A Phase III, Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial ... (NCT05021536)

Phase III Trial of AMX0035 for Amyotrophic Lateral Sclerosis Treatment

Overview

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)

Phase III Trial of AMX0035 for Amyotrophic Lateral Sclerosis Treatment

Overview

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["@amx00352022"].

Trial Details

| 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 |

Conditions Studied

• Amyotrophic Lateral Sclerosis (ALS)

Scientific Background

Disease Context

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[@als2024].

The pathogenesis of ALS involves multiple interconnected mechanisms:

1. Protein Misfolding and Aggregation

• TDP-43 protein inclusions in 97% of ALS cases
• SOD1 mutations in ~20% of familial cases
• C9orf72 hexanucleotide repeat expansions (most common genetic cause)

• Impaired energy metabolism
• Defective calcium buffering
• Increased reactive oxygen species (ROS)
• Apoptotic pathway activation[@mitochondria2023]

• Unfolded protein response (UPR) activation
• Disrupted calcium homeostasis
• Pro-apoptotic signaling

• Glutamate-induced neuronal damage
• Impaired glutamate transporters
• AMPA/kainate receptor hyperactivity

• Microglial activation
• Astrocytosis
• Peripheral immune cell infiltration[@energy2023]

Therapeutic Mechanism: Dual-Target Combination

AMX0035 combines two well-characterized compounds with complementary mechanisms:

Sodium Phenylbutyrate (PB)

Sodium phenylbutyrate is an FDA-approved drug for urea cycle disorders. In ALS, it acts as:

a) HDAC Inhibitor

• Inhibits class I/IIa histone deacetylases
• Reduces histone hyperacetylation
• Upregulates protective gene expression
• Promotes transcription of neurotrophic factors

• Enhances protein folding capacity
• Reduces UPR activation
• Decreases CHOP expression (pro-apoptotic factor)

• Improves mitochondrial biogenesis
• Enhances ATP production
• Reduces ROS generation[@neuroprotection2023]

Taurursodiol (TURSO)

Taurursodiol is a hydrophilic bile acid with well-established safety. Its mechanisms include:

a) Mitochondrial Membrane Stabilization

• Prevents mitochondrial permeability transition
• Inhibits cytochrome c release
• Maintains membrane potential

• Inhibits caspase activation
• Blocks Bcl-2 family protein interactions
• Prevents DNA fragmentation

• Scavenges reactive oxygen species
• Enhances endogenous antioxidant systems
• Reduces lipid peroxidation

Synergistic Effects

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 |

Study Design

This is a Phase 3, randomized, double-blind, placebo-controlled clinical trial building on the successful Phase 2 CENTAUR trial.

Pivotal Phase 2 CENTAUR Trial (Results)

The Phase 2 CENTAUR trial (NCT03421527) demonstrated significant efficacy[@amx00352022]:

• Primary endpoint met: ALSFRS-R decline reduced by 2.5 points over 24 weeks (p=0.023)
• Secondary endpoints: Slower decline in muscle strength (ALSFRS-R bulbar, respiratory)
• Safety: Comparable to placebo, no new safety signals

Phase 3 Design Features

Randomization and Blinding

• 2:1 randomization: 443 participants to AMX0035, 221 to placebo
• Double-blind: Matching placebo formulation
• Stratification: By site, baseline ALSFRS-R, disease duration

Treatment Regimen

• AMX0035: 3 g sodium phenylbutyrate + 1 g taurursodiol, once daily
• Placebo: Matching powder for oral suspension
• Duration: 48 weeks (with optional open-label extension)

Inclusion Criteria

• Age ≥18 years
• Definite, probable, or possible ALS (Awad criteria)
• Disease duration ≤24 months
• Baseline ALSFRS-R ≥30 points
• Stable riluzole use (or none)

Exclusion Criteria

• Tracheostomy or permanent ventilation
• FVC <50% predicted
• BMI <18.5 kg/m²
• Significant hepatic/renal impairment
• Use of other investigational therapies

Outcome Measures

Primary Endpoints

ALSFRS-R Slope Change
The primary endpoint measures the rate of functional decline over 48 weeks:

• Assessed monthly
• Compared to natural history controls
• Clinically meaningful: ≥3 points over 48 weeks

• Bulbar function (speech, swallowing)
• Respiratory function
• Fine motor skills
• Gross motor function
• Manual dexterity[@phase32023]

Secondary Endpoints

Exploratory Endpoints

• Neuroimaging: Brain and spinal cord MRI
• Neurophysiology: Motor unit number estimation (MUNE)
• Pharmacokinetics: Plasma levels of PB/TURSO
• Genetic substudy: Correlation of response with C9orf72, SOD1, FUS mutations

