Matisse Pharma’s histone-neutralizing polyanion takes FDA Fast Track designation for sepsis

Edited by Robert McTiernan··3 min read

Netherlands-based Matisse Pharmaceuticals B.V. announced receipt of US FDA Fast Track Designation for isupartob sodium, a histone-neutralizing synthetic polyanion, for the treatment of sepsis. The designation follows IND clearance for the compound announced on May 19, 2026, and marks the first expedited regulatory recognition for Matisse’s lead program.

Fast Track Designation, granted to therapies addressing serious conditions with significant unmet medical need, confers eligibility for rolling NDA submission, more frequent FDA interaction during development, and potential eligibility for Priority Review and Accelerated Approval. No prior expedited designations have been disclosed for isupartob sodium.

Isupartob sodium works through electrostatic neutralization: the compound’s highly negatively charged structure binds circulating positively charged extracellular histones released by the innate immune system during sepsis. These histones are cytotoxic to endothelial cell membranes and initiate a self-reinforcing cascade of cell death, inflammation, and progressive organ failure. By binding and neutralizing these histones upstream in the inflammatory response, isupartob aims to interrupt that cascade before irreversible organ damage occurs.

The most detailed public clinical evidence predating this designation comes from a Phase I first-in-human study — published in a peer-reviewed paper indexed on PubMed (PMID: 40824474) — evaluating isupartob sodium (then designated M6229) in ten critically ill sepsis patients in the ICU at Amsterdam University Medical Center. The study’s primary endpoints of safety and tolerability were met: the drug was deemed safe following a six-hour continuous intravenous infusion. Pharmacokinetics were reported as close to dose-proportional during prolonged infusion, supporting Phase II dose selection. Pharmacodynamic data suggested intravascular neutralization of extracellular histones, consistent with the proposed mechanism. Specific quantitative biomarker reductions and full PK parameters were not disclosed in the publicly available abstract.

The IND clearance and Fast Track Designation together confirm the FDA found the Phase I data package sufficient to support clinical advancement, but the development timeline beyond IND stage has not been disclosed.

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Research context

Sepsis kills an estimated 11 million people annually from approximately 49 million cases worldwide, and accounts for more than 20% in-hospital mortality. Children under five represent roughly 40% of cases, with close to three million pediatric deaths each year. A 2020 analysis by Buchman et al. in Critical Care Medicine identified sepsis as the most common cause of in-hospital deaths in the US, with costs exceeding USD 62 billion annually. Despite this burden, no targeted therapy addressing the dysregulated host immune response has received regulatory approval from the FDA, EMA, or any comparable authority.

The competitive landscape for sepsis therapeutics has seen repeated late-stage failures. Earlier attempts to target specific cytokines — including TNF-alpha and IL-1 — did not produce approved therapies. More recently, companies including Asahi Kasei and AM-Pharma have explored cytoprotective and anti-inflammatory approaches, and Adrenomed has investigated adrecizumab, targeting adrenomedullin in septic shock. None have reached approval. Isupartob sodium’s mechanism — upstream histone neutralization — is mechanistically distinct from those previous efforts.

Heparin, which also carries a negative charge and has demonstrated some histone-binding capacity in preclinical models, has been studied in sepsis, but its anticoagulant properties limit dosing in critically ill patients. The Phase I publication for isupartob sodium specifically describes it as a “low-anticoagulant heparin,” suggesting the compound retains electrostatic histone-binding activity while reducing bleeding risk — a potential differentiator relative to unmodified heparin in this population.

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