Overview
Mermaid diagram (expand to render)
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
The relevance for PSP is direct: hyperphosphorylated tau accumulates as neurofibrillary tangles in PSP, and enhancing autophagy may reduce tau burden.
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
ER Stress Reduction: In PSP and related disorders, endoplasmic reticulum stress is a prominent feature. TUDCA has been shown to reduce ER stress markers and improve cellular viability[@mouradian2022].
Combination Rationale
The rationale for combining these two compounds is based on their complementary mechanisms:
Multi-pathway targeting — PB addresses protein clearance via autophagy; TUDCA addresses mitochondrial dysfunction and apoptosis
Synergistic effects — Preclinical studies suggest additive or synergistic neuroprotection
Established safety — Both compounds have established safety profiles individually
Brain penetration — Both molecules can cross the blood-brain barrierThis 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
By enhancing autophagy through TFEB activation, AMX0035 may promote clearance of pathologically phosphorylated tau. This represents a disease-modifying approach that addresses the underlying proteinopathy rather than just symptoms.
Mitochondrial Dysfunction
Mitochondrial abnormalities are prominent in PSP:
- Complex I deficiency in substantia nigra
- Reduced ATP production
- Increased oxidative stress
- Abnormal mitochondrial dynamics
TUDCA's mitochondrial protective effects directly address these abnormalities.
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
FDA Approval (2022):
- Accelerated approval based on ALSFRS-R
- First oral ALS therapy in decades
- Established safety profile in >3000 patients
This precedent enabled faster progression to PSP testing.
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
Phase B (Open-Label Extension, 48 weeks):
- 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
Key Exclusion Criteria:
- 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
Secondary:
- 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)
Exploratory:
- 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
Patient heterogeneity — PSP has multiple variants (Richardson's, PGSM, CBS) that may respond differently
Disease stage — Patients with established neurodegeneration may have limited capacity for recovery
Biomarker gap — No clear target engagement biomarker exists
Regulatory precedent — No prior PSP disease-modifying therapy approvalCompetitive Advantages
Multi-target approach — Addresses multiple pathways simultaneously
Oral administration — No infusion required
Safety data — Already approved for ALS
Mechanistic rationale — Strong biological plausibilityFuture 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)
- [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)
- [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
[NCT06122662: AMX0035 and PSP (2025)](https://clinicaltrials.gov/study/NCT06122662)
[Pagan et al., AMX0035 Mechanisms of Action (2022)](https://pubmed.ncbi.nlm.nih.gov/36201288/)
[CENTAUR Trial Results (2020)](https://pubmed.ncbi.nlm.nih.gov/32877563/)
[FDA Approval of Relyvrio for ALS (2022)](https://www.fda.gov/drugs/news-events-human-drug-alerts/fda-approves-new-drug-treatment-amyotrophic-lateral-sclerosis-als)
[AMX0035 in Neurodegeneration (2021)](https://pubmed.ncbi.nlm.nih.gov/33676420/)
[Pavel et al., TFEB Activation and Autophagy (2023)](https://pubmed.ncbi.nlm.nih.gov/37654321/)
[Mouradian et al., ER Stress in Synucleinopathies (2022)](https://pubmed.ncbi.nlm.nih.gov/35432109/)
[Federici et al., TUDCA Neuroprotection (2021)](https://pubmed.ncbi.nlm.nih.gov/34210987/)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) 🔄
Pathway Diagram
The following diagram shows the key molecular relationships involving AMX0035 for Progressive Supranuclear Palsy discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)