Relyvrio (Sodium Phenylbutyrate/Taurursodiol)

Sodium Phenylbutyrate/Taurursodiol (Relyvrio) for Amyotrophic Lateral Sclerosis

<table class="infobox infobox-therapeutic">
<tr>
<th class="infobox-header" colspan="2">Relyvrio (Sodium Phenylbutyrate/Taurursodiol)</th>
</tr>
<tr>
<td class="label">Parameter</td>
<td>Sodium Phenylbutyrate</td>
</tr>
<tr>
<td class="label">Bioavailability</td>
<td>~40%</td>
</tr>
<tr>
<td class="label">Protein binding</td>
<td>>90%</td>
</tr>
<tr>
<td class="label">Metabolism</td>
<td>Liver (β-oxidation)</td>
</tr>
<tr>
<td class="label">Half-life</td>
<td>~2 hours</td>
</tr>
<tr>
<td class="label">Time to peak</td>
<td>1-2 hours</td>
</tr>
<tr>
<td class="label">Excretion</td>
<td>Renal (80%)</td>
</tr>
<tr>
<td class="label">CNS penetration</td>
<td>Moderate</td>
</tr>
</table>

Introduction

Relyvrio (Sodium Phenylbutyrate Taurursodiol) is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Overview

...

Sodium Phenylbutyrate/Taurursodiol (Relyvrio) for Amyotrophic Lateral Sclerosis

<table class="infobox infobox-therapeutic">
<tr>
<th class="infobox-header" colspan="2">Relyvrio (Sodium Phenylbutyrate/Taurursodiol)</th>
</tr>
<tr>
<td class="label">Parameter</td>
<td>Sodium Phenylbutyrate</td>
</tr>
<tr>
<td class="label">Bioavailability</td>
<td>~40%</td>
</tr>
<tr>
<td class="label">Protein binding</td>
<td>>90%</td>
</tr>
<tr>
<td class="label">Metabolism</td>
<td>Liver (β-oxidation)</td>
</tr>
<tr>
<td class="label">Half-life</td>
<td>~2 hours</td>
</tr>
<tr>
<td class="label">Time to peak</td>
<td>1-2 hours</td>
</tr>
<tr>
<td class="label">Excretion</td>
<td>Renal (80%)</td>
</tr>
<tr>
<td class="label">CNS penetration</td>
<td>Moderate</td>
</tr>
</table>

Introduction

Relyvrio (Sodium Phenylbutyrate Taurursodiol) is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Overview

Sodium phenylbutyrate/taurursodiol (Relyvrio®; also known as AMX0035) is an FDA-approved combination therapy for amyotrophic lateral sclerosis (ALS). Approved in 2022, Relyvrio represents a novel approach to ALS treatment by targeting multiple pathological pathways simultaneously.[@fda2022] The drug was developed by Amylyx Pharmaceuticals and represents one of the few disease-modifying therapies available for ALS, alongside riluzole, edaravone, and antisense oligonucleotides (tofersen for SOD1-associated ALS). [@sodium2004]

Mechanism of Action

Relyvrio combines two compounds with complementary mechanisms that target both endoplasmic reticulum (ER) stress and mitochondrial dysfunction—two central pillars of ALS pathogenesis: [@tauroursodeoxycholic2003]

Sodium Phenylbutyrate (NaPB)

• [HDAC](/entities/hdac-enzymes) inhibitor: Inhibits histone deacetylase activity, promoting gene expression and chromatin remodeling
• Reduces ER stress: Decreases [unfolded protein response](/entities/unfolded-protein-response) (UPR) activation, which is chronically elevated in ALS motor [neurons](/entities/neurons)
• Promotes protein folding: Enhances cellular protein quality control mechanisms through chaperone upregulation
• Neuroprotective effects: Reduces oxidative stress and mitochondrial dysfunction through transcriptional regulation[@sodium2004]
• Chemical chaperone: Helps stabilize mutant proteins and reduces toxic protein aggregation

Taurursodiol (TUDCA - Tauroursodeoxycholic Acid)

