Relyvrio (sodium phenylbutyrate/taurursodiol, also known as AMX0035) is a combination therapy approved by the FDA in 2022 for the treatment of amyotrophic lateral sclerosis (ALS)[@fda2022]. This dual-agent therapeutic targets multiple pathological pathways in ALS, including endoplasmic reticulum (ER) stress, mitochondrial dysfunction, and oxidative stress[@saxena2023].
The drug combines two active compounds:
Sodium phenylbutyrate (NaPBA): A chemical chaperone that reduces ER stress
Taurursodiol (TUDCA): A mitochondrial protectant that reduces [apoptosis](/entities/apoptosis)
This combination represents a novel approach to ALS treatment by simultaneously addressing multiple interconnected pathological mechanisms[@pupillo2022].
Mechanism of Action
Sodium Phenylbutyrate
Sodium phenylbutyrate is a small-molecule compound that acts as a chemical chaperone:
ER Stress Reduction: NaPBA upregulates expression of endoplasmic reticulum chaperone proteins (e.g., BiP, GRP94), reducing the [unfolded protein response](/entities/unfolded-protein-response) (UPR)[@ryu2004]
Protein Misfolding Mitigation: By stabilizing protein conformation, NaPBA reduces aggregation of mutant proteins common in ALS (SOD1, [TDP-43](/mechanisms/tdp-43-proteinopathy), FUS)
Histone Deacetylase (HDAC) Inhibition: NaPBA inhibits Class I and IIa HDACs, potentially modulating gene expression patterns
Taurursodiol
Taurursodiol (tauroursodeoxycholic acid) is a bile acid with potent mitochondrial protective effects:
Most adverse events were mild to moderate and did not lead to treatment discontinuation.
Dosing and Administration
Dose Adjustments
Renal impairment: Use with caution; no specific dose adjustment
Hepatic impairment: Monitor liver function tests
Concurrent use: Can be combined with riluzole or edaravone
Regulatory Status
Relyvrio received FDA approval in September 2022 under the FDA's Animal Efficacy Rule, based on substantial evidence of effectiveness from animal models combined with human safety data[@amx].
Comparison with Other ALS Therapies
Combination Therapy Potential
Relyvrio can be combined with other ALS therapies:
Riluzole: No significant drug-drug interactions
Edaravone: Different mechanisms; potential complementary effects
Antisense oligonucleotides: May provide synergistic benefits
Ongoing trials are exploring these combinations.
Pipeline and Future Directions
Ongoing Trials
NCT05033145: Relyvrio in combination with edaravone
NCT05500262: Biomarker studies in Relyvrio-treated patients
NCT05756165: Relyvrio for other neurological disorders
Unknown, FDA Approves Relyvrio for Treatment of ALS (2022)
[Saxena S, et al, AMX0035, a combination of sodium phenylbutyrate and taurursodiol, for the treatment of ALS (2023)](https://pubmed.ncbi.nlm.nih.gov/37350764/)
[Pupillo E, et al, Sodium phenylbutyrate/taurursodiol (AMX0035): a new therapeutic approach for ALS (2022)](https://pubmed.ncbi.nlm.nih.gov/35862731/)
[Ryu H, et al, Sodium phenylbutyrate in ALS: from bench to bedside (2004)](https://pubmed.ncbi.nlm.nih.gov/15211508/)
[Castro-Caldas J, et al, Tauroursodeoxycholic acid prevents neuronal death in a rat model of perinatal asphyxia (2020)](https://pubmed.ncbi.nlm.nih.gov/32759579/)
[Paganoni S, et al, Trial of Sodium Phenylbutyrate-Taurursodiol for Amyotrophic Lateral Sclerosis (2020)](https://pubmed.ncbi.nlm.nih.gov/32833240/)