Design of the RHEMEDY Study: A Phase 2/3 Safety, Efficacy and Pharmacokinetics Study of CSL889 in Adults and Adolescents With Sickle Cell Disease During Vaso-Occlusive Crisis

Abstract Background Vaso-occlusive crisis (VOC) is the primary reason for hospitalization among patients with sickle cell disease (SCD). The severe pain that characterizes VOC is due to impaired blood circulation triggered by adhesion of neutrophils, platelets and rigid erythrocytes to the blood vessel wall. Currently, there are no approved treatments aimed at immediately improving blood circulation during a VOC episode. Current treatment with analgesics such as opioids only addresses the resulting pain without improving blood circulation. Experiments in sickle cell mice show that free heme and depletion of hemopexin, the natural plasma protein that neutralizes heme, contribute to vaso-occlusion. Free heme activates sterile inflammatory pathways that promote adhesiveness of neutrophils, platelets and endothelial cells. Free heme is generated by intravascular hemolysis in SCD, which overwhelms and depletes plasma hemopexin. In sickle cell mice with vaso-occlusion triggered in various ways, restoring hemopexin levels through intravenous (IV) administration of hemopexin restores blood flow (Gentinetta 2022). Our recent phase 1 study [NCT04285827] demonstrated the safety and pharmacokinetics (PK) of single IV doses of hemopexin purified from human plasma (CSL889) in adults with SCD with or without VOC. The RHEMEDY study (CSL889_2001, NCT06699849) seeks to evaluate the safety, effectiveness, and PK of CSL889 in adults and adolescents with SCD experiencing VOC. The goal is to administer CSL889 in an acute treatment center (emergency departments or infusion centers) or hospital as soon as possible after onset of acute pain due to VOC. Methods RHEMEDY is a 2-part, phase 2/3, multicenter, randomized, multiple-dose, double-blind, placebo-controlled adaptive study. Adults (and adolescents > =12 years; US, Canada, and others as approved) with SCD (any genotype) presenting within 72 hours of onset of a VOC requiring treatment with parenteral (injected or intranasal) opioids will be eligible. In part A (corresponding to Phase 2), 160 subjects will be randomized equally to one of 3 different dosing regimens of CSL889 or placebo The first dose of investigational product (IP) must be administered within 12 hours of the first parenteral opioid; IP will be added to standard-of-care treatment for VOC. The IP will be given IV once daily for 5 days or until their VOC resolves, whichever occurs first. In part B (Phase 3), 100 subjects will be randomized equally to a regimen selected from part A or placebo. Sample size can be adjusted up to 300 subjects based on observations at interim analysis. Informed consent will be sought preferably when subjects are in their usual state of health, prior to VOC. An independent data monitoring committee will oversee study conduct and safety. Results The primary efficacy endpoint is the time to resolution of VOC, measured by the time from first IP administration to discontinuation of parenteral opioids. Secondary endpoints include hospital admission rate, length of acute care and hospital stay, percentage of subjects experiencing VOC complications (acute chest syndrome [ACS], acute kidney injury, stroke), re-presentation to acute care for VOC/ACS, total opioid consumption, and speed of adequate pain relief. Safety endpoints include treatment-emergent adverse events and treatment-emergent anti-drug antibodies. PK parameters will be calculated, primarily from the first 24 adult and first 8 adolescent subjects. Conclusions The RHEMEDY study of CSL889 will provide data that may support registration of CSL889 to treat acute VOC. CSL889 has potential to treat an underlying cause of VOC with a new approach to shorten a VOC episode. The trial will assess any potential reduction in need for hospitalization or in duration of hospitalization. Figure 1Overall study design.Figure 2Individual subject flow.

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