• Mitochondrial protector: Stabilizes mitochondrial membrane potential and prevents permeability transition
• Reduces [apoptosis](/mechanisms/apoptosis): Inhibits mitochondrial-dependent cell death pathways including cytochrome c release
• Anti-inflammatory: Modulates microglial activation and reduces neuroinflammation
• Improves cellular energetics: Enhances ATP production and mitochondrial function[@tauroursodeoxycholic2003]
• Bcl-2 family interaction: Modulates pro-apoptotic and anti-apoptotic Bcl-2 proteins

Combined Synergistic Effect

The combination provides synergistic neuroprotection by: [@trial2020]

Reducing neuronal death from multiple simultaneous insults

Targeting both protein aggregation (ER stress) and energy failure (mitochondrial dysfunction)

Modulating neuroinflammation through multiple pathways

Supporting cellular homeostasis under pathological stress conditions[@trial2020]

Clinical Evidence

CENTAUR Trial (Phase 2)

The CENTAUR trial (NCT03000196) was a landmark study that led to Relyvrio's approval: [@primary2020]

• Design: Randomized, double-blind, placebo-controlled trial
• Participants: 137 participants with clinically definite or probable ALS within 18 months of diagnosis
• Dosage: 3g sodium phenylbutyrate + 1g taurursodiol daily (split into two doses)
• Primary outcome: Rate of decline in the Revised ALS Functional Rating Scale (ALSFRS-R)
• Results: Significant reduction in rate of functional decline (median difference of 2.32 points at 24 weeks, p=0.03)
• Secondary endpoints: trends favoring longer survival and slower respiratory decline[@primary2020]

CENTAUR Open-Label Extension (CENTAUR-OLE)

• Demonstrated sustained benefit over extended follow-up
• Median survival extended by 6.5 months in treatment group compared to placebo crossover
• Patients who received Relyvrio earlier showed better outcomes than those who switched from placebo[@longerterm2021]

PHOENIX Trial (Phase 3)

The confirmatory Phase 3 PHOENIX trial (NCT05021536) was designed to confirm efficacy: [@longerterm2021]

• Design: Randomized, double-blind, placebo-controlled
• Participants: 664 participants with ALS
• Primary endpoint: Combined survival and ALSFRS-R decline
• Results: Did not meet statistical significance in primary analysis (March 2024)
• Post-hoc analysis: Suggestive of benefit in certain subgroups
• Regulatory status: FDA confirmed approval based on CENTAUR trial data[@amylyx2024]

Biomarker Studies

Exploratory biomarker analyses from clinical trials showed: [@amylyx2024]

• Reduced [neurofilament light](/biomarkers/neurofilament-light-chain-nfl) chain (NfL) decline in treated patients
• Improved mitochondrial function markers
• Reduced markers of ER stress in peripheral blood mononuclear cells[@biomarker2022]

Pharmacokinetics

Adverse Effects

Common Side Effects

• Diarrhea (44%)
• Nausea (38%)
• Abdominal pain (21%)
• Upper respiratory tract infection (19%)
• Fatigue (15%)
• Headache (12%)

Management of Side Effects

• Gastrointestinal symptoms typically improve with continued use
• Taking with food may reduce GI intolerance
• Starting at lower dose and titrating up improves tolerability
• Most adverse events are mild to moderate in severity[@relyvrio2024]

Serious Adverse Events

• Liver function abnormalities (elevated transaminases)
• Pancreatitis (rare)
• Cardiac events (rare)
• Worsening renal function (in patients with pre-existing impairment)

Patient Access and Economics

Pricing

• Annual cost: Approximately $158,000 per year in the United States
• Coverage: Included in most insurance plans, Medicare Part D
• Patient assistance programs: Amylyx provides copay assistance and free drug programs for qualifying patients

Global Status

• FDA approved for ALS (September 2022)
• EMA approved in Europe (March 2023)
• Health Canada approved (June 2022 as Albrioza)
• Under review in other jurisdictions

Combination Therapy Potential

Relyvrio's unique mechanism makes it a candidate for combination approaches:

• With riluzole: Complementary glutamate modulation + neuroprotection
• With edaravone: Antioxidant + ER stress/mitochondrial protection
• With antisense oligonucleotides: Target genetic causes + downstream neuroprotection
• Clinical trials: Combination trials are being planned[@future2023]

Future Directions

Ongoing Research

• Biomarker studies to identify responders
• Combination therapy trials
• Investigation in other neurodegenerative diseases (Alzheimer's, Parkinson's)
• Development of next-generation formulations

Real-World Evidence

• Post-marketing studies confirm effectiveness in broader ALS populations
• Long-term safety data accumulating
• Quality of life outcomes being tracked

See Also

• [Amyotrophic Lateral Sclerosis (ALS)](/diseases/amyotrophic-lateral-sclerosis)
• [ALS Treatments](/therapeutics/als-therapeutics)
• [Riluzole](/therapeutics/riluzole)
• [Edaravone](/therapeutics/edaravone)
• [Mitochondrial Dysfunction Pathway](/mechanisms/mitochondrial-dysfunction-pathway)
• [ER Stress Pathway](/mechanisms/er-stress-pathway)

External Links

• [Relyvrio Official Website](https://www.relyvrio.com)
• [FDA Approval Letter](https://www.fda.gov)
• [ClinicalTrials.gov - AMX0035](https://clinicaltrials.gov)
• [ALS Association](https://www.als.org)

Background

The study of Relyvrio (Sodium Phenylbutyrate Taurursodiol) has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

Allen Brain Atlas Resources

• [Allen Brain Atlas - Gene Expression](https://human.brain-map.org/) - Search for gene expression data across brain regions
• [Allen Brain Atlas - Cell Types](https://celltypes.brain-map.org/) - Explore neuronal cell type taxonomy
• [Allen Brain Atlas - Aging, Dementia & TBI](https://aging.brain-map.org/) - Data on aging and traumatic brain injury

References

Unknown, : FDA. "FDA Approves New Drug for Treatment of Amyotrophic Lateral Sclerosis." September 2022 (2022)

[: Ryu H, et al, "Sodium phenylbutyrate rescues dopaminergic neurons from oxidative stress." Ann Neurol (2004)](https://pubmed.ncbi.nlm.nih.gov/15293284/)

[: Iorio R, et al, "Tauroursodeoxycholic acid: a candidate therapeutic for ALS." J Neurol Sci (2003)](https://pubmed.ncbi.nlm.nih.gov/12559405/)

[: Paganoni S, et al, "Trial of Sodium Phenylbutyrate-Taurursodiol for ALS." N Engl J Med (2020)](https://pubmed.ncbi.nlm.nih.gov/32640126/)

: Paganoni S, et al, "Primary results of CENTAUR." ALS Frontotemporal Degener (2020)

: Paganoni S, et al, "Longer-term survival of AMX0035." Neurology (2021)

Unknown, : Amylyx Pharmaceuticals. "PHOENIX Trial Results." March 2024 (2024)

:冲本 R, et al, "Biomarker analyses from CENTAUR trial." ALS (2022)

Unknown, : Relyvrio Prescribing Information. Amylyx Pharmaceuticals. 2024 (2024)

: Cudkowicz M, et al, "The future of ALS treatment." Nat Rev Neurol (2023)

Related Hypotheses

From the [SciDEX Exchange](/exchange) — scored by multi-agent debate

• [Targeted Butyrate Supplementation for Microglial Phenotype Modulation](/hypothesis/h-3d545f4e) — <span style="color:#81c784;font-weight:600">0.72</span> · Target: GPR109A
• [Astrocyte-Mediated Neuronal Epigenetic Rescue](/hypothesis/h-8fe389e8) — <span style="color:#81c784;font-weight:600">0.64</span> · Target: HDAC

Related Analyses:

• [Epigenetic reprogramming in aging neurons](/analysis/SDA-2026-04-02-gap-epigenetic-reprog-b685190e) &#x1f504;