ABX-TEL
Ambroxol + Telmisartan FDC for Multiple System Atrophy
Overview
Multiple System Atrophy is an α-synucleinopathy with oligodendroglial inclusions, demyelination, and BBB dysfunction. No disease-modifying therapy exists. The disease involves autophagy dysfunction, oxidative stress, and calcium dysregulation.
Unmet Medical Need
No disease-modifying therapy for MSA. Need for dual attack on lysosomal proteostasis and neurovascular unit dysfunction.
Therapeutic Hypothesis
Once-daily FDC: Sustained-release ambroxol to chaperone GCase → improved lysosomal function, reduced α-syn. pH-independent IR telmisartan (CNS-penetrant ARB/PPAR-γ agonist) to stabilize BBB and damp microglial/astroglial inflammation.
Computational Work Performed
- PBPK modeling with CNS Kp,uu,brain for both drugs
- GI/absorption modeling for SR ambroxol sustained CSF exposure
- ASD + micro-pH control design for telmisartan
- Formulation compatibility analysis
Next Milestones (Success Criteria)
- 1In-vitro: Ambroxol in iPSC-oligos (↑GCase, ↓pS129-α-syn)
- 2Telmisartan in BBB tri-culture (↑TEER, ↓permeability, ↓cytokines)
- 3Combo superiority on TEER and cytokines
- 4PLP-α-syn model: DCE-MRI Ktrans, plasma NfL, brain GCase/α-syn
- 5Compare combo vs single agents on glial and BBB markers
Competitive Landscape
No approved disease-modifying therapies for MSA. Supportive care is the current standard. Some lysosomal-targeted therapies being explored in related synucleinopathies.
Key Differentiation
- First rationale-based FDC targeting both lysosomal and neurovascular dysfunction
- Dual mechanism: GCase chaperone + BBB stabilization/PPAR-γ agonism
- Uses repurposed, well-characterized drugs with known safety profiles
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