Background: Crizanlizumab is a novel inhibitor of P-selectin, a key player in multicellular adhesion and inflammatory signaling, that leads to vaso-occlusion in sickle cell disease (SCD)., Objectives: The SOLACE-adults study evaluated the pharmacokinetics, pharmacodynamics (P-selectin inhibition), safety, and efficacy of crizanlizumab, with or without hydroxyurea/hydroxycarbamide, in patients with SCD., Design: Phase II, single-arm, multicenter study., Methods: Patients with SCD aged 16-70 years, with ⩾1 vaso-occlusive crisis (VOC) within 12 months before screening, received crizanlizumab 5.0 or 7.5 mg/kg intravenous infusion every 4 weeks; dose groups were enrolled sequentially., Results: Of 57 patients enrolled, 45 received crizanlizumab 5.0 mg/kg and 12 received 7.5 mg/kg for a median duration of 206 and 170 weeks, respectively. Crizanlizumab concentrations reached maximum levels after a 30-min infusion and remained steady for 6 h, without significant accumulation. P-selectin inhibition was nearly complete for both doses. The median (interquartile range) absolute change in the annualized rate of VOCs leading to healthcare visit from baseline was -0.79 (-3.04, 2.01) in the 5.0 mg/kg group and -0.98 (-1.11, -0.41) in the 7.5 mg/kg group. All patients experienced at least one adverse event (AE), with no apparent differences between the two doses in the frequency and severity of AEs. Grade ⩾3 AEs occurred in 60% of the 5.0 mg/kg group and 58% of the 7.5 mg/kg group. Two patients in the 5.0 mg/kg group and one in the 7.5 mg/kg group had severe crizanlizumab-related infusion-related reactions, which resolved with treatment. No patients developed antibodies against crizanlizumab., Conclusion: Crizanlizumab 5.0 and 7.5 mg/kg demonstrated a dose-proportional increase in exposure, sustained P-selectin inhibition, a tolerable safety profile, and a sustained reduction in VOCs leading to healthcare visit. This suggests that crizanlizumab is a useful treatment option for patients with SCD who have experienced VOCs., Trial Registration: NCT03264989., Competing Interests: J.K. reports receipt of research funding from NHLBI, BEAM, Bluebird Bio, CDC, HRSA, Novartis, Novo Nordisk, and Takeda; consultancy for Austin Pharmaceuticals, Bausch, BEAM, Bluebird Bio, ECOR-1, Fulcrum, Novartis, and Watkins, Lourie, Roll & Chance; membership on an entity’s Board of Directors or advisory committees with Austin Pharmaceuticals, Bluebird Bio, Ciesi, Glycomimetics, and Novartis; and honoraria from Guidepoint Global; D.M. reports consultancy from Editas, GBT, Novartis, Novo Nordisk, and Pfizer; A.K. reports receipt of research funding from Akira Bio, Forma/Novo-Nordisk, GBT/Pfizer, and Novartis; consultancy for Novartis; membership on an entity’s Board of Directors or advisory committees with Bluebird Bio, GBT/Pfizer, and Novartis; and event adjudication committee (EAC) Chair for Vertex; N.S. reports receipt of research funding from GBT/Pfizer; consultancy for Agios Pharmaceuticals, Bluebird Bio, Forma, GBT/Pfizer, and Vertex; and speaker bureau for Alexion Pharmaceuticals and GBT/Pfizer; D.L. reports clinical trial activity as principal investigator or sub-investigator for Annexon Biosciences Inc., Baxalta, BeiGene Ltd., Bioverativ Inc., Celgene, Delta, Exact Sciences, Janssen Research and Development, Immunovant Inc., Incyte Corp., Novartis, Partner Therapeutics, Principia Biopharma Inc., Sanofi-Aventis LLC, Takeda, and Vifor Pharma; D.K., M.N., and E.R. are employees of Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA; H.M. is an employee of Novartis Healthcare Private Limited, Hyderabad, India; and A.E.M. is an employee of BioMedical Research, Cambridge, MA, USA; S.M. and S.M.N. have nothing to disclose., (© The Author(s), 2024.)