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[1].
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.
| 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 |
AMX0035 represents a multi-target approach that combines two well-characterized compounds with complementary mechanisms:
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[2]. TFEB activation promotes:
The relevance for PSP is direct: hyperphosphorylated tau accumulates as neurofibrillary tangles in PSP, and enhancing autophagy may reduce tau burden.
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[3].
Anti-apoptotic Effects: TUDCA inhibits mitochondrial apoptosis pathways by:
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[4].
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.
PSP is classified as a 4-repeat (4R) tauopathy characterized by:
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 abnormalities are prominent in PSP:
TUDCA's mitochondrial protective effects directly address these abnormalities.
Both components of AMX0035 have anti-inflammatory properties:
The approval of AMX0035 (Relyvrio) for ALS in 2022 provides critical proof-of-concept:
CENTAUR Trial (Phase 2):
FDA Approval (2022):
This precedent enabled faster progression to PSP testing.
The ORION trial (A35-009) employs a rigorous design:
Phase A (Controlled, 48 weeks):
Phase B (Open-Label Extension, 48 weeks):
Key Inclusion Criteria:
Key Exclusion Criteria:
Primary:
Secondary:
Exploratory:
The success in ALS does not guarantee success in PSP, but the established safety profile and mechanistic rationale justify the trial.
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.
If successful, AMX0035 could be combined with:
Future trials may incorporate: