Abstract
Background
SCD is a group of autosomal recessive red blood cell (RBC) disorders caused by a single point mutation in the β- globin gene, with either homozygous inheritance, or heterozygous co-inheritance with other pathogenic variants of the β-globin gene. This point mutation results in the production of hemoglobin S, which 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. In addition to VOEs, patients with SCD may experience severe chronic anemia, chronic pain, immune dysfunction, and progressive multi-organ damage. The current treatment strategy for patients with SCD includes hydroxyurea, along with newer treatments such as L-glutamine, crizanlizumab, and voxelotor. However, despite the availability of these treatments, considerable morbidity and mortality among patients with SCD represents a significant unmet medical need. Activation of the complement pathway has been described in patients with SCD at baseline, in acute pain crisis, and in delayed hemolytic transfusion reaction. Accumulating nonclinical data suggest the potential 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 anti-C5 monoclonal antibody that allows for small-volume subcutaneous (SC) self-injection. Crovalimab demonstrated rapid and sustained complement inhibition with promising efficacy and safety in a Phase I/II study (Röth et al. Blood 2020), in patients with paroxysmal nocturnal hemoglobinuria, a complement-mediated disorder.
Study Design and Methods
CROSSWALK-c (NCT number pending) is a placebo-controlled, randomized, double-blind, Phase IIa study evaluating the efficacy and safety of crovalimab as adjunct therapy in preventing VOEs in patients with SCD. Patients aged ≥ 12 years to ≤ 55 years, weighing ≥ 40 kg, with a confirmed diagnosis of SCD, homozygous hemoglobin S (HbSS) or sickle cell β 0 thalassemia (HbSβ 0), and presenting with ≥ 2 to ≤ 10 VOEs are eligible for this study. Patients on concurrent SCD-directed therapies are also eligible. Vaccination against Neisseria meningitidis, Haemophilus influenzae type B, and Streptococcus pneumonia are required for enrollment. Patients with a history of hematopoietic stem cell transplant are excluded from the study. Eligible patients will be randomized 1:1 to the crovalimab or placebo treatment arms (Figure). An initial intravenous loading dose of crovalimab or placebo will be administered on Day 1 Week 1, followed by four weekly SC doses on Day 2 Week 1, and then on Weeks 2-4. Maintenance dosing will be administered from Week 5, followed by once every 4 weeks thereafter, for 48 weeks. All patients will receive study treatment according to a weight-based tiered dosing schedule. The primary objective is to evaluate the efficacy of crovalimab compared with placebo, based on the annualized rate of medical facility VOEs. Secondary efficacy objectives include the annualized rate of acute chest syndrome, the annualized rate of home VOE, and change in urinary albumin-creatinine ratio, tricuspid regurgitant jet velocity, and Patient-Reported Outcomes Measurement Information System (PROMIS)-Fatigue score in adults, from baseline to Week 49. Safety, pharmacokinetics, immunogenicity, and exploratory biomarker objectives will also be evaluated.
Figure 1 Figure 1.
Disclosures
Callaghan: Agios Pharmaceuticals: Current Employment; Roche/Genentech: Consultancy, Speakers Bureau; Global Blood Therapeutics: Consultancy, Speakers Bureau; Forma: Consultancy; Hema Biologics: Consultancy; Takeda: Consultancy, Speakers Bureau; Sanofi: Consultancy; BioMarin: Consultancy; Spark: Consultancy; uniQure: Consultancy; Chiesi: Consultancy; Kedrion: Consultancy; Pfizer: Consultancy. Ataga: Novartis: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy; Forma Therapeutics: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. De Franceschi: F. Hoffmann-La Roche Ltd: Consultancy. Minniti: CSL Behring: Other: Endpoint adjudicator ; Forma: Consultancy; Novo Nordisk: Consultancy; Chiesi: Consultancy; Bluebird Bio: Other: Endpoint adjudicator ; Novartis: Consultancy; GBT: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy. Balachandran: F. Hoffmann-La Roche Ltd: Current Employment. Imbs: F. Hoffmann-La Roche Ltd: Consultancy; Certara Inc.: Current Employment. Perretti: F. Hoffmann-La Roche Ltd: Current Employment. Ramos: Genentech, Inc.: Current Employment. Sostelly: F. Hoffmann-La Roche Ltd: Current Employment. Bartolucci: Bluebird: Consultancy, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Steering committee, Research Funding; Fabre Foundation: Research Funding; Jazz Pharma: Other: Lecture fees; AGIOS: Consultancy; INNOVHEM: Other: Co-founder; Emmaus: Consultancy; Addmedica: Consultancy, Other: Lecture fees, Research Funding; Hemanext: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy; GBT: Consultancy.
A double blind, placebo controlled randomized evaluation of the efficacy of a Polyherbal Preparation (FaradinR) in treating sickle cell anaemia in Nigerian children
