AMX0035 for Progressive Supranuclear Palsy

Overview

AMX0035 (branded as Relyvrio in the United States and Albrioza in Canada) is an oral small molecule combination therapy being evaluated in the ORION trial (A35-009, NCT06122662) for patients with Progressive Supranuclear Palsy (PSP). This represents a significant advancement in the PSP therapeutic pipeline, representing the first combination therapy approach to reach late-stage clinical testing for this devastating neurodegenerative disorder["@nct"].

Overview

AMX0035 (branded as Relyvrio in the United States and Albrioza in Canada) is an oral small molecule combination therapy being evaluated in the ORION trial (A35-009, NCT06122662) for patients with Progressive Supranuclear Palsy (PSP). This represents a significant advancement in the PSP therapeutic pipeline, representing the first combination therapy approach to reach late-stage clinical testing for this devastating neurodegenerative disorder["@nct"].

The development of AMX0035 for PSP builds upon a unique trajectory in drug development — it became one of the few drugs to receive regulatory approval for one neurodegenerative disease (ALS) and then be subsequently evaluated for another (PSP). This path provides both momentum and critical safety data for the PSP indication while raising important questions about the translatability of therapeutic approaches across different proteinopathies.

Trial Details

| Field | Value |
|-------|-------|
| NCT Number | NCT06122662 |
| Trial Name | ORION (A35-009) |
| Sponsor | Amylyx Pharmaceuticals Inc. |
| Phase | Phase 2b/3 |
| Status | Active, not recruiting (as of 2025) |
| Design | Randomized, double-blind, placebo-controlled with optional open-label extension |
| Duration | 48 weeks (controlled) + 48 weeks (open-label) |
| Enrollment | Approximately 180 patients |
| Primary Endpoint | Change in PSP Rating Scale (PSPRS) from baseline to 48 weeks |

Mechanism of Action

AMX0035 represents a multi-target approach that combines two well-characterized compounds with complementary mechanisms:

Sodium Phenylbutyrate (PB)

Sodium phenylbutyrate is a small molecule drug approved since 2009 for urea cycle disorders. Its mechanism of action in neurodegeneration centers on histone deacetylase (HDAC) inhibition and transcription factor EB (TFEB) activation:

HDAC Inhibition: PB inhibits class I and IIa HDACs, leading to increased histone acetylation and altered gene expression. This epigenetic modulation can promote expression of neuroprotective genes and reduce inflammatory responses.

TFEB Activation: Most relevant for neurodegenerative applications, PB upregulates TFEB — the master regulator of the autophagy-lysosomal pathway[@pavel2023]. TFEB activation promotes:

• Increased transcription of autophagy-related genes
• Enhanced lysosomal biogenesis
• Improved clearance of pathological protein aggregates including tau
• Restoration of cellular proteostasis

Tauroursodeoxycholic Acid (TUDCA)

Tauroursodeoxycholic acid is a hydrophilic bile acid derived from ursodeoxycholic acid through taurine conjugation. Its neuroprotective properties have been demonstrated in multiple models:

Mitochondrial Protection: TUDCA acts as a chemical chaperone that stabilizes mitochondrial membrane potential, reduces mitochondrial permeability transition, and protects against apoptosis[@federici2021].

Anti-apoptotic Effects: TUDCA inhibits mitochondrial apoptosis pathways by:

• Preventing cytochrome c release
• Inhibiting caspase activation
• Modulating Bcl-2 family protein interactions

Combination Rationale

The rationale for combining these two compounds is based on their complementary mechanisms:

This combination targets multiple pathological pathways simultaneously, which may be necessary given the complex pathogenesis of PSP.

Scientific Rationale for PSP

Tau Pathology

PSP is classified as a 4-repeat (4R) tauopathy characterized by:

• Accumulation of hyperphosphorylated tau in neurofibrillary tangles
• Predominant involvement of subcortical structures (basal ganglia, brainstem)
• Progressive neuronal loss and gliosis

Mitochondrial Dysfunction

Mitochondrial abnormalities are prominent in PSP:

• Complex I deficiency in substantia nigra
• Reduced ATP production
• Increased oxidative stress
• Abnormal mitochondrial dynamics

Neuroinflammation

Both components of AMX0035 have anti-inflammatory properties:

• HDAC inhibition can modulate microglial activation
• TUDCA reduces inflammatory cytokine production
• Combined approach may provide broader anti-inflammatory effects

Precedent from ALS

The approval of AMX0035 (Relyvrio) for ALS in 2022 provides critical proof-of-concept:

CENTAUR Trial (Phase 2):

• 137 participants with ALS
• Primary endpoint: ALSFRS-R slope of decline
• Results: 2.49 points slower decline over 24 weeks (p=0.03)
• Secondary endpoint: Survival benefit of 4.8 months

• Accelerated approval based on ALSFRS-R
• First oral ALS therapy in decades
• Established safety profile in >3000 patients

Clinical Trial Design

Phase 2b/3 ORION Trial Structure

The ORION trial (A35-009) employs a rigorous design:

Phase A (Controlled, 48 weeks):

• Randomized 1:1 to AMX0035 or placebo
• Primary endpoint: Change in PSPRS total score
• Key secondary endpoints: MoCA, ADL scales, MRI atrophy rates

• All participants receive AMX0035
• Long-term safety and efficacy assessment

Inclusion Criteria

Key Inclusion Criteria:

• Age 40-85 years
• Clinical diagnosis of probable PSP per NINDS-SPSP criteria
• PSPRS score 20-70
• Disease duration 1-6 years
• Stable antiparkinsonian medications

