A Phase 1 Study of Prasugrel in Subjects with Sickle Cell Disease: Effects on In Vivo Markers of Platelet Activation and of Coagulation
Authors: Jakubowski Joseph A. , Zhou Chunmei , Small David S. , Winters Kenneth J. , Lachno D. Richard , Frelinger Andrew L. , Howard Jo , Jurcevic Stipo , Payne Christopher D. 
Published: October 2019

Abstract 1049

Introduction:

Evidence suggests that platelets are activated in sickle cell disease (SCD) and this appears to increase further during painful crises caused by vascular occlusions from sickled red blood cells. Antiplatelet therapy may be useful in reducing the frequency and severity of acute pain episodes and reducing the risk of thrombotic complications. Prasugrel, an ADP receptor antagonist, irreversibly inhibits the P2Y12 ADP receptor, blocking ADP-stimulated platelet activation and aggregation and reducing downstream procoagulant activities. Here we present the first evaluation of prasugrel's effects on markers of in vivo platelet activation and of coagulation in subjects with SCD.

Methods:

Twenty-six adult subjects were enrolled and 25 completed the study: 12 with SCD and 13 well-matched healthy controls. Subjects were examined before and after 12±2 days of treatment with oral prasugrel (5.0 mg/day for subjects weighing <60 kg and 7.5 mg/day for subjects weighing ≥60 kg). Markers of platelet activation and coagulation included whole-blood platelet-monocyte and -neutrophil aggregates, and whole blood platelet-associated P-selectin and platelet CD40L, all measured by flow cytometry and presented as percent (%) of marker positive cells. Plasma soluble (s) P-selectin, CD40L, and plasma prothrombin fragment 1.2 (F1.2) were evaluated by ELISA.

Results:

Results from the biomarkers are presented in the table. Prior to prasugrel administration (baseline), subjects with SCD had significantly higher levels of the following biomarkers compared to healthy subjects: Platelet-monocyte aggregates, platelet-neutrophil aggregates, platelet CD40L, and plasma F1.2. In addition, subjects with SCD had numerically higher values of sCD40L, as well as platelet-associated and sP-selectin.

Prasugrel treatment resulted in numerical decreases in levels of all biomarkers (with the exception of platelet-associated CD40L for control subjects), most notably in SCD subjects with elevated baseline levels.

Prasugrel was safe and well tolerated with no serious adverse events observed during the study. No subject discontinued the study due to an adverse event (AE) and the majority of AEs were mild. No subjects with SCD reported any bleeding-related AEs.

Conclusion:

In this study, compared to healthy controls, baseline elevation of several platelet-activation and coagulation markers among adult subjects with SCD is consistent with that seen in previous studies of both children and adults with SCD. The decrease in platelet activation biomarkers following 12 days of prasugrel treatment in subjects with SCD suggests prasugrel interrupts SCD-related platelet activation in vivo and raises the possibility that prasugrel may modulate the frequency and/or severity of painful crises associated with SCD. These data support additional studies of the safety and efficacy of prasugrel in the treatment of vascular complications associated with SCD.

Disclosures:

Jakubowski: Eli Lilly and Company: Employment, Equity Ownership. Off Label Use: This abstract discusses prasugrel treatment in patients with sickle cell disease. Please see USPI for most up-to-date information. Zhou:Eli Lilly and Company: Employment, Equity Ownership. Small:Eli Lilly and Company: Employment, Equity Ownership. Winters:Eli Lilly and Company: Employment, Equity Ownership. Lachno:Eli Lilly and Company: Employment, Equity Ownership. Frelinger:Takeda: Research Funding; Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Consultancy, Research Funding; GLSynthesis: Research Funding. Howard:Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Payne:Eli Lilly and Compnay: Employment, Equity Ownership.