Presented at the American Academy of Neurology (AAN) 2024 Annual Meeting April 17, 2024

Results from the Global Phase 3 PHOENIX Trial Evaluating Sodium Phenylbutyrate and Taurursodiol in ALS

Leonard H. van den Berg, et al. (Amylyx Pharmaceuticals)

Bottom Line

The phase 3 PHOENIX trial failed to confirm the efficacy of AMX0035 in amyotrophic lateral sclerosis, missing all primary and secondary endpoints and leading to the drug's voluntary market withdrawal.

Key Findings

1. PHOENIX did not meet its primary endpoint: the mean change from baseline in the ALSFRS-R total score at 48 weeks was -14.98 points in the AMX0035 group compared to -15.32 points in the placebo group, resulting in a non-significant treatment difference of 0.343 points (95% CI -1.22 to 1.91, p=0.667).

2. The trial failed to achieve statistical significance across all secondary endpoints, including slow vital capacity (SVC) and patient-reported quality of life measures (ALSAQ-40).

3. There was no significant benefit observed even in a post-hoc subset of participants who strictly met the enrollment criteria of the earlier phase 2 CENTAUR trial.

4. AMX0035 was generally well tolerated with an adverse event profile similar to previous studies; however, gastrointestinal events such as diarrhea were more frequent in the treatment arm (approximately 31% vs. 10% for placebo).

Study Design

Design

Randomized Controlled Trial

Double-Blind

Sample

664

Patients

Duration

48 weeks

Median

Setting

Multicenter, US and Europe

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

Intervention AMX0035 (a fixed-dose combination of 3 g sodium phenylbutyrate and 1 g taurursodiol/ursodoxicoltaurine) administered orally or via feeding tube daily for 3 weeks, then twice daily.

Comparator Matching placebo administered orally or via feeding tube.

Outcome Change from baseline in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) total score at week 48.

Study Limitations

• The trial enrolled a broader, more heterogeneous population (symptom onset up to 24 months) than the phase 2 CENTAUR trial (up to 18 months), potentially masking effects in specific fast-progressing subgroups.

• The high background use of other approved ALS therapies (riluzole and edaravone) may have narrowed the window to detect a modest additive therapeutic benefit.

Clinical Significance

The negative results of the PHOENIX trial represent a major clinical disappointment, definitively establishing that AMX0035 (Relyvrio/Albrioza) does not alter ALS disease progression. Consequently, the drug was voluntarily withdrawn from the market in early 2024. The trial underscores the critical necessity of conducting large, adequately powered phase 3 confirmatory trials for rare disease therapeutics that receive accelerated or conditional approvals based on phase 2 data.

Historical Context

AMX0035 received full FDA approval in September 2022 following intense patient advocacy and a highly unusual, reconvened FDA advisory committee meeting that narrowly supported the drug based on the 137-patient phase 2 CENTAUR trial (which showed a 25% slower decline in ALSFRS-R and a post-hoc survival benefit). Because the data were viewed by many regulators as borderline, Amylyx pledged to voluntarily withdraw the drug if the larger phase 3 PHOENIX trial failed. When PHOENIX missed all endpoints, the manufacturer honored this commitment, establishing a landmark precedent for post-market regulatory accountability and the withdrawal of definitively ineffective neurodegenerative treatments.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the proposed mechanism of action of sodium phenylbutyrate and taurursodiol (AMX0035) in ALS, and how does this relate to the underlying cellular pathophysiology of the disease?

Key Response

AMX0035 was designed to simultaneously target endoplasmic reticulum (ER) stress through sodium phenylbutyrate and mitochondrial dysfunction through taurursodiol. Understanding this mechanism helps connect basic cellular biology of motor neuron degeneration to targeted therapeutic strategies.

Resident

How should you counsel a patient with ALS who is currently taking AMX0035 (Relyvrio) regarding the results of the PHOENIX trial and its subsequent market withdrawal?

