New England Journal of Medicine September 03, 2020

Trial of Sodium Phenylbutyrate-Taurursodiol for Amyotrophic Lateral Sclerosis

Sabrina Paganoni, Eric A Macklin, Suzanne Hendrix, James D Berry, Michael A Elliott, et al.

Bottom Line

In the Phase 2 CENTAUR trial, the combination of sodium phenylbutyrate and taurursodiol modestly but significantly slowed the rate of functional decline compared to placebo over 24 weeks in patients with recently diagnosed amyotrophic lateral sclerosis.

Key Findings

1. In a modified intention-to-treat analysis, the mean rate of change in the ALSFRS-R score was -1.24 points per month in the sodium phenylbutyrate-taurursodiol group versus -1.66 points per month in the placebo group.

2. The treatment difference in the rate of decline of the ALSFRS-R score was 0.42 points per month (95% CI, 0.03 to 0.81; P = 0.03), favoring the active drug.

3. Over the 24-week trial period, this equated to a mean difference of 2.32 points on the ALSFRS-R total score.

4. Secondary outcomes, including rates of decline in isometric muscle strength, slow vital capacity, and plasma neurofilament H levels, did not differ significantly between the two groups.

5. Adverse events were mostly gastrointestinal, occurring more frequently in the active-drug group, notably diarrhea, nausea, salivary hypersecretion, and abdominal pain.

Study Design

Design

RCT

Double-Blind

Sample

137

Patients

Duration

24 weeks

Median

Setting

Multicenter, US

Population Adults with definite ALS (El Escorial criteria) who had an onset of symptoms within the previous 18 months and a slow vital capacity of more than 60% of the predicted value.

Intervention Sodium phenylbutyrate-taurursodiol (3 g of sodium phenylbutyrate and 1 g of taurursodiol) administered orally or via feeding tube once a day for 3 weeks, then twice a day.

Comparator Matching placebo administered orally or via feeding tube.

Outcome The rate of decline in the total score on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) through 24 weeks.

Study Limitations

• The trial had a relatively small sample size (137 participants), which limits the power to detect differences in secondary outcomes and rare adverse events.

• The short double-blind follow-up duration of 24 weeks is insufficient to fully evaluate long-term efficacy and safety.

• None of the secondary clinical or biomarker endpoints showed statistically significant differences at 24 weeks.

• The distinct taste and gastrointestinal side effect profile of the active drug could have led to unintended unblinding of participants.

• The study population was restricted to patients with definite ALS within 18 months of symptom onset, potentially limiting generalizability to those with longer-standing or atypical disease.

Clinical Significance

The CENTAUR trial demonstrated that a combination of sodium phenylbutyrate and taurursodiol (AMX0035) slowed functional decline in patients with early ALS. Although secondary endpoints at 24 weeks were not met, subsequent open-label extension data suggested a survival benefit. These results supported conditional regulatory approvals (e.g., RELYVRIO in the US, ALBRIOZA in Canada) for a disease with very few therapeutic options. However, its clinical significance was later sharply curtailed when the larger, confirmatory Phase 3 PHOENIX trial (2024) failed to meet primary and secondary endpoints, ultimately leading to the drug being voluntarily withdrawn from the market.

Historical Context

Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive, fatal neurodegenerative disease with historically few disease-modifying therapies. Prior to AMX0035, only riluzole and edaravone were approved, both offering modest benefits. Sodium phenylbutyrate-taurursodiol was designed to synergistically target two pathways implicated in ALS motor neuron death: endoplasmic reticulum stress and mitochondrial dysfunction. The positive Phase 2 CENTAUR trial was widely celebrated by the ALS community and patient advocacy groups, leading to intense lobbying that successfully pressured the FDA into approving the drug in 2022 despite the agency's initial hesitation regarding the single, small-scale Phase 2 data. This controversy highlighted the tension between regulatory rigor and the desperate need for therapies in fatal diseases, a cautionary tale cemented by the drug's subsequent Phase 3 failure.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How does the dual mechanism of sodium phenylbutyrate and taurursodiol theoretically target the underlying cellular pathophysiology of amyotrophic lateral sclerosis (ALS)?

Key Response

This tests foundational knowledge of ALS pathophysiology. Sodium phenylbutyrate acts as a chemical chaperone mitigating endoplasmic reticulum (ER) stress, while taurursodiol (TUDCA) prevents Bax translocation, preserving mitochondrial integrity. Targeting both pathways synergistically attempts to halt the neuronal apoptosis characteristic of ALS.

Resident

A recently diagnosed ALS patient asks about starting sodium phenylbutyrate-taurursodiol. How do you counsel them regarding its expected clinical benefit and side effect profile compared to existing therapies like riluzole and edaravone?

