AMX0035

AMX0035, marketed as Relyvrio in the United States and Albrioza in Canada, is a fixed-dose oral combination of sodium phenylbutyrate (3 grams per sachet) and taurursodiol (1 gram per sachet) developed by Amylyx Pharmaceuticals for the treatment of amyotrophic lateral sclerosis (ALS) and under investigation for Alzheimer disease. The therapeutic rationale is simultaneous modulation of two convergent cell-death pathways implicated in motor neuron degeneration: endoplasmic reticulum (ER) stress, addressed by the chemical chaperone and histone deacetylase (HDAC) inhibitor activity of sodium phenylbutyrate, and mitochondrial apoptotic signaling, addressed by the bile acid cytoprotectant taurursodiol (the taurine conjugate of ursodeoxycholic acid). Sodium phenylbutyrate upregulates molecular chaperones including heat shock protein 70 (HSP70) and DJ-1, reduces accumulation of misfolded proteins in the ER lumen, and inhibits class I and class II histone deacetylases (excluding class III, HDAC6, and HDAC10), thereby promoting a transcriptional program favoring cell survival. Taurursodiol stabilizes the mitochondrial membrane by inhibiting Bax translocation, reducing mitochondrial permeability transition pore opening, and raising the apoptotic threshold by preventing cytochrome c release into the cytosol. In preclinical models, the combination produced synergistic reduction of hydrogen peroxide-induced neuronal cell death beyond either component alone.

The clinical evidence base for AMX0035 in ALS rests principally on the Phase 2 CENTAUR trial (NCT03127514), a 24-week, randomized, double-blind, placebo-controlled study conducted across 25 Northeast ALS Consortium (NEALS) sites in 137 participants with ALS of no more than 18 months symptom duration [1]. The primary endpoint was the rate of decline on the ALS Functional Rating Scale-Revised (ALSFRS-R): participants receiving AMX0035 showed a mean decline of 1.24 points per month versus 1.66 points per month on placebo, a difference of 0.42 points per month (95% CI 0.03 to 0.81; p = 0.03). Long-term survival analysis of the CENTAUR cohort showed a median survival advantage of 6.5 months favoring those originally randomized to AMX0035 (hazard ratio 0.57; 95% CI 0.35 to 0.92; p = 0.023) [2]. On the basis of these Phase 2 data and an external-control survival analysis, the FDA granted accelerated approval to Relyvrio on September 29, 2022, for the treatment of ALS in adults. Health Canada had previously granted approval to Albrioza in June 2022.

The confirmatory Phase 3 PHOENIX trial (NCT05021536), a 48-week, randomized, placebo-controlled study in 664 adults with ALS, did not meet its primary endpoint of slowing ALSFRS-R decline (p = 0.667) or any secondary endpoints [3]. No significant treatment effect was observed even in the subset of participants who met the original CENTAUR eligibility criteria. Following the PHOENIX results, Amylyx Pharmaceuticals discontinued marketing of Relyvrio as of October 31, 2024, and submitted a formal request for withdrawal of FDA approval on February 28, 2025. The European Medicines Agency had previously declined to authorize the compound for marketing in the European Union.

A separate Phase 2 trial (PEGASUS) evaluated AMX0035 in 96 adults with mild cognitive impairment or dementia due to Alzheimer disease over 24 weeks [4]. The trial met its primary endpoint of safety and tolerability but did not demonstrate slowing of cognitive decline. AMX0035 produced significant reductions in cerebrospinal fluid biomarkers of tau pathology (phosphorylated tau 181 and total tau, both p < 0.001) and modulation of the amyloid beta 42/40 ratio (p < 0.05), suggesting biological activity on core Alzheimer disease pathology despite the absence of a clinical cognitive signal in this short-duration study.

The pharmacokinetics of the two components are well characterized independently. Sodium phenylbutyrate is rapidly absorbed (Tmax approximately 1 hour), with a plasma half-life of approximately 0.76 hours, and is metabolized by beta-oxidation to phenylacetate (half-life approximately 1.2 hours) and subsequently conjugated with glutamine to form phenylacetylglutamine, which is renally excreted. Taurursodiol, a hydrophilic bile acid conjugate, undergoes hepatic first-pass extraction via bile acid transporters, enters the enterohepatic circulation, and is metabolized by intestinal bacteria; systemic bioavailability is limited by efficient hepatic uptake. The combination is administered as a powder for oral suspension, mixed in 250 milliliters of water, taken once daily for the first three weeks and twice daily thereafter. The principal adverse events are gastrointestinal (diarrhea, abdominal pain, nausea), occurring predominantly during the first three weeks of dosing, with rates of discontinuation due to adverse events of approximately 19 percent in the CENTAUR trial compared to 8 percent on placebo.

This monograph reviews the chemistry, formulation, and component pharmacology of AMX0035; the dual-pathway mechanistic rationale; the complete pharmacokinetic profiles of both components; the preclinical neuroprotection data; the clinical evidence from CENTAUR, PHOENIX, and PEGASUS; sourcing, reconstitution, and handling considerations; stack interactions; the adverse-event and safety profile; and a comparative assessment of five alternative ALS therapeutic agents (riluzole, edaravone, tofersen, masitinib, and dexpramipexole) against AMX0035 on five competency standards.