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Pyro-PPAR

Lanifibranor + Diroximel Fumarate for Pyroptosis-High MASH

F2-F3 MASH (NASH)Fixed-Dose Combination
Precision pyroptosis-targeting

Overview

Even with resmetirom and GLP-1s, residual fibrotic risk remains in MASH, especially in inflammasome/pyroptosis-high patients. NLRP3 inflammasome activation triggers caspase-1 cleavage of GSDMD, executing pyroptosis and propagating stellate-cell fibrogenesis.

Unmet Medical Need

Address residual unmet need despite emerging standards (resmetirom, GLP-1s) by targeting pyroptosis—a root inflammatory driver of fibrosis—in 'pyroptosis-high' patients.

Therapeutic Hypothesis

Fixed-dose combo: Lanifibranor (pan-PPAR) for metabolic and direct antifibrotic effects. DRF→MMF fumarate to block NLRP3–caspase-1–GSDMD pyroptosis via GSDMD succination. Precision strategy in pyroptosis-high subgroup (high plasma GSDMD-N, IL-1β/IL-18).

Computational Work Performed

  • Bliss/Loewe synergy models and SynergyFinder consensus scoring
  • PK framework for DRF→MMF using FDA NDA clinical pharmacology
  • QD enteric/SR DRF profile design: AUC-match BID with ≥30% Cmax reduction
  • CMC risk assessment for acid-catalyzed ester hydrolysis
  • Physically segregated FDC design (bilayer/capsule with barrier excipients)

Next Milestones (Success Criteria)

  • 1
    In-vitro synergy (Bliss/Loewe) on IL-1β/GSDMD-N and Pro-C3/COL1A1
  • 2
    Forced-degradation compatibility per ICH Q1A(R2)
  • 3
    AMLN mouse study: QD DRF AUC-match with ≥30% Cmax reduction vs BID
  • 4
    Fibrosis benefit over monotherapies with GSDMD-N/Pro-C3 alignment

Competitive Landscape

Resmetirom (THR-β) approved for F2-F3. Semaglutide/Wegovy accelerated approval for MASH (2025). FGF21 analogs (efruxifermin, pegozafermin) in late-stage. Selective NLRP3 inhibitors under development.

Key Differentiation

  • First precision strategy enriching for 'pyroptosis-high' MASH
  • Pairs antifibrotic metabolic backbone with direct pyroptosis blocker
  • Direct PD markers (GSDMD succination/2-SC mapping) for clean signal

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