Amylyx Announces Plans to Submit NDA for AMX0035 for ALS

Amylyx Pharmaceuticals has announced that it is prepared to submit a new drug application (NDA) to the FDA for its investigational agent AMX0035—a combination of sodium phenylbutyrate and taurursodiol (also known as ursodoxicoltaurine)—for the treatment of amyotrophic lateral sclerosis (ALS).¹

This decision was made based on a recent discussion between the FDA and Amylyx, according to the company. Joshua Cohen, co-CEO, chairman, and cofounder, Amylyx, said in a statement that the company was “thrilled to move toward the US submission” and that they “look forward to continuing to work with the FDA.”

“For those living with ALS, time is the most important resource, and we remain focused on advancing AMX0035 through the clinical development process as quickly as possible,” Justin Klee, co-CEO and cofounder, Amylyx, added to the statement.¹ “We’re endlessly grateful for all of the support and efforts of ALS Finding a Cure, the ALS Association, I AM ALS, the Healey & AMG Center at Mass General and the Northeast ALS Consortium, and all CENTAUR trial participants for their critical involvement as we approach this milestone.”

The ALS Association lauded the news of Amylyx's decision to move forward with the submission of an NDA—marking its ongoing and longstanding support of the combination therapy. In June 2016, the association provided $750,000 in grant funding to Amylyx for a pilot trial of the therapy, following that up with a $1.46 million grant to the Northeast ALS Consortium (NEALS) to aid in funding the phase 2 clinical trial. Then, in September 2020, the organization, along with I AM ALS, submitted more than 50,000 signatures to the FDA in favor of the therapy being approved, and in May 2021, the group brought members of the community to speak directly with the agency officials.²

"We are excited that people with ALS may soon have another treatment option that will help make ALS livable," Calaneet Balas, president and CEO, The ALS Association, said in a statement.² "We are further encouraged that the FDA appears to have finally heard the loud and clear message from the ALS community that people with ALS are willing to accept greater risk to try potential treatments. We thank everyone who advocated and shared their voice with the FDA and urge the agency to approve AMX0035 swiftly."

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The upcoming NDA submission will be supported by the phase 2/3 CENTAUR trial (NCT03127514), which included a study population of 135 patients with ALS who were randomly assigned in a 2:1 fashion to active treatment or placebo. Data from CENTAUR published in late 2020 showed that those treated with AMX0035 (n = 87) reported an average Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score of 2.32 points higher than the placebo group (n = 48; P = .03) in the primary prespecified analysis after 24 weeks.³

Additional analyses of the change from baseline showed a 2.92-point higher mean ALSFRS-R score for the AMX0035 group (P = .01). The total mean rates of change per month on ALSFRS-R total score was –1.24 points per month with AMX0035 compared to −1.66 points per month with placebo (difference, 0.42 points per month; 95% CI, 0.03-0.81; P = .03).³

“AMX0035 has shown potential to provide those living with ALS and their families hope for the future,” Sabrina Paganoni, MD, PhD, principal investigator of the CENTAUR trial; investigator, Healey & AMG Center for ALS, Massachusetts General Hospital; and assistant professor of PM&R, Harvard Medical School and Spaulding Rehabilitation Hospital, said in the statement.¹ “We are very excited to learn of this positive development and optimistic that AMX0035 may make a real difference in the lives of people with ALS around the world.”

In October 2020, survival data from CENTAUR showed the median overall survival being 25 months (95% CI, 19.0-33.6) for those treated with AMX0035 compared with a median survival of 18.5 months in the placebo group (95% CI, 13.5-23.2) for an HR of 0.56 (95% CI, 0.34-0.92; P = .023), equating to a 44% lower risk of death. The estimated probability of survival at 1 year for those in the treatment group was 80.9% (95% CI, 71.1-87.7) and for placebo was 72.9% (95% CI, 58.0-83.3). For 2 years, the estimates were 51.6% (95% CI, 38.9-62.9) and 33.9% (95% CI, 19.4–49.1), respectively. The median time to censoring was 21.3 months.⁴

“This is another great step forward for Americans living with ALS. In the CENTAUR trial, led by the Northeast ALS Consortium and the Healey & AMG Center at Mass General, AMX0035 was found to both slow ALS progression and extend life,” said Merit Cudkowicz, MD, co-principal investigator of the CENTAUR trial; cofounder, Northeast ALS Consortium; director, Healey & AMG Center for ALS, chair, Neurology, Massachusetts General Hospital, in the statement.¹

AMX0035 is also being investigated for its potential in other neurodegenerative diseases, such as Alzheimer disease. In June 2020, Amylyx announced that it had completed enrollment and dosing in 96 of the previously planned 100 participants in the phase 2 PEGASUS trial (NCT03533257), which will assess the safety, tolerability, drug target engagement, and neurobiological effects of treatment with AMX0035 in patients with early dementia due to Alzheimer disease or late mild cognitive impairment.⁵

REFERENCES
1. Amylyx Pharmaceuticals Announces Plan to Submit New Drug Application (NDA) for AMX0035 for the Treatment of ALS in the Coming Months. News release. Amylyx Pharmaceuticals. September 15, 2021. Accessed September 15, 2021. https://www.businesswire.com/news/home/20210915005297/en/Amylyx-Pharmaceuticals-Announces-Plan-to-Submit-New-Drug-Application-NDA-for-AMX0035-for-the-Treatment-of-ALS-in-the-Coming-Months
2. ALS Association Applauds Amylyx AMX0035 Announcement, Urges Swift FDA Approval. News release. ALS Association. September 15, 2021. Accessed September 15, 2021. https://www.prnewswire.com/news-releases/als-association-applauds-amylyx-amx0035-announcement-urges-swift-fda-approval-301376985.html
3. 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
4. Paganoni S, Hendrix S, Dickson SP, et al. Long‐Term Survival of Participants in the CENTAUR Trial of Sodium Phenylbutyrate‐Taurursodiol in ALS. Muscle Nerve. 2020;63(1):31-39. doi:10.1002/mus.27091
5. Amylyx Pharmaceuticals announces completion of enrollment in the PEGASUS trial of AMX0035 in Alzheimer’s disease. News release. Amylyx Pharmaceuticals. June 15, 2020. Accessed September 15, 2021. https://www.biospace.com/article/releases/amylyx-pharmaceuticals-announces-completion-of-enrollment-in-the-pegasus-trial-of-amx0035-in-alzheimer-s-disease/