AMX0035 Leads to Prolonged Tracheostomy-Free and Ventilation-Free Survival in ALS


As of the cutoff date, median time to first hospitalization was not yet reached in the AMX0035 treatment group compared with 14.1 months in the group originally randomized to placebo.

Sabrina Paganoni, MD, PhD

Sabrina Paganoni, MD, PhD

Newly published results from the phase 2/3 CENTAUR trial (NCT03127514)—the main study used in AMX0035’s (Amylyx Pharmaceuticals) new drug application (NDA) submission—showed that treatment with the investigational agent reduced occurrence of tracheostomy/permanent assisted ventilation (PAV), and delayed first hospitalization among patients with amyotrophic lateral sclerosis (ALS).1,2

Key events evaluated were considered death, tracheostomy, PAV, and first hospitalization. AMX0035, a proprietary oral fixed-dose combination of phenylbutyrate and taurursodiol, lowered the risk of any key event 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/PAV-free survival duration was 4.8 and 7.3 months longer, respectively, in participants randomized to study drug vs those on placebo.

"People living with ALS often require medical interventions like mechanical ventilation as the disease progresses and impacts the muscles of respiration,” principal investigator Sabrina Paganoni, MD, PhD, investigator, Sean M. Healey & AMG Center for ALS, Mass General, and associate professor, Harvard Medical School, said in a statement.1 "These interventions come at a great cost, both personally and financially, for people living with the disease and developing therapies that can help delay these interventions can have a positive impact on their lives."

CENTAUR was a multicenter trial that randomized 137 participants with definite ALS within 18 months from symptom onset with either AMX0035 or placebo for 6 months, followed by an open-label extension. The majority (77%) of patients, including 71% randomized to study drug and 88% originally randomized to placebo, were receiving riluzole (Rilutek) and/or edaravone (Radicava) at or prior to trial entry.2

At the end of the analysis, the odds of death or tracheostomy/PAV were 49% lower among those originally randomized to AMX0035 vs placebo (HR, 0.51; 95% CI, 0.32-0.84; P = .0007), with median tracheostomy/PAV-free survival durations of 25.8 (IQR, 14.8-33.6) months and 18.5 (IQR, 11.7-months not reached), respectively. Additionally, treatment with the study drug also resulted in 44% lowered odds of first hospitalization (HR, 0.56; 95% CI, 0.34-0.95; P = .03).

READ MORE: FDA Approves Oral Version of Edaravone for ALS

"We’re encouraged by the positive data that we continue to collect from the CENTAUR study on the potential benefits of AMX0035 for people with ALS, including a lower occurrence of first hospitalization based on data collected up to 35 months following administration,” Machelle Manuel, PhD, head, Global Medical Affairs, Amylyx, said in a statement.1 "These results suggest that AMX0035, if approved, may help extend the time before greater care needs arise—a meaningful benefit for those living with ALS and their loved ones. We will continue to explore other potential benefits of AMX0035 during the follow-up period and plan to evaluate its potential in other neurodegenerative diseases."

The results from the death-only analysis were similar to that published in 2020. In the survival analysis of CENTAUR, the therapy was shown to be associated with a 6.5-month longer median survival compared with placebo. AMX0035 resulted in a median survival of 25 months (95% CI, 19.0-33.6) vs just 18.5 months in the placebo group (95% CI, 13.5-23.2). Furthermore, 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.3

AMX0035 is currently under FDA review, with a PDUFA date set for June 30, 2022. The NDA was submitted in November 2021 and backed by data from CENTAUR, which showed that the drug met its primary end point, demonstrating a 2.32 difference relative to placebo on ALS Functional Rating Scale-Revised over 24 weeks of treatment.4 If approved, it would join riluzole and edaravone as the only medications greenlit by the FDA for ALS.

In March 2022, a public hearing by the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee added to the speculation of AMX0035’s future, voting that the current data is not sufficient in demonstrating efficacy. The committee voted 6-4 (6 no; 4 yes; 0 abstain) that the data from the trial and its open-label extension did not adequately establish the agent as an effective medication for the treatment of ALS.5

1. Amylyx Pharmaceuticals announces publication of data showing randomization to AMX0035 prolonged tracheostomy/ventilation-free survival and reduced occurrence of first hospitalization. News release. Amylyx Pharmaceuticals. May 16, 2022. Accessed May 16, 2022.
2. Paganoni S, Hendrix S, Dickson SP, et al. Effect of sodium phenylbutyrate/taurursodiol on tracheostomy/ventilation-free survival and hospitalization in amyotrophic lateral sclerosis: long-term results from the CENTAUR trial. J Neurol Neurosurg Psychiatry. Published online May 16, 2022. doi:10.1136/jnnp-2022-329024
3. 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. Published online October 16, 2020. doi: 10.1002/mus.27091
4. 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
5. FDA. Peripheral and Central Nervous System Drugs Advisory Committee Meeting. March 30, 2022. Accessed May 16, 2022.
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