Pharmacokinetics, pharmacodynamics, safety, and efficacy of crizanlizumab in patients with sickle cell disease

Abstract

Crizanlizumab is an anti-P-selectin monoclonal antibody indicated to reduce the frequency/prevent recurrence of vaso-occlusive crises (VOCs) in patients with sickle cell disease (SCD) aged ≥16 years. This analysis of an ongoing phase 2, nonrandomized, open-label study reports the pharmacokinetics (PK), pharmacodynamics (PD), safety, and efficacy of crizanlizumab 5.0 mg/kg (N = 45) and 7.5 mg/kg (N = 12) in patients with SCD with a history of VOCs. The median treatment duration was 104.7 and 85.7 weeks in the 5.0 and 7.5 mg/kg groups, respectively. For both doses, serum crizanlizumab concentrations rose to near maximum levels shortly after infusion, and near complete and sustained ex vivo P-selectin inhibition was observed. Grade ≥3 adverse events (AEs) occurred in 48.9% and 33.3% of patients in the 5.0 and 7.5 mg/kg groups, respectively; only 1 event was deemed treatment-related (7.5 mg/kg group). No treatment-related serious AEs occurred. One infusion-related reaction was recorded (5.0 mg/kg, grade 2 "pain during infusion"), which resolved without treatment withdrawal. Infections occurred in 57.8% and 41.7% of patients in the 5.0 and 7.5 mg/kg groups, respectively; none were drug-related. No treatment-related bleeding events were reported. No patients developed immunogenicity. The median (range) absolute reduction from baseline in the annualized rate of VOCs leading to a health care visit was -0.88 (-14.7 to 13.3) and -0.93 (-2.0 to 0.4) in the 5.0 and 7.5 mg/kg groups, respectively. Results here demonstrate the PK/PD properties of crizanlizumab in patients with SCD and the potential sustained efficacy and long-term safety of the drug after >12 months' treatment. This trial was registered at www.clinicaltrials.gov as #NCT03264989.

Trial registration: ClinicalTrials.gov NCT03264989 NCT01895361.

Graphical abstract

Figure 1.

SOLACE-adults study design. HC, hydroxycarbamide.

Figure 2.

Serum concentration-time profiles for crizanlizumab. Mean and median serum concentration-time profiles for the crizanlizumab 5.0 and 7.5 mg/kg dose groups at starting dose (A) and steady state (PAS2) (B).

Figure 3.

Serum PD-time profiles for crizanlizumab. Mean and median serum PD-time profiles for the crizanlizumab 5.0 and 7.5 mg/kg dose groups at starting dose (A) and steady state (PDS2) (B).

Figure 4.

Predose serum concentration-time and serum PD-time profiles for crizanlizumab. Mean and median predose serum concentration-time (A) and serum PD-time profiles (B) for crizanlizumab 5.0 and 7.5 mg/kg (PAS2 and PDS2, respectively).