Inclacumab
Inclacumab is an investigational monoclonal antibody originally developed by Roche for cardiovascular disease and later acquired by Global Blood Therapeutics, 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 -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 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 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 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 and peak troponin I reduced by 23.8%. 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.
Sickle cell disease studies
P-selectin-mediated platelet-leukocyte aggregate 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.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 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.