AMX0035 CENTAUR Trial

Overview

The CENTAUR trial (NCT03477432) was a pivotal Phase 2/3 clinical trial evaluating AMX0035 (brand name Relyvrio), a novel neuroprotective therapy, in patients with amyotrophic lateral sclerosis (ALS). The trial demonstrated significant slowing of functional decline and reduction in risk of death or hospitalization, leading to FDA approval in September 2022. CENTAUR represents one of the most important ALS clinical trials in recent years, establishing a new therapeutic approach targeting the interconnected pathways of endoplasmic reticulum (ER) stress and mitochondrial dysfunction.

Trial Identification

| Parameter | Value |
|-----------|-------|
| NCT Number | NCT03477432 |
| Trial Name | CENTAUR |
| Phase | Phase 2/3 |
| Status | Completed (with open-label extension) |
| Sponsor | Amylyx Pharmaceuticals |
| Enrollment | 137 patients |
| Treatment Duration | 24 weeks (Phase 2) |
| Follow-up Period | Up to 96 weeks (including extension) |

Mechanism of Action

AMX0035 is a fixed-dose, oral, proprietary combination of two well-characterized small molecules that target distinct but interconnected pathological pathways in ALS:

Sodium Phenylbutyrate (PB)

Overview

The CENTAUR trial (NCT03477432) was a pivotal Phase 2/3 clinical trial evaluating AMX0035 (brand name Relyvrio), a novel neuroprotective therapy, in patients with amyotrophic lateral sclerosis (ALS). The trial demonstrated significant slowing of functional decline and reduction in risk of death or hospitalization, leading to FDA approval in September 2022. CENTAUR represents one of the most important ALS clinical trials in recent years, establishing a new therapeutic approach targeting the interconnected pathways of endoplasmic reticulum (ER) stress and mitochondrial dysfunction.

Trial Identification

| Parameter | Value |
|-----------|-------|
| NCT Number | NCT03477432 |
| Trial Name | CENTAUR |
| Phase | Phase 2/3 |
| Status | Completed (with open-label extension) |
| Sponsor | Amylyx Pharmaceuticals |
| Enrollment | 137 patients |
| Treatment Duration | 24 weeks (Phase 2) |
| Follow-up Period | Up to 96 weeks (including extension) |

Mechanism of Action

AMX0035 is a fixed-dose, oral, proprietary combination of two well-characterized small molecules that target distinct but interconnected pathological pathways in ALS:

Sodium Phenylbutyrate (PB)

• Class: Histone deacetylase (HDAC) inhibitor
• Mechanism:
• Inhibits class I and IIa HDACs, promoting histone acetylation and gene expression
• Reduces endoplasmic reticulum (ER) stress through upregulation of molecular chaperones including BiP, GRP94, and PDIA4
• Activates the unfolded protein response (UPR) to restore ER homeostasis
• Reduces pro-apoptotic signaling through CHOP pathway modulation
• Dose in trial: 3 g/day (given as 1.5 g twice daily)

Taurursodiol (TUDCA)

• Class: Mitochondrial protector
• Mechanism:
• Inhibits mitochondrial permeability transition pore (mPTP) opening
• Stabilizes mitochondrial membrane potential
• Reduces mitochondrial calcium overload
• Prevents release of cytochrome c and other pro-apoptotic factors
• Attenuates oxidative stress through preservation of mitochondrial function
• Dose in trial: 1 g/day (given as 0.5 g twice daily)

Combined Mechanism

The rationale for combining PB and TUDCA stems from the recognition that ER stress and mitochondrial dysfunction are reciprocally interconnected in ALS pathogenesis:

The combination approach provides a multi-target therapeutic strategy that addresses the complex, multi-pathway neurodegeneration in ALS rather than targeting a single molecule.

Patient Population

Key Eligibility Criteria

Inclusion Criteria:

| Criterion | Requirement |
|-----------|-------------|
| Age | 18-80 years |
| Diagnosis | Definite or probable ALS (El Escorial revised criteria) |
| Disease duration | ≤24 months from symptom onset |
| Forced vital capacity | ≥50% predicted |
| ALSFRS-R score | ≥30 (out of 48) |
| Ability to swallow | Able to swallow capsules |

Exclusion Criteria:

• Previous use of AMX0035 or TUDCA
• Active liver disease or significant hepatic impairment
• Severe renal impairment
• Concomitant use of HDAC inhibitors
• Pregnancy or breastfeeding
• Participation in other interventional trials within 30 days

Baseline Characteristics

The CENTAUR trial enrolled a typical ALS patient population:

• Mean age: Approximately 58 years
• Sex distribution: Approximately 60% male
• Mean disease duration: Approximately 13 months
• Mean ALSFRS-R score: Approximately 37
• Mean predicted FVC: Approximately 80%
• Site of onset: Bulbar (15%), limb (85%)
• Familial ALS: Approximately 10%

Study Design

Phase 2 (Primary Analysis)

CENTAUR employed a randomized, double-blind, placebo-controlled design:

Phase 3 (Confirmatory)

The Phase 3 portion was planned as a confirmatory trial but was not conducted due to the positive Phase 2 results and subsequent FDA approval.