• Significant medical comorbidities
• Psychiatric disorders preventing participation
• Prior neurosurgery or implanted devices
• Unable to undergo MRI

Outcome Measures

Primary:

• Change from baseline in PSP Rating Scale (PSPRS) at 48 weeks

• Montreal Cognitive Assessment (MoCA)
• Clinician's Global Impression of Change (CGI-C)
• Brain volume on MRI (whole brain, regional)
• CSF biomarkers (NfL, total tau, p-tau)

• Quality of life measures
• caregiver burden assessments
• Biomarker correlatives

ALS to PSP: Translation Considerations

Similarities

• Both involve protein aggregation (TDP-43 in ALS, tau in PSP)
• Both show mitochondrial dysfunction
• Both have neuroinflammation as a component
• Both are progressive neurodegenerative disorders

Differences

• Different protein aggregates (TDP-43 vs. tau)
• Different anatomical distributions (motor neurons vs. subcortical)
• Different clinical phenotypes
• Different rate of progression

Implications

The success in ALS does not guarantee success in PSP, but the established safety profile and mechanistic rationale justify the trial.

Competitive Landscape

AMX0035 enters a PSP therapeutic landscape with several approaches:

| Approach | Agent | Company | Stage |
|----------|-------|---------|-------|
| Anti-tau antibody | Bepranemab | Roche | Phase 2 |
| Anti-tau ASO | ION863 | Ionis/Alnylam | Phase 1 |
| p38 MAPK inhibitor | Neflamapimod | Various | Phase 2 |
| ROCK inhibitor | Fasudil | Various | Phase 2 |
| Combination therapy | AMX0035 | Amylyx | Phase 2b/3 |

AMX0035's unique position as a multi-target oral therapy differentiates it from antibody and antisense approaches.

Challenges and Considerations

Potential Limitations

Competitive Advantages

Future Directions

Combination Approaches

If successful, AMX0035 could be combined with:

• Anti-tau antibodies for complementary mechanisms
• Tau-directed antisense oligonucleotides
• Neuroprotective agents

Biomarker Development

Future trials may incorporate:

• CSF p-tau181 as a pharmacodynamic marker
• Tau PET for target engagement
• Neurofilament light chain for progression tracking

Cross-References

Related Disease Pages

• [Progressive Supranuclear Palsy](/diseases/progressive-supranuclear-palsy)
• [Corticobasal Syndrome](/diseases/corticobasal-syndrome)
• [4R-Tauopathies](/mechanisms/4r-tauopathies)

Related Mechanism Pages

• [Tau Pathology Mechanisms](/mechanisms/tau-pathology)
• [Autophagy-Lysosomal Pathway](/mechanisms/autophagy-lysosomal-pathway)
• [Mitochondrial Dysfunction in Neurodegeneration](/mechanisms/mitochondrial-dysfunction)
• [ER Stress in Neurodegeneration](/mechanisms/er-stress-pathway)

Related Clinical Trials

• [Neflamapimod PSP Trial](/clinical-trials/neflamapimod-psp)
• [Bepranemab PSP Trial](/clinical-trials/bepranemab-psp-phase-2-nct05318985)
• [ROCK Inhibitor Fasudil Trial](/clinical-trials/rock-inhibitor-fasudil-psp-cbs-nct04734379)

Related Therapeutics

• [Tau-Targeted Therapeutics](/therapies/tau-targeted-therapeutics)
• [Disease-Modifying Therapies](/therapies/disease-modifying)
• [Mitochondrial Protectors](/therapies/mitochondrial-protectors)

External Links

• [ClinicalTrials.gov: NCT06122662](https://clinicaltrials.gov/study/NCT06122662)
• [Amylyx Pharmaceuticals](https://www.amylyx.com)
• [FDA Approval Announcement for Relyvrio](https://www.fda.gov/drugs/news-events-human-drug-alerts/fda-approves-new-drug-treatment-amyotrophic-lateral-sclerosis-als)

References

Related Hypotheses

From the [SciDEX Exchange](/exchange) — scored by multi-agent debate

• [Aquaporin-4 Polarization Rescue](/hypothesis/h-c8ccbee8) — <span style="color:#81c784;font-weight:600">0.67</span> · Target: AQP4
• [Microglial Purinergic Reprogramming](/hypothesis/h-5daecb6e) — <span style="color:#81c784;font-weight:600">0.66</span> · Target: P2RY12
• [Sphingolipid Metabolism Reprogramming](/hypothesis/h-6657f7cd) — <span style="color:#81c784;font-weight:600">0.61</span> · Target: CERS2
• [Complement C1q Subtype Switching](/hypothesis/h-5a55aabc) — <span style="color:#ffd54f;font-weight:600">0.59</span> · Target: C1QA
• [Glial Glycocalyx Remodeling Therapy](/hypothesis/h-c35493aa) — <span style="color:#ffd54f;font-weight:600">0.58</span> · Target: HSPG2
• [Ephrin-B2/EphB4 Axis Manipulation](/hypothesis/h-e6437136) — <span style="color:#ffd54f;font-weight:600">0.56</span> · Target: EPHB4
• [Netrin-1 Gradient Restoration](/hypothesis/h-05b8894a) — <span style="color:#ffd54f;font-weight:600">0.44</span> · Target: NTN1

Related Analyses:

• [4R-tau strain-specific spreading patterns in PSP vs CBD](/analysis/SDA-2026-04-01-gap-005) &#x1f504;

Pathway Diagram

The following diagram shows the key molecular relationships involving AMX0035 for Progressive Supranuclear Palsy discovered through SciDEX knowledge graph analysis: