A Phase III, Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial to Evaluate the Safety and Efficacy of AMX0035 Versus Placebo for 48-week Treatment of Adult Patients With Amyotrophic Lateral Sclerosis (ALS)
AMX0035 is a novel combination therapy consisting of sodium phenylbutyrate (PB) and taurursodiol (TURSO), also known as ursodeoxycholic acid. This fixed-dose combination targets multiple pathological pathways in ALS, including endoplasmic reticulum stress, mitochondrial dysfunction, and apoptosis. The therapy was granted FDA approval in September 2022 based on the Phase 2 CENTAUR trial, with this Phase 3 trial designed to confirm and extend those findings[1].
| Parameter | Value |
|---|---|
| NCT Number | NCT05021536 |
| Phase | PHASE3 |
| Status | ACTIVE_NOT_RECRUITING |
| Sponsor | Amylyx Pharmaceuticals Inc. |
| Enrollment | 664 participants |
| Enrollment Type | ACTUAL |
| Study Type | INTERVENTIONAL |
| Start Date | 2021-10-28 |
| Completion Date | 2026-01-01 |
| Last Updated | 2024-08-14 |
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of upper and lower motor neurons. The disease affects approximately 5-10 per 100,000 individuals globally, with most patients dying within 2-5 years of symptom onset due to respiratory failure[2].
The pathogenesis of ALS involves multiple interconnected mechanisms:
1. Protein Misfolding and Aggregation
2. Mitochondrial Dysfunction
3. Endoplasmic Reticulum Stress
4. Excitotoxicity
5. Neuroinflammation
AMX0035 combines two well-characterized compounds with complementary mechanisms:
Sodium phenylbutyrate is an FDA-approved drug for urea cycle disorders. In ALS, it acts as:
a) HDAC Inhibitor
b) ER Stress Reducer
c) Mitochondrial Function Enhancer
Taurursodiol is a hydrophilic bile acid with well-established safety. Its mechanisms include:
a) Mitochondrial Membrane Stabilization
b) Anti-Apoptotic Effects
c) Anti-Oxidant Properties
The combination of PB and TURSO provides complementary and potentially synergistic benefits:
| Mechanism | PB | TURSO | Combined Effect |
|---|---|---|---|
| ER Stress | +++ | + | Reduced protein toxicity |
| Mitochondrial | ++ | +++ | Enhanced energy, reduced apoptosis |
| Oxidative Stress | ++ | +++ | Comprehensive protection |
| Gene Expression | +++ | + | Neurotrophic support |
This is a Phase 3, randomized, double-blind, placebo-controlled clinical trial building on the successful Phase 2 CENTAUR trial.
The Phase 2 CENTAUR trial (NCT03421527) demonstrated significant efficacy[1:1]:
ALSFRS-R Slope Change
The primary endpoint measures the rate of functional decline over 48 weeks:
The ALSFRS-R evaluates:
This Phase 3 trial was conducted as a post-marketing requirement following the FDA's 2022 accelerated approval of AMX0035 (marketed as Relyvrio)[8]. The approval was based on:
The Phase 3 trial aimed to confirm the magnitude of benefit observed in Phase 2 and provide more robust long-term data.
AMX0035 represents a paradigm shift in ALS therapy:
1. Multi-Target Approach
Unlike single-target therapies (riluzole, tofersen), AMX0035 addresses multiple pathological pathways simultaneously.
2. Oral Administration
Unlike intravenous therapies (nidoflen, NurOwn), AMX0035 can be taken at home, improving patient accessibility.
3. Combination Potential
AMX0035 can potentially be combined with:
This trial includes extensive biomarker collection:
Neurofilaments as Response Markers
Neurofilament light chain (NfL) is a validated biomarker of neuronal injury[9]:
Sample Collection
The trial was conducted at approximately 65 sites across North America and Europe:
The Phase 2 CENTAUR trial established the safety profile:
| Adverse Event | AMX0035 (n=87) | Placebo (n=48) |
|---|---|---|
| GI symptoms | 34% | 23% |
| Constipation | 21% | 14% |
| Nausea | 16% | 8% |
| Fatigue | 14% | 8% |
AMX0035 operates in a competitive ALS therapeutic landscape:
| Drug | Mechanism | Status | Company |
|---|---|---|---|
| Riluzole | Glutamate modulation | Approved | Sanofi |
| Edaravone | Antioxidant | Approved | Mitsubishi Tanabe |
| Tofersen | SOD1 ASO | Approved | Biogen |
| AMX0035 | PB+TURSO combo | Approved | Amylyx |
| Reldesemtiv | Fast skeletal troponin | Phase 3 | Cytokinetics |
| Pridopidine | Dopamine stabilizer | Phase 3 | Prilenia |
| NurOwn | MSC-NTF cells | Phase 3 | BrainStorm |
Following the 48-week treatment period, participants were eligible for:
The open-label extension provides: