Rationale and Design of a Phase II Open-Label, Multicenter Study to Assess the Pharmacokinetics and Pharmacodynamics of Crizanlizumab in Adult Patients with Sickle Cell Disease

Background: Crizanlizumab, a P-selectin inhibitor, was shown to be effective, at a dose of 5.0 mg/kg, for the prevention of vaso-occlusive crises (VOCs) in patients with sickle cell disease (SCD) in the Phase II, randomized, placebo-controlled SUSTAIN study (Ataga KI et al. New Engl J Med 2017;376:429-39). A Phase I study evaluated the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of crizanlizumab manufactured using the SelG1 cell line in healthy volunteers (Stocker JW et al. Blood 2013;122:970). A new cell line (SEG101) has now been developed, and additional PK and PD data are required to assess crizanlizumab produced using this cell line, and to confirm the recommended dose.

Objective: To describe a planned study designed to characterize the PK and PD (ie P-selectin inhibition) profiles of crizanlizumab 5.0 mg/kg, manufactured using the SEG101 cell line, and to provide additional data on the efficacy, safety and immunogenicity of crizanlizumab, in patients with SCD. The study will also evaluate crizanlizumab 7.5 mg/kg, also manufactured using the SEG101 cell line, for the first time in a clinical setting.

Methods: This Phase II open-label, single-arm, multicenter study will be conducted in approximately 20 sites in the USA. To identify at least 27 patients with evaluable PK/PD data, up to 45 patients will be enrolled and will receive crizanlizumab 5.0 mg/kg; subsequently, 10 additional patients will be enrolled (to identify at least 6 evaluable patients) to receive crizanlizumab 7.5 mg/kg as an exploratory objective. Patients aged 18-70 years with SCD of any genotype, and who have experienced at least one VOC in the year prior to study entry, will be eligible for inclusion. Concomitant use of hydroxyurea will only be permitted if the patient has been using it for ≥6 months and plans to continue at a stable dose and schedule for the duration of the study. Crizanlizumab will be administered in the clinic by intravenous infusion every 4 weeks, with an additional loading dose after the first 2 weeks, for at least 2 years or until discontinuation. Dose interruptions and dose reductions (from 7.5 mg/kg to 5.0 mg/kg only) will be allowed if necessary for safety reasons. All patients will undergo complete PK/PD and immunogenicity sampling when they receive the first dose (week 1, day 1: pre-dose to 24 hours post-dose, and on days 4, 8 and 15) and fifth dose (week 15, day 1: pre-dose to 24 hours post-dose, and on days 4, 8, 15, 22 and 29 thereafter). Pre-dose PK, PD and immunogenicity assessments will be performed at each additional study visit until week 51; from week 51, immunogenicity assessments will be performed every 24 weeks. The final safety follow-up visit will take place 105 days after the last dose of study treatment. An interim analysis will be performed when there are at least 27 patients in the crizanlizumab 5.0 mg/kg group with single-dose evaluable PK profiles, at least five of whom have single- and multiple-dose evaluable PK profiles.

Results: The primary objective is to characterize the PK/PD profile of crizanlizumab 5.0 mg/kg using: area-under-the-curve (AUC) to day 15, steady-state AUC calculated to the end of a dosing interval, and maximum observed drug concentration (C_max) as PK parameters; and AUC for P-selectin inhibition to day 15 and at steady state as PD parameters. Other PK (eg time to C_max and half-life) and PD (eg P-selectin inhibition at each time point and P-selectin inhibition time profiles) parameters will be analyzed as secondary variables. The secondary objectives are to assess the efficacy, safety and tolerability of crizanlizumab. Efficacy will be assessed by summarizing the number of VOCs overall, by including healthcare visit and home management, and by subcategory (ie uncomplicated pain crisis, acute chest syndrome, hepatic sequestration, splenic sequestration, priapism). Hospitalizations and emergency room visits will also be evaluated. Safety will be assessed by summarizing adverse events (using the Common Terminology Criteria for Adverse Events version 4.03), laboratory evaluations and vital signs. Immunogenicity will be characterized based on the prevalence of antidrug antibody at baseline and on-treatment.

Conclusion: This study will provide further data on the PK/PD profile, efficacy, safety and immunogenicity of crizanlizumab 5.0 mg/kg, and will provide the first clinical data for crizanlizumab 7.5 mg/kg, in adult patients with SCD who have a recent history of VOC.