Key Response

Residents must learn to set realistic expectations. The benefit on the ALSFRS-R in the CENTAUR trial was statistically significant but modest (a difference of about 2.32 points over 24 weeks). Counseling must include that it is not a cure, is typically used as an add-on therapy, and frequently causes gastrointestinal side effects (diarrhea, nausea) due to the formulation.

Fellow

The CENTAUR trial required patients to have a symptom onset of less than 18 months and meet 'definite' ALS criteria. Why is this specific clinical enrichment strategy utilized in ALS clinical trials, and how does it complicate the extrapolation of efficacy data to the broader ALS population?

Key Response

Fellows must understand trial design nuances in neurodegeneration. Enrolling 'fast progressors' (early onset, widespread disease) ensures the placebo group will show measurable decline on the ALSFRS-R over a short 24-week period, maximizing statistical power. However, this restricts generalizability, making it unclear if 'slow progressors' or late-stage patients derive the same functional benefit.

Attending

Given the modest functional preservation seen in the phase 2 CENTAUR trial, how should clinicians weigh the high financial cost, heavy medication burden, and potential for false hope when engaging in shared decision-making with patients facing a terminal diagnosis?

Key Response

Attendings deal with the practical and ethical realities of prescribing. Balancing a statistical slowing of functional decline against quality of life, out-of-pocket costs, and severe GI tolerability issues requires advanced clinical judgment, particularly in a disease state where desperate patients may pursue any available option regardless of the evidence certainty.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The primary outcome was analyzed using a shared-baseline, mixed-effects modeling approach to account for longitudinal data. How does informative censoring (e.g., missing data due to severe progression or death) threaten the validity of ALSFRS-R slope analyses, and are these statistical models sufficient to handle non-random dropout?

Key Response

Missing data due to death is a massive methodological issue in ALS trials. If patients with the fastest progression die and drop out of the scale, the remaining cohort appears to progress slower (survivor bias). Evaluating whether joint-rank analysis or mixed-effects models adequately penalize for mortality without diluting the functional readout is a classic statistical challenge.

Journal Editor

Considering the distinct, bitter taste and gastrointestinal side-effect profile of sodium phenylbutyrate, how might functional unblinding have influenced the subjective components of the ALSFRS-R score, and how should peer reviewers assess this bias in a phase 2 trial?

Key Response

Editors look for subtle biases that threaten internal validity. The ALSFRS-R contains patient-reported components (e.g., swallowing, speech, dressing). If patients realized they were on the active drug due to GI upset or taste, it could subconsciously inflate their subjective reporting of functional preservation, which a reviewer must flag as a potential confounding factor.

Guideline Committee

Based on the Phase 2 CENTAUR data, should clinical guidelines recommend sodium phenylbutyrate-taurursodiol as a standard-of-care add-on therapy for all ALS patients, or should a recommendation be deferred until a Phase 3 trial confirms the findings, considering the historical precedent of failed ALS drugs?

Key Response

Guideline committees face immense pressure in terminal illnesses with unmet needs. Recommending a drug based on a single Phase 2 trial (which the FDA initially approved via an accelerated pathway, though the drug was later pulled when the Phase 3 PHOENIX trial failed) highlights the tension between providing early access to potentially life-prolonging therapies and maintaining rigorous evidence-based guideline standards.

Clinical Landscape

Noteworthy Related Trials

1994

A Controlled Trial of Riluzole in Amyotrophic Lateral Sclerosis

n = 155 · NEJM

Tested

Riluzole 100 mg daily

Population

Patients with amyotrophic lateral sclerosis

Comparator

Placebo

Endpoint

Survival (time to death or tracheostomy)

Key result: Riluzole significantly improved survival compared to placebo, particularly in patients with bulbar-onset ALS.

2017

Phase 3 Trial of Edaravone in Amyotrophic Lateral Sclerosis

n = 137 · Lancet Neurol

Tested

Edaravone 60 mg intravenously

Population

Early-stage ALS patients with preserved respiratory function

Comparator

Placebo

Endpoint

Change in ALSFRS-R score over 24 weeks

Key result: Edaravone showed a significantly smaller decline in the ALSFRS-R score compared to placebo, indicating a slowing of functional disease progression.

2022

VALOR Trial of Tofersen

n = 108 · NEJM

Tested

Tofersen 100 mg intrathecally

Population

Adults with ALS and a confirmed SOD1 mutation

Comparator

Placebo

Endpoint

Change from baseline to week 28 in the ALSFRS-R score

Key result: Although the primary clinical endpoint was not met at week 28, tofersen significantly reduced cerebrospinal fluid SOD1 protein and plasma neurofilament light chain levels.

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