Trial in Progress: The Randomized, Double-Blind, Placebo-Controlled Phase Ib CROSSWALK-a Trial Evaluating the Safety of Crovalimab for the Management of Acute Uncomplicated Vaso-Occlusive Episodes (VOEs) in Patients with Sickle Cell Disease (SCD)

Background

SCD is a group of autosomal recessive red blood cell (RBC) disorders caused by a single point mutation in the β-globin gene, resulting in the production of hemoglobin S. Hemoglobin S polymerizes within RBCs under certain conditions, leading to the distortion of the RBC membrane and generation of dense and sickle RBCs. These pathologic RBCs contribute to microvascular occlusions in patients with SCD, which present as acute painful episodes called VOEs. Despite the majority of VOEs being managed at home, they remain the most common reason for emergency department (ED) visits and hospitalization among patients with SCD, with > 70% of ED visits and > 90% of hospital admissions for SCD being related to VOEs (Ballas et al. Am J Hematol 2005; Lanzkron et al. Am J Hematol 2010). One of the most severe complications of VOEs is acute chest syndrome, which is a leading cause of mortality among patients with VOEs (Vichinsky et al. N Engl J Med 2000; Bartolucci et al. eBioMedicine 2016). In the absence of targeted therapies for the management of VOEs in patients with SCD, treatment is currently limited to pain management, blood exchange transfusion (with the risk of complications), and other supportive care, representing a significant unmet medical need. Activation of the complement pathway has been described in patients with SCD at baseline, in acute pain crises, and in patients with delayed hemolytic transfusion reaction. Accumulating nonclinical data have suggested a multimodal role for complement dysregulation in the pathophysiology of SCD including vaso-occlusion, hemolysis, inflammation, thrombogenicity, endothelial activation, and end-organ damage (Roumenina et al. Am J Hematol 2020). Crovalimab is a novel, engineered, anti-complement C5 monoclonal antibody. In a Phase I/II study (Röth et al. Blood 2020) in patients with paroxysmal nocturnal hemoglobinuria, a complement-mediated disorder, crovalimab demonstrated rapid and sustained complement inhibition with promising efficacy and safety.

Study Design and Methods

CROSSWALK-a (NCT04912869) is a randomized, double-blind, placebo-controlled, Phase Ib study evaluating the safety of crovalimab for the management of acute uncomplicated VOEs in patients with SCD. Patients aged ≥ 12 years to ≤ 55 years, weighing ≥ 40 kg, and with a confirmed diagnosis of SCD homozygous hemoglobin S (HbSS) or sickle cell β ⁰ thalassemia (HbSβ ⁰) are eligible for the study (Figure). Patients must present with an acute uncomplicated VOE, requiring hospitalization and treatment with parenteral opioid analgesics. Vaccinations against Neisseria meningitidis, Hemophilus influenzae type B, and Streptococcus pneumoniae must be up to date. Eligible patients will be randomized 2:1 to receive either a single intravenous weight-based tiered dose of crovalimab or placebo. Patients in both study arms will continue to undergo pain management and receive other supportive care for their VOE and may also continue to receive ongoing concurrent SCD-directed therapies. Patients will be followed during the hospitalization until discharge and will continue to be followed post-discharge during an observational period. The maximum total study duration for an individual patient will be 12 weeks, which includes the hospitalization and observational periods. The primary objective is to evaluate the incidence and severity of adverse events according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0, incidence and severity of infusion-related reactions and hypersensitivity, and change from baseline in targeted vital signs and clinical laboratory test results. Efficacy, pharmacokinetics, pharmacodynamics, immunogenicity, and exploratory biomarker endpoints will also be evaluated.

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