Laymans Summary

Sickle cell disease is an inherited blood disorder that causes frequent pain episodes, and multiple organ complications. Currently, there is only one known cure for sickle cell disease which is bone marrow transplantation that is inaccessible for most Kenyans. Most patients however are usually on treatments that help control the disease e.g hydroxyurea and folic acid, or prevent infections e.g. palludrine and Penicillin V, or manage symptoms as they arise e.g. painkillers for pain episodes and blood transfusion for anemia. There is a need for new treatments that help improve the patients’ quality of life. Pain episodes are mainly caused by the blockage of blood flow to various parts of the body. One of the causes of this blockage includes formation of clots in the blood vessels. A molecule called p-selectin; produced by our bodies contributes to formation of this clots. This study drug prevents the function of p-selectin leading to the reduction of clots thus a decrease in pain episodes. A total of 240 participants will be enrolled across 75 site. They will randomly be assigned to either the treatment arm or the placebo arm.Kenya have 5 sites participating in this study.

The Abstract

Sickle cell disease is one of the most commonly inherited blood disorders in the world characterized by Vaso-occlusive crises, anemia, stroke and multiple organ damage. Vaso-occlusive crises is the most common presentation of sickle cell disease (Salinas Cisneros and Thein 2020).Vaso-occlusive crises is caused by activation of the endothelial cells, neutrophils, monocytes and platelets by the sickled red blood cells. The activation of these cells leads to their expression of the p-selectin molecule promoting the aggregation and adhesion of these cells to one another and to the endothelial cells leading to clot formation and blockage of the microvascular channels (Salinas Cisneros and Thein 2020).

There is only one known cure of sickle cell disease which is the hematopoietic stem cell transplant (HSCT) that is not easily accessible to most patients due to its cost and unavailability in the country. Most patients with sickle cell disease are therefore mainly on supportive treatment. These reasons inform the need for more affordable and accessible treatments. The study participants will be randomly allocated to either receive a placebo or inclacumab in the ratio of 1:1. They will receive the intravenous treatment every 12 weeks through Week 36. The mechanism of action is to counter the action of p-selectin molecule leading to reduced adhesion of molecules hence reduced episodes of vaso-occlusive crises. The study aims to assess the safety and efficacy of inclacumab as compared to placebo in reducing the frequency of vaso-occlusive crises. During the study period participants can receive standard of care treatment except for crizanlizumab. The study will be carried out in approximately 75 sites with a sample size of 240 participants.

INTRODUCTION

Sickle cell disease (SCD) is an autosomal recessive disease characterized by chronic hemolysis, inflammation and vaso-occlusion presenting as recurrent pain episodes (variously termed sickle cell-related pain crises or VOCs), multi-organ dysfunction, and early death (Kato, 2018). Vaso-occlusion in SCD is driven by a series of complex and often redundant receptor–ligand interactions involved in the adhesion of circulating cells to the damaged endothelium and exposed sub-endothelium. Extensive research demonstrates that P-selectin mediated cellular interactions with sickled red blood cells (RBCs), leukocytes and platelets play a crucial role in the pathophysiology of vaso-occlusion in SCD. By contrast, blocking P-selectin-mediated cellular interactions or reducing the levels of P-selectin reduces or eliminates vaso-occlusion in animal models. Taken together, these data led to the hypothesis that blocking P-selectin could reduce the risk of VOCs in SCD patients. Results from a randomized, placebo-controlled Phase 2b trial of crizanlizumab, a humanized monoclonal antibody, in SCD bolstered the hypothesis that blocking the interaction of P-selectin with its receptors could prevent vaso-occlusion and VOCs (Ataga, 2017). In summary, there is a high unmet need for treatment options in SCD and there is a scientific rationale, supported by clinical data, that p-selectin inhibition has the potential to reduce the risk for acute vaso-occlusions.

