- This randomized, double-blind, placebo-controlled phase 2 trial, conducted at 25 U.S. centers, evaluated the efficacy and safety of the AMX0035, a combination of sodium phenylbutyrate and taurursodiol for patients with amyotrophic lateral sclerosis (ALS)
- After 24 weeks, there was an estimated 2.32-point absolute difference between the active-drug and placebo groups on the 48-point Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised
- The slowing of ALS progression occurred in a population in which many participants were already receiving FDA-approved medications for the treatment of ALS—riluzole, edaravone or both
- Secondary outcomes showed numerical benefit of AMX0035 over placebo although they did not reach statistical significance between the two groups
- Overall, AMX0035 was safe and well tolerated. Treatment-emergent adverse events that were more (≥2%) frequent in the AMX0035 group were primarily gastrointestinal events
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Administered individually, sodium phenylbutyrate and taurursodiol (also known as tauroursodeoxycholic acid) have been shown to reduce neuronal death in experimental models of amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. The safety of individual drugs has been tested in pilot clinical trials in patients with ALS.
Now, an oral co-formulation of sodium phenylbutyrate and taurursodiol, dubbed AMX0035, has shown promising efficacy and safety in ALS. Sabrina Paganoni, MD, PhD, of the Sean M. Healey & AMG Center for ALS and Spaulding Rehabilitation Hospital, and Merit E. Cudkowicz, MD, MSc, chief of the Department Neurology and director of the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital, and colleagues report the results of the 24-week, phase 2 CENTAUR trial in The New England Journal of Medicine.
The randomized, double-blind, placebo-controlled trial was designed by the Northeast Amyotrophic Lateral Sclerosis Consortium (NEALS) in collaboration with Amylyx Pharmaceuticals. Twenty-five NEALS-affiliated centers in the U.S. conducted the study between June 2017 and September 2019.
137 patients participated and had symptom onset of ALS no more than 18 months previously. They were randomly assigned 2:1 to receive AMX0035 or placebo orally or through a feeding tube for 24 weeks. The dosage of AMX0035 was 3 g sodium phenylbutyrate and 1 g taurursodiol once daily for the first three weeks, then twice daily through week 24.
71% of participants were using riluzole at or before trial entry, 34% used edaravone, and 28% used both.
The primary efficacy outcome was the rate of decline in total score on the 48-point Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R). After 24 weeks, there was an estimated 2.32-point absolute difference between the AMX0035 and placebo groups in the least-squares mean ALSFRS-R total scores (95% CI, 0.18–4.47; P = 0.03).
The change was greater on the fine motor subscale of the ALSFRS-R than in the three other subscales. In sensitivity analyses that accounted for use of riluzole and/or edaravone, the results were in the same direction as the results of the primary analysis, but the analysis that corrected for edaravone did not reach statistical significance.
The change was greater on the fine motor subscale of the ALSFRS-R than in the three other subscales. In sensitivity analyses that accounted for use of riluzole and/or edaravone, the results were consistent with the results of the primary analysis.
Secondary outcomes showed numerical benefit of AMX0035 over placebo although they did not reach statistical significance between the two groups. These included a decline in isometric muscle strength; slow vital capacity and plasma levels of the phosphorylated axonal neurofilament H subunit; a potential biomarker of motor neuron degeneration; and time to composite events including death, tracheostomy, permanent ventilation and hospitalization.
Adverse events (AEs) occurring at 2% or greater frequency in the AMX0035 group were primarily gastrointestinal (diarrhea, nausea, salivary hypersecretion and abdominal discomfort); all but salivary hypersecretion were previously linked to taurursodiol. Gastrointestinal AEs were more frequent in the active-drug group than in the placebo group during the first three weeks, but afterward, were more frequent in the placebo group.
The incidence of serious AEs was greater with placebo than AMX0035 (19% vs. 12%). For respiratory serious AEs, the rates were 8% and 3%, respectively.
19% of patients taking AMX0035 and 8% in the placebo group discontinued the trial because of AEs, most commonly diarrhea (6% with AMX0035, 0% with placebo) and respiratory failure (6% with placebo, 0% with AMX0035).
A 132-week open-label extension trial is ongoing.
Since the publication of this manuscript, a second report by Dr. Paganoni, Dr. Cudkowicz and colleagues report beneficial effects of AMX0035 on long term survival in Muscle & Nerve. Over a 3-year follow-up period, trial participants who were originally randomized to AMX0035 lived on average 6.5 months longer than those who were originally randomized to placebo.
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