Clinical Significance

FDA Approval Context

This Phase 3 trial was conducted as a post-marketing requirement following the FDA's 2022 accelerated approval of AMX0035 (marketed as Relyvrio)[@approval2023]. The approval was based on:

• Phase 2 CENTAUR trial demonstrating functional benefit
• Acceptable safety profile
• Unmet medical need in ALS

Impact on ALS Treatment Landscape

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:

• Riluzole (standard of care)
• Gene-specific therapies (tofersen for SOD1)
• Future disease-modifying agents

Biomarker Development

This trial includes extensive biomarker collection:

Neurofilaments as Response Markers
Neurofilament light chain (NfL) is a validated biomarker of neuronal injury[@nfl2024]:

• Elevated in ALS vs. controls
• Correlates with disease progression
• May predict treatment response
• Used for patient stratification

• Serum NfL at baseline, 12, 24, 48 weeks
• CSF NfL in subset of participants
• Longitudinal tracking for exposure-response analysis

Participating Sites

The trial was conducted at approximately 65 sites across North America and Europe:

United States Sites

• Phoenix, Arizona
• Los Angeles, California
• Orange, California
• San Francisco, California
• Aurora, Colorado
• Miami, Florida
• Atlanta, Georgia
• Chicago, Illinois
• Boston, Massachusetts
• Detroit, Michigan

Canadian Sites

• Toronto, Ontario
• Montreal, Quebec
• Calgary, Alberta

European Sites

• London, United Kingdom
• Paris, France
• Munich, Germany
• Milan, Italy
• Barcelona, Spain
• Amsterdam, Netherlands

Safety Profile

Adverse Events in Phase 2

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% |

Safety Monitoring

• Monthly liver function tests
• Renal function monitoring
• ECG for QT prolongation
• Adverse event collection throughout treatment period

Special Considerations

• GI symptoms managed with dose titration
• No drug-drug interactions with riluzole
• No effect on respiratory function
• No cognitive impairment observed

Competitive Landscape

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 |

Long-Term Follow-Up

Following the 48-week treatment period, participants were eligible for:

• Open-label extension: All participants could receive AMX0035
• Follow-up study: Continued monitoring for survival and safety
• Registry participation: Integration with ALS registries

• Long-term safety data
• Durability of treatment effect
• Real-world effectiveness data

Related Resources

• [Clinical Trials Overview](/clinical-trials/overview)
• [Drug Development Pipeline](/clinical-trials/drug-pipeline)
• [Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)
• [Riluzole](/drugs/riluzole)
• [Sodium Phenylbutyrate](/drugs/sodium-phenylbutyrate)
• [Mitochondrial Dysfunction](/mechanisms/mitochondrial-dysfunction)
• [ER Stress in Neurodegeneration](/mechanisms/er-stress-pathway)

External Links

• [ClinicalTrials.gov Record](https://clinicaltrials.gov/study/NCT05021536)
• [Amylyx Pharmaceuticals](https://www.amylyx.com)
• [FDA Approval Announcement](https://www.fda.gov/drugs/news-events-human-drug-alerts/fda-approves-new-treatment-amyotrophic-lateral-sclerosis-als)
• [PubMed Search](https://pubmed.ncbi.nlm.nih.gov/?term=NCT05021536)

References

Patient Experience and Quality of Life

Impact on Daily Living

ALS significantly impacts daily life, and AMX0035 aims to preserve function for as long as possible:

Motor Function Preservation:

• Maintaining ability to perform self-care activities
• Preserving speech and swallowing function
• Extending independent mobility
• Reducing caregiver burden

• ALS typically spare cognition in most patients
• Frontotemporal dementia can occur in some cases (especially C9orf72)
• AMX0035 includes cognitive assessments to monitor this

Caregiver Considerations

The trial emphasizes caregiver support and education:

Access and Affordability

Pricing and Coverage:

• AMX0035/Relyvrio is priced at approximately $158,000 per year
• Medicare covers the medication under Part B
• Many private insurers have established coverage policies
• Patient assistance programs available for eligible patients

• United States: Approved and available
• Canada: Under review
• Europe: Under review by EMA
• Japan: Under review by PMDA

Conclusion

AMX0035 represents a significant advance in ALS therapeutics, offering a novel dual-mechanism approach that targets both mitochondrial dysfunction and endoplasmic reticulum stress - two fundamental pathological pathways in ALS. The Phase 3 trial (NCT05021536) is evaluating whether the positive signals from the Phase 2 CENTAUR trial can be confirmed in a larger population.

The development of AMX0035 exemplifies several important trends in ALS drug development:

Whether the Phase 3 trial confirms efficacy or not, the trial will provide valuable data on the role of mitochondrial and ER pathways in human ALS, potentially informing future therapeutic development.

References