AMX0035 Slows Functional Decline in ALS in Phase 2/3

Sabrina Paganoni, MD, PhD

Data from the phase 2/3 CENTAUR trial (NCT03127514) of AMX0035 (Amylyx Pharmaceuticals) suggest that the combination drug of sodium phenylbutyrate–taurursodiol slows functional decline in patients with amyotrophic lateral sclerosis (ALS) compared with placebo.^1,2

In a study population of 135 patients with ALS who were randomly assigned in a 2:1 fashion to active treatment or placebo, 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.¹

Analysis 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).

“This is a milestone in our fight against ALS,” principal investigator Sabrina Paganoni, MD, PhD, investigator, Healey & AMG Center for ALS, Massachusetts General Hospital, told NeurologyLive. “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 (Radicava, MT Pharma; 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.

“This tells us that AMX0035 can be safely combined with these methods of treatment, and actually leads to improvement over the standard of care. Ultimately, we think we might need a combination of different treatments to fight ALS most effectively,” Paganoni explained. She noted that it is her belief that as long as therapies are proven safe in their combined use, it makes sense to use a combination of agents that target the various cellular and molecular mechanisms at play in ALS.

READ MORE: AMX0035 Takes Dual Approach to Dementia

The investigators also assessed a number of secondary outcomes for AMX0035, including lung function, the decline in muscle strength, and hospitalization rates, although the study was not powered for these outcomes. The former 2 measures were evaluated via percent predicted slow vital capacity (SVC) and Accurate Test of Limb Isometric Strength (ATLIS).

Percent predicted SVC showed that the progression in lung function deterioration was numerically slower in patients taking AMX0035 (–3.10 [±0.31] per month; least-squares mean, 66.17 [±2.81]) compared with placebo (–4.03 [±0.42]; least-squares mean, 61.06 [±2.81]) for a least-squares mean difference of 5.11 points (P = .08).

Additionally, the rate of decline in overall muscle strength was numerically slower in those taking AMX0035 (–3.03 [±0.19] per month; least-squares mean, 39.08 [±1.99]) compared with placebo (–3.54 [±0.26] per month; least-squares mean, 36.26 [±2.22]), for a least-squares mean difference of 2.82 points (P = .12). When assessing the effect of AMX0035 on progression for the upper- and lower-limb scores, the combination agent was nominally statistically significant for the upper limb measurements (least-squares mean difference, 4.27 points; P = .04).

Hospitalization rates for those treated with AMX0035 (17.5% [±4.1]) were numerically lower than placebo (29.7% [±6.6]) for a hazard ratio of 0.54 (95% CI, 0.27–1.12; P = .09).

"We are incredibly excited about the results today, which showed a statistically significant benefit on the prespecified primary outcome. Additionally, the trial showed numerical trends supporting the drug's effect on muscle strength and pulmonary function," Justin Klee and Josh Cohen, co-chief executive officers, Amylyx Pharmaceuticals, told NeurologyLive. "Participants in CENTAUR were also allowed to receive therapies currently approved by the FDA, so this data marks an advance beyond today's available treatments."

They added that they are currently working collaboratively with global health agencies in an effort to move AMX0035 forward in the pipeline as quickly as possible.

As for safety, the rate of treatment-emergent adverse events (AEs) was 96% (46 of 48) for placebo and 97% (86 of 89) for the AMX0035 group, most of which were not serious, did not lead to modification or interruption of study drug dosing, and were not considered related to the study drug. There were fewer serious AEs in the active group (12%; 11 of 89) compared with the placebo group (19%; 9 of 48).

Gastrointestinal AEs, generally characterized as mild, were more frequently reported in the AMX0035 group (28.1%) compared with placebo (12.5%) in the first 3 weeks of the trial, though the levels were comparable to placebo at time points thereafter.

“I am so proud of the ALS community efforts that made this milestone possible,” said Merit Cudkowicz, MD, chief medical officer of ALS Finding a Cure; director of the Sean M. Healey & AMG Center for ALS, and chief of neurology at Massachusetts General Hospital, in a statement.² “The CENTAUR study was designed and run through NEALS, was supported by a partnership between The ALS Association and ALS Finding a Cure, and is a phenomenal example of what can happen when a community works closely together to accelerate ALS progress.”

REFERENCES
1. 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
2. Amylyx Pharmaceuticals Announces New England Journal of Medicine Publication of Pivotal AMX0035 Data Demonstrating Statistically Significant Benefit in People with ALS. News release. Amylyx Pharmaceuticals. September 2, 2020. Accessed September 2, 2020.https://www.businesswire.com/news/home/20200902005945/en/Amylyx-Pharmaceuticals-Announces-New-England-Journal-Medicine