5572697 trials in progress: the thrive studies evaluating the efficacy, safety, and long-term treatment with inclacumab, a p-selectin inhibitor, in patients with sickle cell disease

Background: Sickle cell disease (SCD) is an autosomal recessive red blood cell (RBC) disorder caused by a single point mutation in the β-globin gene, resulting in the production of hemoglobin S. Hemoglobin S polymerization within deoxygenated RBCs contributes to hemolysis, anemia, vaso-occlusion, and end-organ damage. Additionally, abnormal heterocellular adhesive interactions between RBCs and endothelial cells, leukocytes, and platelets play a central role in triggering painful vaso-occlusive crises (VOCs) in patients with SCD. Inclacumab is a recombinant, fully human monoclonal antibody directed against human P-selectin, a cell adhesion molecule produced by endothelial cells and platelets. Inclacumab interferes with the adhesion of sickle RBCs, platelets, and leukocytes to endothelium by binding P-selectin and preventing P-selectin binding to its ligands. This is the putative mechanism by which inclacumab may potentially reduce the incidence of VOCs. Aims: We aim to conduct two global, multicenter, phase 3 studies and an open-label extension (OLE) study to evaluate the safety and efficacy of inclacumab in individuals with SCD. Methods: THRIVE-131 (NCT04935879) is a randomized, double-blind, placebo-controlled, multicenter trial in which ~240 participants aged ≥12 years experiencing 2 to 10 VOCs in the previous 12 months will be randomized 1:1 to receive intravenous (IV) inclacumab or placebo every 12 weeks for 48 weeks (Figure). The primary endpoint is the rate of VOCs during the 48-week treatment period. THRIVE-132 (NCT04927247) is a randomized, double-blind, placebo-controlled, multicenter trial in which ~280 participants aged ≥12 years experiencing 2 to 10 VOCs in the previous 12 months will be randomized 1:1 to receive a single dose of IV inclacumab or placebo within 5 days of resolution of an index VOC that required admission to a healthcare facility and treatment with parenteral pain medication. The primary endpoint is the proportion of participants with readmission for a VOC within 90 days of randomization. After completion of their participation in THRIVE-131 or THRIVE-132, participants may enroll in THRIVE-133 OLE, in which the long-term safety of inclacumab will be investigated. In THRIVE-133 OLE, participants will receive IV inclacumab every 12 weeks as long as the clinical benefit of treatment outweighs the risk and until access to inclacumab from an alternative source (eg, through commercialization or a managed-access program) becomes available. Results: Recruiting for both THRIVE-131 and THRIVE-132 began in October 2021 and is ongoing. Summary – Conclusion: The THRIVE-131 and THRIVE-132 phase 3 studies will examine the efficacy of inclacumab in reducing the frequency of VOCs and readmissions due to VOCs, and the THRIVE-133 OLE study will examine the long-term safety of inclacumab in individuals with SCD. Funding: These studies are supported by Global Blood Therapeutics. Figure: Designs of the THRIVE StudiesReferences 1. Kato, GJ, Piel, FB, Reid, CD, et al. Sickle Cell Disease. Nat Rev Dis Primers. 2018;4(18010). 2. Ware RE, de Montalembert M, Tshilolo L, Abboud MR. Sickle cell disease. Lancet. 2017;390(10091):311-323. 3. Ataga, KI, Kutlar, A, Kanter, J, et al. Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease. N Engl J Med. 2017;376(5):429-439. 4. Morrison, M, Palermo, G, Schmitt, C. Lack of ethnic differences in the pharmacokinetics and pharmacodynamics of inclacumab in healthy Japanese and Caucasian subjects. Eur J Clin Pharmacol. 2015;71(11):1365-1374. 5. Kling, D, Stucki, C, Kronenberg, S, et al. Pharmacological control of platelet-leukocyte interactions by the human anti-P-selectin antibody inclacumab – preclinical and clinical studies. Thromb Res. 2013;131(5):401-410. 6. Schmitt, C, Abt, M, Ciorciaro, C. First-in-Man Study With Inclacumab, a Human Monoclonal Antibody Against P-Selectin. J Cardiovasc Pharmacol. 2015;65(6):611-619.