Inclacumab (also known as LC-1004-002, RO4905417, and PF-07940370) is an investigational monoclonal antibody originally developed by Roche for cardiovascular disease and later acquired by Global Blood Therapeutics (GBT), which was subsequently acquired by Pfizer in 2022 for $5.4 billion. It is a fully human monoclonal antibody against P-selectin being developed primarily for the treatment of sickle cell disease with vaso-occlusive crises.
Mechanism of action Inclacumab is a recombinant monoclonal antibody against P-selectin, with potential anti-inflammatory, antithrombotic, and antiatherogenic properties. P-selectin works to mediate leukocyte, platelet, and endothelial interactions through the binding of P-selectin to the P-selectin glycoprotein ligand (PSGL)-1 located on the surface of leukocytes. A crystal structure of inclacumab and P-selectin reveals that inclacumab directly binds to an epitope in the PSGL-1 binding region on P-selectin and thus competitively inhibits P-selectin and its ligand interaction.
Clinical development
Phase I studies This phase 1, open-label, single-ascending-dose study of inclacumab in healthy participants was conducted at a single clinical facility (Linear Clinical Research, Nedlands, Western Australia) between September 2020 and May 2021. Plasma PK parameters were generally dose-proportional, with a terminal half-life of 13 to 17 days. Inclacumab displayed a well-tolerated safety profile for up to 29 weeks following a single dose of 20 or 40 mg/kg in healthy subjects.
Cardiovascular studies The SELECT-ACS (Selective Antagonist of P-selectin for Ischemia Reperfusion) trial was a randomized, double-blind, placebo-controlled study that enrolled 544 patients with non-ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention. The study evaluated two doses of inclacumab (5 mg/kg and 20 mg/kg) compared to placebo. Results showed that inclacumab 20 mg/kg significantly reduced troponin I levels, with placebo-adjusted reductions of 24.4% at 24 hours (p=0.05) and peak troponin I reduced by 23.8% (p=0.05). Benefits were greater when administered within 3 hours before PCI. The SELECT-CABG trial evaluated inclacumab in patients undergoing coronary artery bypass graft surgery but failed to show significant differences in pre-specified secondary efficacy measures, with similar rates of major adverse cardiovascular events between placebo and inclacumab groups (13.9% vs 14.2%, p=0.88).
Sickle cell disease studies P-selectin-mediated platelet-leukocyte aggregate (PLA) formation has been shown to contribute to vaso-occlusion. The THRIVE clinical program consisted of three Phase 3 studies: THRIVE-131, THRIVE-132, and THRIVE-133 (open-label extension). THRIVE-131 was the pivotal Phase 3 efficacy study that enrolled participants aged ≥12 years with sickle cell disease experiencing 2-10 vaso-occlusive crises in the previous 12 months. The primary endpoint was the rate of VOCs during the 48-week treatment period with inclacumab administered every 12 weeks. The trial failed to meet its primary endpoint of significant reduction in the rate of vaso-occlusive crises compared to placebo, though the therapy was generally well tolerated. The study was subsequently discontinued in November 2025. THRIVE-132 (NCT04927247) was designed to evaluate the proportion of participants with readmission for a VOC within 90 days of randomization but was terminated due to slow patient recruitment.
Safety profile This selectivity is an essential safety requirement because blockade of P-selectin and E-selectin or of P-selectin and L-selectin results in an immunocompromised phenotype based on evidence from double-selectin knockout mice. Two inclacumab-related treatment-emergent adverse events were reported in 1 participant; no dose-limiting toxicities were observed.
Regulatory status Inclacumab was granted orphan drug and rare pediatric disease designations by the U.S. Food and Drug Administration (FDA) in 2022. The drug remains investigational and has not received regulatory approval for any indication. Following the failure of the THRIVE-131 Phase 3 trial to meet its primary endpoint, the future regulatory pathway remains uncertain.
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