Anti-Adhesive Therapy for Sickle Cell Disease

Study to Assess Safety and Impact of SelG1 with or without Hydroxyurea Therapy in Sickle Cell Disease Patients with Pain Crises

NCT01895361

Selexys Pharmaceuticals Corporation

National Heart, Lung, and Blood Institute (NHLBI)

44 participating centers in the United States and Jamaica.

174 patients

This is a phase II, randomized, placebo-controlled, double-blind clinical trial of the experimental agent SelG1 given at two dose levels (study arms: high-dose SelG1, low-dose SelG1, placebo). Key eligibility criteria include the following: 1) a common sickle cell disease (SCD) genotype (HbSS, HbSC, HbSβ⁰-thalassemia, or HbSβ⁺-thalassemia); 2) age 18 to 65 years; 3) receiving a stable dose of hydroxyurea or erythropoietin (if prescribed); and 4) experienced two to 10 acute painful episodes in the past 12 months. Key exclusion criteria include the following: 1) receiving chronic transfusion therapy or planned exchange transfusion during the study; 2) hemoglobin concentration < 4.0 g/dL; 3) planned initiation, termination, or dose alteration of hydroxyurea during the study; and 4) anticoagulation therapy (aspirin is not exclusionary). Each patient will receive the study drug for 12 months in the form of 14 intravenous injections. The primary endpoint is the rate of SCD-related painful episodes (“crises”) within one year. Secondary endpoints include the following: one-year rate of SCD-related painful episodes comparing concomitant use or non-use of hydroxyurea, time to first SCD-related painful episode, time to second SCD-related painful episode, number of hospitalization days per year, absolute change from baseline in hemoglobin concentration, and absolute change from baseline in lactate dehydrogenase concentration.

SCD is the name for a group of related genetic disorders of blood caused by a predominance of sickle hemoglobin (Hb S) in red blood cells (RBCs). In SCD, RBCs become dehydrated, inflexible, and abnormally adhesive. These characteristics promote microvascular obstruction, or vaso-occlusion, due to intercellular adhesive interactions among RBCs, leukocytes, platelets and the endothelium. The consequences of vaso-occlusion are ischemia, infarction, and ischemia-reperfusion injury of multiple organs and tissues. The hallmark vaso-occlusive clinical syndrome of SCD is the acute painful episode (previously called “crisis”).

Many studies within the past 15 years, mainly in murine models of SCD, have demonstrated a key role for P-selectin and its ligands in the intercellular adhesive interactions and pathophysiology of vaso-occlusion in SCD. Indeed, blockade or genetic absence of P-selectin has been shown to decrease or eliminate these adhesive interactions and the consequent vaso-occlusion. Together, these studies support the development of anti–P-selectin therapy for humans with SCD. Selexys Pharmaceuticals Corporation has engineered a humanized monoclonal antibody directed against P-selectin called SelG1. A phase I clinical study showed that SelG1 was safe and well tolerated in healthy males and females. There were no infection-related adverse events, alterations in coagulation test results, bleeding, or formation of specific antibodies against SelG1. Pharmacodynamic analysis showed that a single 5 mg/kg dose of SelG1 was sufficient to block P-selectin activity for at least 28 days. The current phase II trial is testing the use of SelG1 as preventive therapy for vaso-occlusive complications of SCD, specifically acute painful episodes. SelG1 is being tested as monthly infusions at two dose levels (5 mg/kg and 2.5 mg/kg). Potential adverse effects of P-selectin inhibition that will be monitored include bleeding, given the inhibition of P-selectin on activated platelets, and the possibility of infection because P-selectin is a mediator of neutrophil adhesion to the vascular endothelium.

SelG1 joins a growing number of anti-adhesive therapies such as rivipansel (previously called GMI-1070), pentosan polysulfate sodium (PPS), tinzaparin, and propranolol that are being tested for treatment of complications of SCD in clinical trials that are either recently completed or ongoing. These different agents have oral (propranolol, PPS), subcutaneous (tinzaparin), and intravenous (SelG1, rivipansel) routes of administration. Some are being developed for abortive therapy of an ongoing painful episode (rivipansel), while SelG1 and some others are being tested for prevention of vaso-occlusive complications. These are exciting times for the SCD community because it appears that soon there will be therapeutic options beyond hydration, analgesics, and supportive care for painful episodes and other vaso-occlusive complications of SCD.