Pharmacokinetics/Pharmacodynamics, Safety and Efficacy of Crizanlizumab in Patients with Sickle Cell Disease and a History of Vaso-Occlusive Crises: Results from the Phase II, Multicenter, Open-Label Solace-Adults Study

Background: SCD is an inherited blood disorder characterized by hemolytic anemia, endothelial damage and acutely painful VOCs that cause chronic and potentially life-threatening complications. P-selectin is an adhesion protein that plays a key role in the multicellular interactions leading to a VOC. The Phase II SUSTAIN study showed that crizanlizumab (SelG1), a humanized monoclonal anti-P-selectin antibody, reduced the annualized rate of VOCs leading to a healthcare visit by 45.3% vs placebo (P=0.01) in SCD patients (pts) [Ataga K et al. N Engl J Med 2017]. Aims: To evaluate the pharmacokinetics (PK) and pharmacodynamics (PD; ex vivo P-selectin inhibition) of crizanlizumab (SEG101), as well as safety and efficacy in SCD pts with a history of VOCs. Methods: SOLACE-adults is a Phase II, multicenter, open-label PK-PD study that enrolled SCD pts aged 16-70 years who had experienced ≥1 VOC in the 12 months prior to study start (NCT03264989). Pts received crizanlizumab by intravenous infusion over 30 minutes at 5.0 mg/kg or 7.5 mg/kg on: Week 1, Day 1 (Wk1D1); Wk3D1; and then on D1 of every 4-wk cycle. PK and PD assessments were performed in all pts pre- and post-dose on days 1, 2, 4, 8, and 15 of the first dose (Wk1D1) and then on days 1, 2, 4, 8, 15, 22 and 29 of the fifth dose (Wk15D1). Adverse events (AEs) were evaluated based on MedDRA v22.1 and AE severity based on CTCAE v5.0. Pts were continuously monitored for VOCs, with the relevant medical and treatment information collected in case of occurrence. Results: A total of 57 pts were enrolled: 45 received crizanlizumab 5.0 mg/kg (female, n=25 [56%]; mean [SD] age, 32 [13] years) for a median of 65 (range, 6-90) wks and 12 received 7.5 mg/kg (female, n=6 [50%]; mean [SD] age, 27 [12] years) for a median of 43 (range, 9-49) wks. In the 5.0 and 7.5 mg/kg arms, respectively, 6 (13%) and 2 (17%) pts discontinued treatment, primarily because of patient decision (n=4; 9%) in the 5.0 mg/kg arm and because of death and AE (both n=1; 8%) in the 7.5 mg/kg arm. The most common AEs were headache (5.0 mg/kg, n=11 [24%]; 7.5 mg/kg, n=3 [25%]) and pyrexia (5.0 mg/kg, n=9 [20%]; 7.5 mg/kg, n=2 [17%]). Grade ≥3 AEs occurred in 18 (40%) pts in the 5.0 mg/kg arm and in 2 pts (17%) in the 7.5 mg/kg arm. Serious AEs were reported in 11 pts (24%) in the 5.0 mg/kg arm and in 1 pt (8%) in the 7.5 mg/kg arm; none were deemed drug-related. One pt in each of the 5.0 (2%) and 7.5 mg/kg (8%) arms discontinued treatment because of AEs.