N/A MARCH 08, 2024

Trial of Sodium Phenylbutyrate–Taurursodiol for Amyotrophic Lateral Sclerosis (PHOENIX)

Not yet formally published in a peer-reviewed journal as a primary outcome report (data shared via top-line results announcement by Amylyx Pharmaceuticals).

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Bottom Line

The PHOENIX Phase 3 trial failed to confirm the clinical efficacy of AMX0035 in slowing functional decline in patients with amyotrophic lateral sclerosis (ALS).

Key Findings

1. The primary endpoint, defined as the change from baseline in the ALS Functional Rating Scale-Revised (ALSFRS-R) total score at 48 weeks, was not met (p=0.667).

2. There was no statistically significant difference in clinical progression between the AMX0035 and placebo groups.

3. Secondary endpoints, including respiratory function (slow vital capacity), patient-reported quality of life, and other functional measures, showed no significant differences between the two study arms.

4. The study confirmed that AMX0035 maintained a consistent, generally safe, and well-tolerated profile, with no new safety signals identified.

Study Design

Design

RCT

Double-Blind

Sample

664

Patients

Duration

48 wk

Median

Setting

Multicenter, US and Europe

Population Adults with clinically definite or clinically probable amyotrophic lateral sclerosis (ALS) within 24 months of symptom onset.

Intervention Oral, fixed-dose combination of sodium phenylbutyrate and taurursodiol.

Comparator Matching placebo, with both groups permitted to continue stable background standard-of-care (riluzole and/or edaravone).

Outcome Change from baseline in ALS Functional Rating Scale-Revised (ALSFRS-R) total score at 48 weeks.

Study Limitations

• The trial failed to replicate the positive functional findings observed in the smaller, Phase 2/3 CENTAUR trial.

• The study permitted concurrent use of riluzole and edaravone, which may introduce variability, although this reflected standard of care.

• The inclusion of a broader, more heterogeneous population compared to the CENTAUR trial may have affected the ability to detect a treatment signal, though sensitivity analyses in a subset resembling the original CENTAUR population yielded similar negative results.

Clinical Significance

The negative results of the PHOENIX trial led to the withdrawal of AMX0035 (Relyvrio/Albrioza) from the market for the treatment of ALS, as the confirmatory evidence required for its regulatory approval was not achieved.

Historical Context

AMX0035 was initially approved by the FDA in 2022 based on the smaller, phase 2 CENTAUR trial and subsequent open-label extension survival analyses, which showed potential benefits. PHOENIX was explicitly designed and mandated as a confirmatory Phase 3 trial to definitively validate these early positive findings in a larger, global, and more diverse patient population.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

The combination of sodium phenylbutyrate and taurursodiol was designed to target two specific cellular organelles implicated in ALS pathophysiology; which are they, and what are their respective roles in motor neuron death?

Key Response

Sodium phenylbutyrate acts as a chemical chaperone to reduce endoplasmic reticulum (ER) stress and the unfolded protein response, while taurursodiol (TUDCA) is a bile acid that stabilizes the mitochondrial membrane, preventing apoptosis. Both ER stress and mitochondrial dysfunction are foundational mechanisms in the proteotoxicity and metabolic failure seen in ALS.

Resident

Given the negative results of the PHOENIX trial, how should the pharmacological management of a patient with ALS change regarding the use of AMX0035 (Relyvrio) compared to standard therapies like Riluzole?

Key Response

While AMX0035 was previously approved based on functional benefits seen in the Phase 2 CENTAUR trial, the Phase 3 PHOENIX trial failed to show a significant difference in the ALSFRS-R score compared to placebo. Consequently, the manufacturer has withdrawn the drug from the market in most regions, and Riluzole (which extends survival) and Edaravone (in specific populations) remain the primary evidence-based pharmacological options.

Fellow

Analyze the potential reasons for the discrepancy between the positive results of the CENTAUR trial and the failure of the PHOENIX trial, specifically focusing on the 'rapid progressor' enrichment criteria used in the Phase 2 study.

