Updated Design of the RHEMEDY Study: A Phase 2 Safety, Proof-of-Concept and Pharmacokinetics Study of CSL889 in Adults and Adolescents with Sickle Cell Disease During Vaso-Occlusive Crisis
Victor Gordeuk, David C Brousseau, Christian Kassasseya, Paul M Shore, Michael Araco, William D Hedrich, Kerstin Jung, Lucia Norverto, Francine R Wilson, Heng Zou, Gregory J Kato, Paula Tanabe, Bart J BiemondAbstract
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 ischemia as a result of impaired microvascular 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 microvascular circulation during a VOC. Current treatment with analgesics such as opioids addresses only the resulting pain without improving tissue ischemia. Free heme, generated by intravascular hemolysis in SCD, overwhelms and depletes hemopexin, the natural plasma protein that neutralizes heme. Free heme activates sterile inflammatory pathways that promote adhesiveness of neutrophils, platelets and endothelial cells. Experiments in sickle cell mice show that free heme and depletion of hemopexin contribute to vaso-occlusion, and that restoring hemopexin levels through intravenous (IV) administration of hemopexin restores blood flow (Gentinetta 2022). Our phase 1 study [NCT04285827] demonstrated the safety and characterized the pharmacokinetics (PK) of single IV doses of hemopexin purified from human plasma (CSL889) in adults with SCD, with or without VOC. The current RHEMEDY study (CSL889_2001, NCT06699849) seeks to evaluate the safety, proof-of-concept (POC), and PK of CSL889 dosed repeatedly 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. The study design described here has been modified from its original design.
Methods
RHEMEDY is a phase 2, multicenter, randomized, multiple-dose, double-blind, placebo-controlled study. Adults and adolescents (≥ 12 years) with SCD (any genotype) presenting within 72 hours of onset of a VOC requiring treatment with parenteral opioids are eligible. 70 subjects are planned to be randomized to one of 2 different dosing regimens of CSL889 (high-exposure or low-exposure) or placebo (4:1:2). Comparing high-exposure to placebo supports safety and POC; low-exposure informs safety and PK modeling for future dose selection. The first dose of investigational product (IP) must be administered within 12 hours after the first dose of parenteral opioid administration. The IP will be given IV once daily for 5 days or until VOC resolves, whichever occurs first. Standard of care treatment for VOC will continue throughout. 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 use, and speed of adequate pain relief. Safety endpoints include treatment-emergent adverse events and treatment-emergent anti-drug antibodies. PK will be assessed primarily from the first 20 adult and first 5 adolescent subjects.
Conclusions
The RHEMEDY study of CSL889 will provide proof-of-concept data intended to support a pivotal trial of CSL889 to treat acute VOC. CSL889 has the potential to target 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.