Key Response

Residents must navigate difficult conversations about stopping therapies. Counseling should include explaining the lack of efficacy demonstrated in the Phase 3 trial, assisting with safe discontinuation, and pivoting the focus to other evidence-based disease-modifying therapies (like riluzole) and robust multidisciplinary symptom management.

Fellow

The FDA originally approved AMX0035 based on the Phase 2 CENTAUR trial. As a neuromuscular fellow, how do you reconcile the conflicting efficacy results between the CENTAUR and PHOENIX trials, and what does this teach us about ALS trial design?

Key Response

Differences likely stem from patient heterogeneity; CENTAUR enrolled faster-progressing patients, while PHOENIX had broader inclusion criteria. This highlights the statistical risks of regulatory approval based on a single Phase 2 study and the critical need for robust, adequately powered Phase 3 data in highly variable neurodegenerative diseases.

Attending

The withdrawal of Relyvrio removes a heavily discussed treatment option for ALS. How does this outcome reshape our approach to shared decision-making regarding early access or accelerated approval drugs in fatal neurodegenerative diseases?

Key Response

Attendings must balance patient hope for novel therapies with the reality of incomplete efficacy data and potential financial or physical toxicity. This case serves as a paradigm for discussing the uncertainty of accelerated approvals, emphasizing the importance of managing expectations and prioritizing quality of life.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

How did the statistical powering, patient heterogeneity, and primary endpoint selection (ALSFRS-R slope) in the PHOENIX trial impact its ability to detect a drug effect compared to the earlier CENTAUR trial?

Key Response

ALSFRS-R trajectories are highly variable and non-linear. Evaluating whether the mixed models for repeated measures (MMRM) or joint rank analyses adequately accounted for slower disease progression and missing data in the broader PHOENIX cohort is critical for designing and powering future ALS clinical trials.

Journal Editor

In reviewing the PHOENIX trial manuscript, how would you critically evaluate the risk of unblinding due to the known gastrointestinal side effect profile of the treatment, and could this have influenced the subjective components of the ALSFRS-R?

Key Response

A critical reviewer would flag whether GI side effects disproportionately unblinded the treatment arm. While unblinding typically biases results toward positive outcomes, evaluating this ensures the negative result wasn't confounded by dropout imbalances or reporting bias, confirming that the failure to meet endpoints was a true lack of biological efficacy.

Guideline Committee

Given the definitive negative results of the PHOENIX trial and subsequent market withdrawal, what specific updates must be made to ALS management guidelines regarding AMX0035, and what level of evidence supports this change?

Key Response

Previous consensus guidelines had tentatively included AMX0035 based on Phase 2 data. The committee must now issue a strong recommendation against its use, citing Level A evidence (a well-powered Phase 3 RCT showing lack of efficacy), formally removing it from algorithms and refocusing guidelines on riluzole, edaravone, and symptomatic care.

Clinical Landscape

Noteworthy Related Trials

1994

Riluzole ALS Trial

n = 155 · NEJM

Tested

Riluzole 100 mg daily

Population

Patients with probable or definite ALS

Comparator

Placebo

Endpoint

Survival without tracheostomy

Key result: Riluzole significantly prolonged survival and time to tracheostomy compared to placebo without improving muscle strength.

2017

Edaravone Phase 3 Trial (MCI186-19)

n = 137 · Lancet Neurol

Tested

Edaravone 60 mg IV

Population

Patients with early-stage ALS and preserved respiratory function

Comparator

Placebo

Endpoint

Change in ALSFRS-R score at 24 weeks

Key result: Edaravone treatment resulted in a significantly smaller decline in the ALSFRS-R score compared to placebo.

2020

CENTAUR Trial

n = 137 · NEJM

Tested

Sodium phenylbutyrate and taurursodiol (AMX0035)

Population

Adults with definite ALS within 18 months of symptom onset

Comparator

Placebo

Endpoint

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

Key result: AMX0035 resulted in a significantly slower functional decline compared to placebo over 24 weeks.

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