https://haematologica.org/article/view/12032
A phase I / IIa trial of PXS-5505, a novel pan-lysyl oxidase inhibitor, in advanced myelofibrosis
Hi all, as per SNT announcement let's bring it down to laypersons understandings.
What's being tested?A new drug called PXS-5505 (now called SNT-5505) that blocks lysyl oxidase (LOX) enzymes - proteins that act like "glue" to stiffen scar tissue in bone marrow.
Unlike existing treatments that only address symptoms, this drug aims to reverse fibrosis (scarring) at its source.Who’s in the trial?
Patients with advanced myelofibrosis (a bone marrow cancer causing severe scarring) who
on’t respond to standard JAK inhibitor drugs (like ruxolitinib)Can’t tolerate existing therapies due to side effectsHave limited treatment options and short life expectancy (~1 year)
Key findings so far:Safety: No serious side effects directly linked to PXS-5505.Fibrosis Improvement:60% showed reduced scarring in bone marrowStable collagen levels even in long-term treatmentSymptom Relief:80% of patients had better quality of life (reduced fatigue, pain)
Stable blood counts (critical for avoiding transfusions)
Why this matters:
Myelofibrosis patients currently have no anti-scarring drugs available. If approved, PXS-5505 could become the first treatment targeting the root cause rather than just symptoms.
What’s next?The drug is now being tested in combination with ruxolitinib (current standard therapy) to see if dual action against both inflammation (JAK) and scarring (LOX) works better.
Results will be presented at the EHA 2025 conference.
Science simplified:
Think of bone marrow as a sponge. In myelofibrosis, the sponge gets clogged with scar tissue (like hardened glue). PXS-5505 works by dissolving that glue, potentially restoring the sponge’s ability to make healthy blood cells.
If Phase 3 replicates Phase 2’s safety and fibrosis-modifying activity, FDA approval is probable, particularly given its orphan status and mechanistic novelty. However, survival data and durability of response (beyond 52 weeks) would further de-risk regulatory decisions.
Ok a detailed analysis
Mechanism of ActionTarget: Pan-lysyl oxidase (LOX) inhibitor (LOX, LOXL1-4).
Function: Blocks copper-dependent amine oxidase activity, preventing collagen/elastin cross-linking in the extracellular matrix (ECM).
Rationale: Myelofibrosis (MF) is driven by LOX-mediated ECM stiffening, impairing hematopoiesis.Clinical Trial Design (PXS5505-MF-101)Phase: 1/2a open-label study.Population
ose Escalation Phase (DEP): Established 200 mg BID as the maximum tolerated dose.
Cohort Expansion Phase (CEP): 24 relapsed/refractory MF patients (median age 72; 54% completed 24 weeks).Endpoints
rimary: Safety, tolerability, pharmacokinetics.Secondary:Bone marrow (BM) collagen reduction (trichrome staining)
Symptom improvement (MF-SAF TSS)Spleen volume reduction (MRI/CT).Key FindingsSafety:No dose-limiting toxicities or treatment-related SAEs.Steady-state plasma concentrations achieved by Day 28.
Efficacy:BM Fibrosis: Collagen content reduction observed in 60% of patients (qualitative histopathology).Symptom Burden:Stable hemoglobin/platelet counts (no JAK inhibitor-induced cytopenias).
Preliminary TSS improvements (quantitative data not disclosed).LOX Inhibition: Robust systemic enzyme activity reduction confirmed.Preclinical ValidationPancreatic Cancer
XS-5505 reduced tumor desmoplasia, improved gemcitabine perfusion, and extended survival in KPC mice (median survival: 171 vs. 125 days; p=0.0338).
Decreased collagen cross-linking and stiffness in human PDX models.Systemic Fibrosis:Attenuated dermal thickness in scleroderma models (p<0.05).Reduced pulmonary fibrosis (bleomycin model) and cardiac/kidney/liver fibrosisScientific ContextLOX in MF Pathogenesis:
Upregulated in MF BM stroma, driven by megakaryocyte-derived TGF-β.Cross-links collagen I/III, creating a pro-fibrotic niche.Therapeutic Gap: JAK inhibitors (ruxolitinib) alleviate symptoms but do not reverse fibrosis .
Next StepsPhase 2 Combination Trial: PXS-5505 + ruxolitinib (NCT04676529) to assess synergy.
Biomarkers:Serum PRO-C3 (collagen III formation marker)LOX activity assays (plasma/tissue).Phase 3 Endpoints: Likely to include BM fibrosis reversal (≥1-grade improvement) and progression-free survival.
Competitive AdvantagesDisease Modification: Unlike JAK inhibitors, targets ECM remodeling.Safety: No myelosuppression (vs. anemia/thrombocytopenia with ruxolitinib).
Broad Applicability: Preclinical efficacy in pancreatic cancer and systemic fibrosis.RisksHeterogeneous Response: Fibrosis reversal may require prolonged treatment (>24 weeks).
Biomarker Limitations: Current histopathology grading (WHO criteria) lacks sensitivity for early ECM changes.Regulatory PathwayOrphan Drug Designation:
Accelerated approval possible with fibrosis reversal as a surrogate endpoint.Breakthrough Therapy: Potential if Phase 3 demonstrates TSS50 + SVR35 + collagen reduction.
Kpax ( can't get rid of the memes apologies)