Key Response

The Phase 2 CENTAUR trial utilized stricter inclusion criteria, enrolling patients earlier in their disease course (within 18 months of onset) who met 'Definite ALS' criteria, effectively enriching for rapid progressors where a treatment effect might be more visible. The PHOENIX trial included a broader, more heterogeneous population (up to 24 months from onset and lower diagnostic certainty levels), which may have diluted the therapeutic signal or included patients with more advanced, irreversible pathology.

Attending

The PHOENIX trial's failure raises significant questions regarding the regulatory pathways for rare, fatal neurodegenerative diseases. How does this outcome impact your approach to counseling patients who are interested in 'Right to Try' or early-access medications based on Phase 2 data?

Key Response

This study serves as a cautionary tale that Phase 2 'signals' are not synonymous with clinical efficacy. It emphasizes the need for balanced shared decision-making: acknowledging the patient's urgency while being transparent about the high failure rate of Phase 3 trials (the 'valley of death'). It also highlights the financial and emotional burden placed on families when they invest in treatments that are eventually proven ineffective.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The PHOENIX trial utilized the ALSFRS-R as its primary endpoint. Discuss the limitations of this scale in detecting neuroprotective effects in Phase 3 trials and whether alternative measures, such as Neurofilament Light Chain (NfL) or digital biomarkers, could have provided a more nuanced interpretation of the drug's activity.

Key Response

The ALSFRS-R is a functional, patient-reported outcome that is susceptible to high inter-rater variability and floor effects. While it measures clinical impact, it may not be sensitive enough to capture biological modulation. If AMX0035 had a biological effect (e.g., lowering NfL) that didn't translate to functional scores within the trial's timeframe, the trial would still be 'negative,' suggesting a need for composite endpoints or validated biomarkers as surrogates for neuronal preservation.

Journal Editor

From a critical appraisal perspective, does the high rate of concomitant Riluzole and Edaravone use in the PHOENIX study (over 70-80%) constitute a threat to the trial's internal validity or merely its ability to detect a marginal benefit?

Key Response

This reflects 'real-world' ALS care, but it creates a high 'background' of treatment that can mask the effect of the study drug if their mechanisms overlap or if there is a ceiling effect on functional preservation. A reviewer would demand a post-hoc subgroup analysis of patients not on background therapy to determine if AMX0035 has any standalone efficacy, which is critical for determining if the drug is truly ineffective or just redundant.

Guideline Committee

Considering the PHOENIX trial results, how should current ALS clinical guidelines (such as those from the AAN or EAN) be updated regarding the Level of Evidence for AMX0035, and what is the implications for the 'Conditional' recommendations previously issued?

Key Response

Previous guidelines gave a conditional or weak recommendation for AMX0035 based on Level B/C evidence from the CENTAUR trial. Following the PHOENIX trial's failure to meet its primary endpoint in a larger, powered cohort, the Level of Evidence for efficacy must be downgraded to 'Level U' (unproven) or the drug should be recommended against. This highlights the importance of 'living guidelines' that can rapidly incorporate trial failures to prevent the continued use of non-efficacious, expensive therapies.

Clinical Landscape

Noteworthy Related Trials

1994

Riluzole Trial

n = 155 · NEJM

Tested

Riluzole

Population

Patients with amyotrophic lateral sclerosis

Comparator

Placebo

Endpoint

Survival time

Key result: Patients treated with riluzole had a significantly longer survival time compared to the placebo group.

2018

ORARIAL Trial

n = 202 · Lancet Neurol

Tested

Edaravone

Population

Patients with early-stage amyotrophic lateral sclerosis

Comparator

Placebo

Endpoint

Change in ALSFRS-R score

Key result: Edaravone significantly slowed the decline of physical function in a specific subgroup of ALS patients over 24 weeks.

2020

CENTAUR Trial

n = 137 · NEJM

Tested

Sodium phenylbutyrate–taurursodiol (AMX0035)

Population

Patients with amyotrophic lateral sclerosis

Comparator

Placebo

Endpoint

Rate of decline in the ALS Functional Rating Scale-Revised (ALSFRS-R) score

Key result: Participants receiving AMX0035 had a slower rate of decline in ALSFRS-R scores than those receiving placebo.

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