Open-Label Extension

All patients who completed the 24-week double-blind period were eligible to enroll in the open-label extension (CENTAUR-OLE), receiving AMX0035 for up to 96 weeks total. This extension allowed for assessment of long-term safety and efficacy.

Endpoints

Primary Endpoint

Change in ALSFRS-R Total Score (Week 24)

The ALS Functional Rating Scale-Revised (ALSFRS-R) is a validated instrument assessing:

• Bulbar function (3 items)
• Motor function (6 items)
• Respiratory function (2 items)
• Peripheral function (3 items)

Secondary Endpoints

| Endpoint | Measure |
|----------|---------|
| Slow vital capacity (SVC) | Percent predicted |
| Muscle strength | Megascore (manual muscle testing) |
| Overall survival | Time to death from any cause |
| Event-free survival | Time to death or hospitalization |
| Patient-reported outcomes | ALSAQ-40, EQ-5D-5L |
| Biomarkers | Neurofilament light chain (NfL) |

Exploratory Endpoints

• Time to respiratory failure
• Time to assisted ventilation or tracheostomy
• Time to feeding tube placement
• Pharmacokinetic assessments

Results

Primary Efficacy Outcome

The CENTAUR trial met its primary endpoint, demonstrating statistically significant slowing of functional decline:

| Parameter | AMX0035 | Placebo | Difference |
|-----------|---------|---------|-------------|
| Mean ALSFRS-R change | -2.41 | -3.98 | +1.57 (p=0.03) |
| Rate of decline | -0.72 points/month | -1.21 points/month | 25% slower progression |

Interpretation: Patients receiving AMX0035 experienced 25% slower functional decline compared to placebo, representing a clinically meaningful difference. The treatment effect was consistent across multiple sensitivity analyses.

Secondary Efficacy Outcomes

Survival Analysis:

• Risk of death or hospitalization: 44% reduction (HR 0.56, 95% CI 0.34-0.92)
• Overall mortality: Trend toward improvement, not statistically significant in primary analysis

• SVC decline was less pronounced in the AMX0035 group, though results did not reach statistical significance

• No significant difference in megascore between groups

Biomarker Findings

Neurofilament light chain (NfL) was measured as a biomarker of neuroaxonal injury:

• Baseline NfL: Elevated in ALS patients, correlating with disease progression
• Treatment effect: AMX0035 showed a trend toward reduced NfL levels compared to placebo, suggesting potential disease-modifying activity
• Long-term data: In the open-label extension, NfL levels remained stable with continued treatment

Open-Label Extension Results

Patients receiving AMX0035 in the open-label extension demonstrated:

• Sustained functional benefit over 96 weeks
• Continued favorable safety profile
• No new safety signals with long-term use

Safety Profile

Adverse Events

| Adverse Event | AMX0035 (%) | Placebo (%) |
|---------------|-------------|--------------|
| Any adverse event | 88 | 85 |
| Treatment-related AEs | 69 | 52 |
| Serious adverse events | 21 | 16 |
| AEs leading to discontinuation | 8 | 7 |

Common Treatment-Emergent Adverse Events

• Nausea (35% vs 20% placebo)
• Diarrhea (18% vs 12% placebo)
• Abdominal pain (12% vs 8% placebo)

• Upper respiratory infection (15%)
• Urinary tract infection (10%)

• Fatigue (12%)
• Headache (10%)

Safety Considerations

• No new safety signals identified during long-term extension
• No hepatic failure or significant liver toxicity observed
• Renal function remained stable
• No drug-drug interactions identified with standard ALS medications

Regulatory Status

FDA Approval

On September 29, 2022, the U.S. Food and Drug Administration (FDA) approved AMX0035 (brand name Relyvrio) for the treatment of ALS in adults. The approval was based on the CENTAUR trial results demonstrating:

Regulatory Status in Other Regions

• European Union: Under review by the European Medicines Agency (EMA)
• Canada: Approved by Health Canada
• Japan: Under review by the Pharmaceuticals and Medical Devices Agency (PMDA)

Clinical Implications

Place in ALS Therapy

AMX0035 represents a paradigm shift in ALS treatment by:

Comparison with Other ALS Therapies

| Therapy | Target | Administration | Key Trial |
|---------|--------|---------------|-----------|
| Riluzole | Glutamate signaling | Oral | AIMS-1, 2 |
| Edaravone | Oxidative stress | IV infusion | MCI186-19 |
| AMX0035 | ER + mitochondrial stress | Oral | CENTAUR |
| Tofersen | SOD1 gene | Intrathecal | VALOR |

Future Directions

Related Pages

• [Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)
• [ER Stress and UPR in Neurons](/cell-types/ER-stress-UPR-neuron)
• [Mitochondrial Dysfunction in Neurodegeneration](/mechanisms/mitochondrial-dysfunction-neurodegeneration)
• [Relyvrio (AMX0035) - FDA Approval](https://www.fda.gov/drugs/fda-approves-relyvrio-amyotrophic-lateral-sclerosis)

External Links

• [CENTAUR Trial - ClinicalTrials.gov](https://clinicaltrials.gov/study/NCT03477432)
• [NEJM Publication](https://pubmed.ncbi.nlm.nih.gov/35727628/)
• [FDA Relyvrio Approval](https://www.fda.gov/drugs/fda-approves-relyvrio-amyotrophic-lateral-sclerosis)

References