A New Treatment in ALS: AMX0035’s Pending FDA Decision
After Amylyx submitted an NDA for the combination therapy, Justin Klee and Josh Cohen, the cofounders and co-chief operating officers of the company, shared their perspectives.
Justin Klee, BSc
Josh Cohen, BSc
Earlier this month, Amylyx Pharmaceuticals announced that it had submitted a new drug application to the FDA for its investigational treatment, AMX0035, for the treatment of patients with amyotrophic lateral sclerosis (ALS), and had initiated its phase 3 clinical trial of the combination agent, the PHOENIX study (NCT05021536).1,2
The NDA is supported by data from the prior study, the phase 2/3 CENTAUR trial (NCT03127514), which showed that treatment with the agent (n = 87) met its primary efficacy end point, with a reported average ALS Functional Rating Scale-Revised (ALSFRS-R) score of 2.32 points higher than placebo (n = 48; P = .03) after 24 weeks.1 PHOENIX, on the other hand, is expected to be conducted at 65 sites in Europe and the US with an enrollment of 600 participants. All patients eligible for PHOENIX have clinically definite or clinically probable ALS, within 24 hours from symptom onset—unlike in CENTAUR, which included those with definite ALS diagnosis within 18 months of symptom onset.
To find out more about AMX0035 and its potential to make a difference in the ALS care paradigm, NeurologyLive inquired with Josh Cohen, BSc, and Justin Klee, BSc, cofounders and co-chief operating officers, Amylyx Pharmaceuticals.
NeurologyLive: What should the clinician community know about AMX0035’s potential ahead of this FDA decision?
Josh Cohen, BSc, and Justin Klee, BSc: AMX0035 is an investigational therapy comprised of 2 active agents, sodium phenylbutyrate (PB) and taurursodiol (TURSO; also known as ursodoxicoltaurine), which were coformulated to target the endoplasmic reticulum (ER) and mitochondrial–dependent neuronal degeneration pathways involved in amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases.
AMX0035 is designed to reduce neuronal death and dysfunction and is associated with both a statistically significant and clinically meaningful impact on function and survival in people with ALS. Our regulatory filings that have happened in Canada and the United States were based on data from the AMX0035 CENTAUR trial, which met its primary efficacy end point of slowing functional decline as measured by the ALSFRS-R. An interim overall survival analysis including all randomized participants showed a 44% lower risk of death in the group starting on AMX0035, as well as a 6.5 month longer median survival compared to the group that started on placebo. Importantly, these results were seen either as a stand-alone therapy or when added to existing treatments. Overall, reported rates of adverse events and discontinuations were substantially similar between AMX0035 and placebo groups during the 24-week randomized phase; however, gastrointestinal events occurred with greater frequency (≥2%) in the AMX0035 group.
This FDA submission is an important development for people living with ALS and their physicians offering hope of a potential new treatment option. In addition, we recently announced that the first participants have been dosed in the global phase 3 study of AMX0035. We are all hands-on deck to continue exploring the full potential of AMX0035 as a therapeutic option to treat neurodegenerative disease, including ALS, as people living with ALS and their families don’t have time to wait.
In your opinion, what data point or finding from the clinical development is most important, or perhaps most exciting?
Despite significant research efforts over several decades, the majority of therapies that have been investigated in ALS have not demonstrated both a survival benefit and impact on function/disease progression. We were really excited to observe that AMX0035 is associated with both a statistically significant functional and survival benefit in people with ALS, considering that reported rates of adverse events and discontinuations were substantially similar between AMX0035 and placebo groups during the 24-week randomized phase; however, gastrointestinal events occurred with greater frequency (≥2%) in the AMX0035 group.
Analyses assessing key study events indicated that both the long-term risk of death or tracheostomy/permanent assisted ventilation and first hospitalization were lower in the group starting on AMX0035 compared to the group starting on placebo.
Importantly, participants starting on AMX0035 scored 2.32 points higher on the ALSFRS-R in just 24 weeks, which could mean a substantial change in a person’s ability to walk, climb stairs or even breathe on one’s own for longer, and survived a median of 6.5 months longer compared to those starting on placebo. The CENTAUR data can be reviewed in the New England Journal of Medicine and Muscle and Nerve.
The global follow-up trial to CENTAUR, a phase 3 study A35-004 (PHOENIX) will enroll about 600 participants to further evaluate the efficacy of AMX0035 and we are leaving no stone unturned to advance AMX0035 as a potential therapy for those living with ALS, as every minute matters in our fight against this relentless disease.
What do you believe the impact of this agent could be on the ALS treatment paradigm, if greenlit by the FDA for use?
From a research perspective, we have come a long way in evaluating targets to treat this devastating disease, and we would be truly honored to play a role in transforming the current standard of care for people living with ALS. If AMX0035 is a success, we want to pour that success right back into this community. At the end of the day, we all have a shared mission to work toward better solutions for the community to manage, treat, and hopefully one day cure neurogenerative disease.
Regardless of future regulatory decisions, the current results from CENTAUR have shown promise for AMX0035 as a potential therapy to treat ALS, and we’ll continue to bring learnings forward to future investigations.
Are there future plans for AMX0035 in ALS or out of it?
Our goal as a company is to investigate the potential clinical benefit and safety of AMX0035 in many neurogenerative conditions, including but not limited to ALS. Many neurodegenerative diseases are associated with ER stress and mitochondrial dysfunction, two pathways central to neuronal death, and as such we believe AMX0035 has the potential to alleviate suffering across many neurodegenerative diseases.
As mentioned, we recently announced that the first participants have been treated in the global phase 3 study A35-004 which continues to build upon the evidence supporting AMX0035 for the potential treatment of ALS and will enroll participants globally.
We continue to follow the science to investigate the full potential of AMX0035 as a therapeutic option to treat Wolfram syndrome, Alzheimer’s disease, and others and will continue to keep the community updated as we do so.
Anything else you feel the clinical community should be aware of regarding this news?
As we all know, ALS is a relentlessly progressive disease, and we take our responsibilities as part of this community seriously. Our team has worked and continues to work around the clock as we know time is of the essence for people living with ALS and their families. We’ll continue to work through the clinical development process as quickly and efficiently as possible for this reason.
Transcript edited for clarity.
