trial randomly assigns patients 3:2 to AMX0035 or placebo, with changes assessed on the primary outcome measure of ALS Functional Rating Scale-Revised. Most of the participants in PHOENIX are members of the NEALs or Treatment Research Initiative to Cure ALS consortia. Aside from the primary outcomes, the study includes other measures of slow vital capacity, quality of life, decline in King’s and Milano-Torino staging, ventilation free survival, and long-term survival.

Josh Cohen

Josh Cohen

Prior to announcement of the pivotal data, NeurologyLive® caught up with Josh Cohen and Justin Klee, cofounders and cochief operating officers of Amylyx, to discuss PHOENIX, and the potential it holds. The duo provided context on the background of the study and how the phase 3 CENTAUR trial (NCT03127514), the study in which AMX0035 was approved on, helped guide future decisions. Furthermore, the two spoke on the integration of the agent into clinical care since its approval and how it may be used with other therapies, including Biogen’s antisense oligonucleotide tofersen (Qalsody).

Can you provide an overview of the phase 3 PHOENIX study and the upcoming data?

Justin Klee: To remind everyone, the first study on AMX0035 was the CENTAUR study. The CENTAUR study comprised 137 participants across 25 centers, with a randomized controlled design that demonstrated a statistically significant benefit on the ALS Functional Rating Scale. Moreover, over the longer term, we observed a benefit on overall survival as well. It's noteworthy that in ALS, for the first time in a single clinical trial, we've observed a treatment impacting both function and survival, which is particularly exciting given the progressive, fatal nature of the disease. This study led to the FDA approval in the fall of 2022, and Health Canada also granted it a notice of compliance with conditions a few months prior. Now, we're conducting the PHOENIX study, which involves 664 participants with ALS, testing Relyvrio. We're examining the ALS Functional Rating Scale as the primary outcome and also assessing more long-term outcomes like overall survival, although this will likely take additional time. We're genuinely excited about having two positive studies supporting a treatment in ALS, which is unprecedented in the field. Additionally, the opportunity to conduct a longer-term trial, lasting 48 weeks with a placebo control, provides a chance to explore long-term benefits further. This complements our ongoing real-world work with thousands of individuals across the United States and Canada. It's an incredibly exciting time, and we eagerly await the results, which we believe will be a major milestone for the ALS community.

Are there aspects of CENTAUR and the approval process that helped shape your approach to PHOENIX?

Josh Cohen: I think one advisor made a compelling point that as you publish your data, you initially believe you know it well, but through regulatory processes, you realize your understanding deepens significantly. In the case of CENTAUR, we had a positive randomized placebo-controlled study published in the New England Journal of Medicine, leading to full approval in the US and notice of compliance with conditions in Canada. We learned a tremendous amount from that study, particularly about how the endpoints perform for people living with ALS and how to design trials that are patient-centric. We're deeply invested in ensuring that our trials accommodate the challenges faced by individuals with mobility limitations, making clinic visits more manageable. In designing the Phoenix study, we aimed to build upon these learnings. We also endeavored to internationally standardize the ALS Functional Rating Scale, ensuring consistency in research practices. Our experience with CENTAUR informed the frequency of assessments in Phoenix, which is critical for minimizing measurement noise. We're incredibly excited about this unprecedented moment in ALS research and hope it serves as an inspiration for continued progress in the field of neurology.

Justin Klee: I echo Josh's sentiments. Working on the Centaur study, we had the privilege of collaborating with some of the best ALS doctors, nurses, therapists, and clinical trialists. The innovative design of the Centaur study was a testament to their expertise and dedication. Expanding the Phoenix study to include sites in Europe allowed us to engage with an even broader group of experts. It's truly an honor to work in this field alongside individuals who not only provide exceptional care to those in need but also actively contribute to advancing research for the future. The dedication and innovation within the ALS community continue to inspire us, and we're proud to be a part of it.

Talk a little about the integration of AMX0035 in clinical care; how has that gone?

Justin Klee: We're keen on partnering with the entire community to transform ALS treatment. About half of ALS patients are primarily cared for by ALS specialists, who offer specialized care and treatment at multidisciplinary care centers. However, the other half may not have access to such centers or specialized care. It's crucial to ensure that everyone diagnosed with ALS receives appropriate care. Historically, there's been a perception that ALS treatment options are limited, but with advancements like Relyvrio, we're challenging that mindset. While ALS remains progressive, interventions like Relyvrio offer meaningful benefits, and it's essential to change the narrative around the disease. We're witnessing a revolution in neurology, with significant advancements across various conditions, including ALS. Relyvrio is just one component of this revolution, and there's much more we can do collectively to improve outcomes for ALS patients.

Has AMX0035 been used in combination with tofersen (Qalsody; Biogen)?

Josh Cohen: Relyvrio is approved for all adults with ALS, and there have been instances where individuals have used both tofersen and Relyvrio concurrently. Combination therapy has been successful in other diseases like multiple sclerosis, various cancers, Hepatitis C, and HIV. While we haven't formally considered combination studies with tofersen due to the rarity of certain mutations, it's an area of ongoing discussion with investigators. Nonetheless, it's encouraging to see individuals benefiting from combination therapy in ALS.

Amylyx Pharmaceuticals announces FDA approval of Relyvrio for the treatment of ALS. News release. Amylyx Pharmaceuticals. September 29, 2022. Accessed September 29, 2022.
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