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

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 events

• Incidence and severity of infusion-related reactions and hypersensitivity

• Change 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 VOEs

• Annualized rate of acute chest syndrome

• Annualized rate of days hospitalized for medical facility VOEs

• Pt-reported fatigue in adults

Safety, PK, PD, immunogenicity, and exploratory biomarker endpoints will also be evaluated.

Primary results will be published upon trial readout.

References

1. Ballas et al, Am J Hematol 2005; 79:17-25.

2. Lanzkron et al , Am J Hematol 2010; 85:797-799.

3. Roumenina et al, Am J Hematol 2020; 95:456-464.

4. Röth et al, Blood 2020; 135:912-920.