In additional data from CENTAUR, Amylyx touted the drug's ability to prolong tracheostomy-free and ventilation-free survival.
The FDA has approved Amylyx Pharmaceuticals’ AMX0035, a coformulation of sodium phenylbutyrate-taurursodiol, for the treatment of amyotrophic lateral sclerosis (ALS).1 The drug, which will be marketed as Relyvrio, becomes the third approved therapy to help slow disease progression or mortality in ALS, following riluzole (Rilutek) in 1995 and edaravone (Radicava; MT Pharma) in 2017.1
"Today’s decision by the U.S. Food and Drug Administration (FDA) to approve RELYVRIO™ (sodium phenylbutyrate and taurursodiol; previously known as AMX0035), for the treatment of ALS in adults is an exciting milestone for Amylyx, representing our first regulatory approval in the U.S. and our second regulatory approval worldwide, and importantly, the broader ALS community, including people living with ALS, their families, and clinicians," Josh Cohen and Justin Klee, cofounders and cochief operating officers, Amylyx, said in a statement.
They added, "While Amylyx is working on launching RELYVRIO, healthcare professionals will be able to write prescriptions for RELYVRIO immediately by enrolling their patients into our comprehensive support program that we are implementing. This support program will provide people living with ALS who have been prescribed RELYVRIO and their loved ones, with a dedicated, single point of contact to guide their treatment journey. Additional details on this program will be included in our press release, which will be issued today."
Approved under the accelerated approval pathway, the regulatory journey for AMX0035 has been unique. Less than a month ago, the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee did an about-face, voting 7-2 (7 yes; 2 no) in favor of recommending the therapy for FDA approval after previously voting against it back in March 2022, citing doubts in the drug's efficacy.2
The new drug application (NDA) for AMX0035, submitted in November 2021, was supported by data from the phase 2/3, randomized, double-blind, CENTAUR trial (NCT03127514). Participants were randomly assigned 2:1 to 3 g of sodium phenylbutyrate and 1 g of taurursodiol administered once a day for 3 weeks and then twice a day, or placebo, over a 24-week treatment period. Published in the New England Journal of Medicine, the study included 137 patients with ALS, with changes on ALS Functional Rating Scale-Revised (ALSFRS-R) as the primary outcome.3
Findings showed that the study met its primary end point, with treated patients reporting an ALSFRS-R score of 2.32 points higher than those on placebo (P = .03) after 24 weeks. Additional data showed that from baseline, there was a 2.92-point higher mean ALSFRS-R score for the AMX0035 group (P = .01) and a –1.24 point change in total ALSFRS-R score compared with –1.66 points per month with placebo (difference, 0.42; 95% CI, 0.03-0.81; P = .03).
At the time of the published analysis, principal investigator Sabrina Paganoni, MD, PhD, investigator, Healey & AMG Center for ALS, Massachusetts General Hospital, told NeurologyLive® "this is a milestone in our fight against ALS. Patients tell us that their number one desire is to be able to maintain physical function for as long as possible. For example, they want to continue to be able to walk, or to continue to be able to negotiate stairs. They want to be able to use their hands so they can cut their food, or type emails, or use the phone. That’s exactly what we measured in the trial."
Notably, 77% of patients assessed in the trial were receiving an approved ALS therapy—either riluzole (n = 96), edaravone (n = 46), or both (n = 38)—during and/or before trial entry. When Paganoni and colleagues conducted sensitivity analyses to correct for this, their findings were similar, with an estimated between-group difference in ALSFRS-R total scores of 2.15 points (95% CI, −0.05 to 4.35) for those on edaravone and 2.34 points (95% CI, 0.19 to 4.48) for those on riluzole.
The NDA was also supported by survival data released in October 2020, which demonstrated a median survival of 25 months (95% CI, 19.0-33.6) for those on study drug compared with a median survival of 18.5 months in the placebo group (95% CI, 13.5-23.2) for a hazard ratio (HR) of 0.56 (95% CI, 0.34-0.92; P = .023), equating to a 44% lower risk of death. Investigators also reported that the estimated probability of survival at 1 and 2 years was 80.9% (95% CI, 71.1-87.7) and 51.6% (95% CI, 38.9-62.9), respectively, for those in the AMX0035 group vs 72.9% (95% CI, 58.0-83.3) and 33.9% (95% CO, 19.4-49.1) at the same time points for those on placebo.4
Despite the data, the original AdComm panel felt as though the results did not adequately establish AMX0035 as an effective treatment for ALS. Some of the committee members expressed concerns over the robustness of the data, while others felt as though the ALSFRS-R scores for those in the placebo group were high, potentially altering the perception of the findings.5
Following the panel’s decision, Justin Klee, cofounder and cochief operating officer, Amylyx, told NeurologyLive®, "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 biostatistical 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, cofounder and chief operating officer, Amylyx, added that "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 prespecified, 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."
Several members of the AdComm panel who voted “no” claimed the ongoing phase 3 PHOENIX study (NCT05021536) would help answer some of the lingering questions regarding the medication. Initiated in November 2021, PHOENIX spans approximately 65 sites in Europe and the US to evaluate the efficacy and safety of AMX0035 in an estimated cohort of 600 patients with clinically definite or clinically probable ALS within 24 months from symptom onset. With results not expected till at least 2024, this trial differs from CENTAUR, which included those with definite ALS diagnosis within 18 months of symptom onset.6
From the time of the first AdComm meeting in March to the original PDUFA date of June 29, 2022, there were several key events that took place, including Health Canada’s decision to approve the drug, which came on June 13, 2022. Marketed as Albrioza, the approval came under Health Canada’s Notice of Compliance With Conditions policy, which requires that Amylyx will need to provide data from PHOENIX to uphold its approved conditions.7
Following the first advisory meeting, Amylyx published additional results from CENTAUR, highlighting AMX0035’s ability to prolong tracheostomy-free and ventilation-free survival. All told, the agent lowered the risk of any key event—death, tracheostomy, permanent assisted ventilation, and first hospitalization—by 47% compared with placebo (HR, 0.53; 95% CI, 0.35-0.81; P = .003). As of the analysis cutoff with the longest follow up of 35 months, median key event-free survival duration and tracheostomy/permanent assisted ventilation (PAV)-free survival duration were 4.8 and 7.3 months longer, respectively, in participants randomized to study drug versus those on placebo.8
In their statement, Cohen and Klee concluded, "We have had the privilege of working closely with the ALS community for nearly a decade, and we are proud of the participant-centric innovation we have advocated for alongside our partners in the community. These initiatives include advocating for and using participant-centric clinical trial designs, allowing continued access to our therapy to all trial participants even after the trial is over, and implementing what is now the largest expanded access program ever in ALS in the U.S. All of these advances were started through conversations with people with ALS and brought to life by clinical leaders in the community. We promise to continue to make our decisions in partnership with stakeholders in the community."
"We also want to thank the countless people who have invested their precious time to make this milestone a reality today. This includes many people with ALS who are no longer with us, who we particularly think about today. We owe it to all of them and every family to do this right, starting with access and continuing to invest in commercialization efforts, research, and pipeline expansion, as we always have, to further our mission of ending the suffering caused by neurodegenerative diseases.”