JUSTIFICATION/RATIONALE

Allogeneic HSCT remains the only curative therapy for sickle cell disease. It is however unavailable for most of patients due to its high cost and it being available only in high income countries. It is also associated with various transplant complications (Kassim and Sharma 2017). Three therapies, hydroxyurea (HU [DROXIA®, 2017]; (also known as hydroxycarbamide), L-glutamine (ENDARI, 2017) and crizanlizumab (ADAKVEO®, 2019), have been approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) to reduce VOCs in patients with SCD (Charache, 1995; Niihara, 2018; Ataga, 2017). The effectiveness of HU is impaired by low compliance rates and frequent treatment discontinuation (Shah, 2019) while L-glutamine provides a modest 25% reduction in annual VOC rates (Niihara, 2018). Crizanlizumab is a monoclonal antibody directed against human P-Selectin and is administered as an infusion every 4 weeks. This is potentially limiting in continued adherence to lifelong therapy as patients need to travel to an infusion centre in order to receive treatment. This extracts a cost on patient and caregiver productivity and frequent intravenous infusions generally attract extra costs to the patient. (Saini, 2009; Richter, 2003).

Inclacumab has a similar mechanism of action as crizanlizumab. Previous studies on inhibition of p-selectin through crizanlizumab, have demonstrated it to be efficacious and safe for use in SCD patients. Additionally, the dose selected is 30mg/kg every 12 weeks and from previous studies population PK simulations project that the inclacumab dose regimen of 30 mg/kg Q12W will maintain concentrations above 10 μg/mL throughout the 48-week study period in the majority of participants, thereby maximizing the pharmacology required for effective reduction of VOC in the SCD population.

This study uses placebo as a comparator on the background of standard of care (SOC) treatment for a VOC. Placebo was chosen as the control because it is necessary to determine the safety and efficacy of inclacumab by allowing efficacy to be estimated controlling for background VOCs with SOC and safety signals to be distinguished from AEs occurring due to SCD. Treatments with stable standard of care are allowed except for crizanlizumab because it has a similar mechanism of action as the study drug and would confound the interpretation of this data In summary, despite the recent availability of new options to treat VOCs, an unmet medical need exists to further reduce the frequency of VOCs while reducing patient burden and enhancing patient adherence to therapy.

NULL HYPOTHESIS

Inclacumab is non superior to placebo in reducing incidences of vaso occlusive crises

OBJECTIVES

The primary objective of this study is:

To evaluate the safety and efficacy of treatment every 12-weeks with inclacumab to reduce the incidence of VOCs in participants with SCD.

Additional objectives of the study are:

To evaluate the PK and PD of inclacumab, the presence of anti-drug antibodies (ADAs), and changes in quality of life (QOL).

STUDY DESIGN

This study will assess the safety and efficacy of inclacumab in reducing the frequency of VOCs in approximately 240 adult and adolescent participants (≥ 12 years of age) with SCD. Initial enrollment will include participants’ ≥ 16 years of age until the independent Data Monitoring Committee (DMC) determines that adequate safety and PK data support the enrollment of participants 12 to 15 years of age. Eligible participants will be randomized with a 1:1 ratio into one of two treatment arms as follows: •

Inclacumab 30 mg/kg administered IV Q12W; or • Placebo administered IV Q12W. At the time of randomization, participants will be stratified by Baseline HU use (yes; no), number of VOCs (2 to 4; 5 to 10) in the preceding 12 months, and geographic region (North America; sub-Saharan Africa; Europe/rest of world).

All participants will undergo safety, efficacy, and PK/PD assessments at Baseline and through Week 48. Visits to the clinical site for infusion of study drug will occur at Baseline (Day 1) and Q12W (Weeks 12, 24, and 36) for a total of 4 infusions. An additional visit at Week 6 will occur for safety, PK, and PD monitoring. The incidence of VOC events will be collected every 4 weeks, with participants contacted by phone at Weeks 4, 8, 16, 20, 28, 32, 40, and 44. Following completion of the Week 48 visit, eligible participants will be given the option to enroll in an open-label extension (OLE) study (under a separate protocol) to receive inclacumab.

Participants will receive their first dose in the OLE study at the same Week 48 visit. Participants enrolling in the OLE study will not be required to return to clinic for the Week 60 visit. Safety, efficacy, and PK/PD assessments will occur at Week 60 for participants not enrolling on the OLE study.

The DMC will regularly review the totality of accumulated safety data from all ongoing Inclacumab studies on an ongoing, unblinded basis with additional emphasis on adolescent participants. Details will be provided in the DMC Charter.