5610845 A PHASE 1 STUDY OF CSL888 (HEMOPEXIN) IN ADULT PATIENTS WITH SICKLE CELL DISEASE

Abstract

Background: Episodes of vaso-occlusive crisis (VOC) are the primary reason for hospitalization among patients with sickle cell disease (SCD). The release of heme from the breakdown of damaged red blood cells is thought to play an important role in contributing to vaso-occlusion in SCD. Free heme promotes activation of endothelium, expression of endothelial cell adhesion molecules and activation of blood cells (neutrophils, monocytes, and platelets) which “stick” to the blood vessel walls. The net result is blockage of blood circulation, resulting in the characteristic pain of VOC. Hemopexin is a 60 kilodalton (kDa) plasma glycoprotein that is mainly expressed in the liver and belongs to the family of acute-phase proteins whose synthesis is induced after an inflammatory event. Hemopexin binds extracellular heme with the highest known affinity (KD < 1pM) of all plasma proteins. In patients with SCD, hemopexin levels are significantly reduced (approximately 85%) compared to healthy controls due to increased consumption. CSL889 is human plasma-derived hemopexin. It is hypothesized that pharmacological administration of CSL889 may decrease heme toxicity, restore normal blood circulation and therefore have beneficial effects in the management of acute VOC in SCD patients. Translation to the clinic is supported by studies performed in vitro demonstrating protection of heme-mediated endothelial cell damage and in vivo using the Townes mouse model of SCD, in which hemopexin was shown ameliorate vaso-occlusion following hemoglobin or hypoxia/reperfusion challenges (Gentinetta et al. 2022). Preclinical repeat dose toxicity studies in animals have evidenced favorable tolerability up to the highest dose level tested. Methods: We describe the design of a Phase 1, first in human, multicenter, open-label study to evaluate the safety, tolerability, and pharmacokinetics (PK) of CSL889 in adult patients with SCD following single intravenous (IV) doses of CSL889 [NCT04285827]. The study will comprise 2 parts. Part A will include patients with SCD in their usual health (not in VOC) who will receive a single dose of CSL889 at one of up to 6 different dose levels. In Part B, patients with SCD who present in VOC requiring intravenous (IV) opioid injections and admission to hospital for further management, will receive a single dose of CSL889 at a level that has been shown to be safe and tolerable in Part A within 36 hours of in-patient admission. All subjects will be followed up for 32 days post-infusion of CSL889. The range of doses to be studied is based on a translational PK model based on data derived from the study of CSL889 in the Townes mouse model of SCD. Results: The primary objective is to determine the safety and tolerability of single doses of CSL889 given to patients with SCD both without (Part A) and with (Part B) active VOC. The secondary objectives are to determine the PK and immunogenicity of CSL889. Exploratory objectives are to determine changes in biomarkers of target engagement (including changes in cell-free heme) and pharmacodynamic biomarkers related to the mechanism of action. Change in pain scores (as measured by Numeric Rating Scale [NRS]) will be additionally evaluated in Part B. Conclusions: Enrollment is in progress. No serious adverse events considered related to the administration of CSL889 have been reported as of 01-Sep-2022. Disclosures: F Wilson, J Jochems, L Lindqvist, K Jung,T Gentinetta, S Costin and GJ Kato are employed by CSL Reference 1. Gentinetta et al, J Clin Med 2022, 11:630