Trials in Progress: The Randomized, Double-Blind, Placebo-Controlled Phase 1b CROSSWALK-a and Phase 2a CROSSWALK-c Trials - Crovalimab for the Treatment and Prevention of Vaso-Occlusive Episodes in Sickle Cell Disease

Abstract

Background and Significance In sickle cell disease (SCD), a single point mutation in the beta-globin gene results in hemoglobin S (HbS) production, which can polymerize upon deoxygenation. Polymerization distorts the red blood cell (RBC) membrane and generates sickled RBCs, contributing to microvascular occlusions, which may present as acute, painful vaso-occlusive episodes (VOEs). For patients (pts) with SCD, 70% of emergency department visits and 90% of hospitalizations are VOE-related. 1,2 Despite existing treatments for VOE prevention, considerable morbidity and mortality remain; acute VOE treatment is limited to supportive care due to a lack of targeted therapies. Accumulating nonclinical data suggest a multimodal role for complement dysregulation in SCD pathophysiology, including in vaso-occlusion, hemolysis, inflammation, thrombogenicity, endothelial activation, and end-organ damage. 3 Crovalimab is a novel, engineered, anti-complement C5 monoclonal antibody that allows for small-volume subcutaneous (SC) injection after an initial intravenous (IV) loading dose. 4 Here, we describe two randomized, double-blind, placebo-controlled trials evaluating crovalimab in pts with SCD: CROSSWALK-a (Phase 1b; NCT04912869) and CROSSWALK-c (Phase 2a; NCT05075824). Study Design and Methods CROSSWALK-a evaluates the safety of crovalimab in managing acute uncomplicated VOEs. CROSSWALK-c evaluates the efficacy and safety of crovalimab as adjunct therapy in preventing VOEs. Pts 12-55 years old, weighing ≥40 kg with a confirmed diagnosis of sickle cell anemia (homozygous HbSS or heterozygous HbS/β 0 thalassemia) and vaccinated against N. meningitidis, H. influenzae type B and S. pneumoniae are eligible (Fig. 1 and 2). Concurrent SCD-directed therapies are allowed. CROSSWALK-a Pts must present with an acute uncomplicated VOE requiring hospitalization and parenteral opioid analgesics, and have had ≤10 VOEs in the 12 months prior to randomization. Eligible pts will be randomized 2:1 to receive a single IV weight-based tiered dose of crovalimab or placebo, and monitored during hospitalization and in an 84-day observational period followed by a safety follow-up period for a total study duration of 322 days (10.5 months). The primary objective of CROSSWALK-a is to evaluate safety up to Day 84, including: Incidence and severity of adverse eventsIncidence and severity of infusion-related reactions and hypersensitivityChange from baseline in targeted vital signs and clinical laboratory test results Efficacy, pharmacokinetic (PK), pharmacodynamic (PD), immunogenicity, and exploratory biomarker endpoints will also be evaluated. CROSSWALK-c Pts with 2-10 VOEs in the 12 months prior to randomization are eligible. Eligible pts will be randomized 1:1 to receive weight-based tiered doses of crovalimab or placebo, consisting of initial loading doses (IV: Day 1; SC: Day 2 and weekly for Weeks 2-4) and monthly maintenance SC doses Weeks 5-49 for 48 weeks of treatment. The primary objective of CROSSWALK-c is to evaluate crovalimab efficacy vs placebo up to 48 weeks, on the basis of: The annualized rate of medical facility VOEs Key secondary efficacy objectives are: Annualized rate of home VOEsAnnualized rate of acute chest syndromeAnnualized rate of days hospitalized for medical facility VOEsPt-reported fatigue in adults Safety, PK, PD, immunogenicity, and exploratory biomarker endpoints will also be evaluated. Primary results will be published upon trial readout.