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Celebrating Diversity Within the Sickle Cell Community: Commitment, Innovation, Practice
Saturday, October 13 • 9:15am - 9:30am
Clinical Development Of Rivipansel (GMI-1070) For The Treatment Of Acute Vaso-Occlusive Crisis In Sickle Cell Disease

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Abstract

Authors:
Dr. Lori Luck- Pfizer Inc., Collegeville, Pennsylvania, Dr. Krupa Sivamurthy- Pfizer Inc., Collegeville, Pennsylvania, Dr. Frank Shafer-Pfizer Inc., Collegeville, Pennsylvania, Dr. Carl Kollmer- Pfizer Inc., Collegeville, Pennsylvania, Ms. Amanda O’brien- Pfizer Inc., Collegeville, Pennsylvania, Mr. David Readett- Pfizer Inc., Collegeville, Pennsylvania

Objectives: Acute therapy for a sickle cell vaso-occlusive crisis (SCD-VOC) remains limited to symptomatic relief predominantly with opioids, which fails to address the underlying pathophysiology of VOC. Preclinical studies have demonstrated a reduction in white blood cell (WBC)-endothelial cell adhesion, in addition to a decrease in secondary capture of sickle red blood cells (sRBCs) through selectin inhibition (Wun T, et al. PLoS One. 2014;9[7]:e101301). This suggests that inhibition of selectin-mediated cell adhesion to vascular endothelium may provide a therapeutic approach that would target the underlying cause of VOC. We describe the clinical development of rivipansel, a pan-selectin inhibitor, for the acute treatment of SCD-VOC.
Methods: We report on the clinical development of rivipansel from Phase 1 to Phase 3 investigation. Phase 1 studies were performed in healthy volunteers and individuals with SCD not experiencing a VOC. The Phase 2 multicenter, randomized, double-blind, placebo-controlled trial that followed enrolled and treated 76 individuals with SCD who were 12 – 60 years of age and hospitalized for a VOC. Subjects received a loading dose and a maximum of 14 maintenance doses of rivipansel or placebo. The primary efficacy endpoint was resolution of VOC and secondary endpoints included cumulative opioid use, length of hospital stay and adverse events (Telen MJ, et al. Blood. 2015;125[17]:2656-64). The subsequent ongoing randomized, double-blind Phase 3 clinical trial will include approximately 350 SCD subjects, 6 years of age and older, admitted to the hospital for VOC. The study design largely mirrors the Phase 2 study but the primary endpoint is time to readiness-for-discharge, defined as the difference between the time of readiness-for-discharge and the start time of the first infusion of study drug. Secondary endpoints include time to discharge, cumulative IV opioid consumption, time to discontinuation of IV opioids and adverse events. Subjects in the Phase 3 study also have the option of entering an open label extension study following their participation in the double blind study (ClinicalTrials.gov identifier: NCT02187003).
Results: The Phase 1 investigations demonstrated safety and tolerability in addition to identifying a Phase 2 starting dose for intravenous rivipansel. The subsequent Phase 2 trial revealed shorter median time to resolution of VOC and time to hospital discharge, as well as lower mean cumulative IV opioid (mg/kg morphine equivalent units) use in the rivipansel group compared to the placebo group. (Table 1) All causality and treatment-related adverse event (AE) rates, including serious AEs in the rivipansel group were comparable to the placebo group (Telen MJ, et al. Blood. 2015;125[17]:2656-64). These encouraging results prompted further investigation of rivipansel in a randomized, double-blind Phase 3 study (ClinicalTrials.gov identifier: NCT02187003) which is ongoing.
Conclusions: The clinical development of rivipansel as an acute therapy for SCD-VOC is based on selectin inhibition that is expected to decrease the adhesion between WBCs, endothelial cells and sRBCs, a key event in the evolution of sickle cell vaso-occlusion. Initial clinical studies have shown encouraging results leading to the ongoing randomized, double-blind Phase 3 study.

Speakers
avatar for Lori Luck, MD

Lori Luck, MD

Medical Director, PFIZER Inc, Collegeville Pennsylvania Global Medical Affairs, Sickle Cell Disease
Lori Luck, M.D. is a pediatric hematologist and joined Pfizer in January, 2017 as the Medical Director, Global Medical Affairs, Sickle Cell Disease. Prior to Pfizer, Dr. Luck worked in Oncology at Genzyme and Leadiant (formally Sigma Tau) in Field Medical Affairs. She completed her... Read More →


Saturday October 13, 2018 9:15am - 9:30am
Constellation B

Attendees (17)