Sickle Cell Disease Emerging Pipeline

Sickle Cell Disease (SCD) is a genetic disease that is a form of inherited anemia arising from problems with the structure and function of red blood cells. It is an inherited disease caused by a defect, a single mutation, in the beta-globin gene that helps make adult hemoglobin. Abnormal hemoglobin, called hemoglobin S, causes sickle cell disease. The signs and symptoms of sickle cell disease include swelling of the hands and feet, anemia, fatigue, extreme tiredness, jaundice, and skin discoloration. Sickle cell disease can lead to complications such as infections, delayed growth, and episodes of pain, acute chest syndrome, and stroke. According to the Centres for Disease Control and Prevention (CDC), approximately 100,000 Americans are affected by sickle cell disease. Sickle Cell Disease occurs among about 1 out of every 365 Black or African-American births. About 1 in 13 Black or African-American babies is born with sickle cell trait (SCT).

Several pharmaceutical companies such as AstraZeneca, Global Blood Therapeutics, Bluebird bio, Micelle BioPharma Inc, Novartis Pharmaceuticals, Cyclerion Therapeutics, and Imara, Inc. are developing the drugs for the treatment of sickle cell disease.

Global Blood Therapeutics (Voxelotor)

Voxelotor is an oral therapy taken once daily that directly inhibits sickle hemoglobin polymerization, which causes red blood cells (RBCs) to deform and become sickle-shaped. Voxelotor acts by binding to hemoglobin and stabilizing RBCs in an oxygenated state. This increases hemoglobin’s affinity for oxygen and inhibits polymerization and the resultant sickling and destruction of RBCs. The potential of Voxelotor to slow the progression of sickle cell disease and its devasting downstream effects across a wide range of studies, including the HOPE-KIDS 2 post-approval confirmatory study using transcranial doppler (TCD) flow velocity to evaluate the reduction in stroke risk in children 2 to 15 years of age. Voxelotor was granted Breakthrough Therapy, Fast Track, Orphan Drug, and Rare Pediatric Disease designations by the U.S. Food and Drug Administration (FDA) for the treatment of patients with Sickle cell disease, as well as Priority Medicines (PRIME) designation from the European Medicines Agency (EMA). The European Commission (EC) has designated Voxelotor as an orphan medicinal product for the treatment of patients with Sickle cell disease.

Bluebird bio (LentiGlobin /BB305/ HGB-210)

LentiGlobin BB305 drug is being developed for the treatment of beta-thalassemia major and severe sickle cell disease by inserting a fully functional human beta-globin gene into the patient’s own hematopoietic stem cells ex-vivo and then transplanting those modified cells into the patient through infusion, also known as autologous stem cell transplantation.

Micelle BioPharma Inc (SC411/ Docosahexaenoic Acid/ Altemia)

SC411(Altemia) is the proprietary product candidate that is being developed for the treatment of Sickle Cell Disease. Altemia consists of a complex proprietary mixture of various fatty acids, primarily in the form of Ethyl Cervonate (Micelle’s proprietary blend of docosahexaenoic acid and other omega-3 fatty acids), and surface-active agents formulated using ALT specifically to address the treatment of SCD. The drug is encapsulated in a soft gelatin capsule for oral administration. Altemia is well-positioned to deliver a narrow, therapeutic dose of certain lipids directly to the membrane of red blood cells of sickle cell patients. The combination of ALT drug delivery technology and highly purified lipids may reduce VOC significantly. It has the potential to address the inflammatory symptoms of SCD and to assist in reducing sickle cell events in general. Altemia is effective in reducing the sickle cell crisis events and related mortality. The double-blind, randomized, multicenter phase II study of SC411 (Altemia) in children with sickle cell disease (SCOT Trial). The SCOT trial investigated the effect of three different doses of SC411 on selected clinical and biochemical endpoints in 67 children with SCD aged 5-17 years old. 

Novartis Pharmaceuticals (Crizanlizumab)

Crizanlizumab (SEG101) is an investigational humanized monoclonal antibody blocking P-selectin mediated multicellular adhesion that is in late-stage development for the prevention of vaso-occlusive crises (VOCs) in patients with sickle cell disease (SCD). Crizanlizumab acts by binding to the molecule called P-selectin on the surface of platelets and endothelium in the blood vessels. It inhibits the interactions between endothelial cells, platelets, red blood cells, sickled red blood cells, and leukocytes.

Cyclerion Therapeutics (IW-1701/ Olinciguat)

Olinciguat is an orally administered, once-daily, vascular sGC stimulator designed for the treatment of sickle cell disease (SCD). Olinciguat has the potential to manifest various properties such as to improve local blood flow to organs, reduce vascular inflammation, and reduce the proportion of sickled cells. Olinciguat has been granted Orphan Drug Designation for Sickle Cell Disease by the U.S. Food and Drug Administration. It is currently in a Phase II study in patients with SCD, the STRONG-SCD study.

Imara, Inc. (IMR-687)

IMR-687 is an oral, once-a-day, potentially disease-modifying treatment for sickle cell disease (SCD) and β-thalassemia. IMR-687 is a highly selective, potent small-molecule inhibitor of PDE9. It acts primarily on red blood cells (RBCs). It has the potential to act on white blood cells (WBCs), adhesion mediators, and other cell types that are implicated in sickle cell disease.

Modus Therapeutics AB (Sevuparin)

Sevuparin is an innovative, proprietary polysaccharide drug with anti-adhesive, anti-aggregate, and anti-inflammatory effects due to its multimodal mechanism of action. The drug candidate has the potential to restore blood flow and prevent further microvascular obstructions in a number of diseases. Modus has completed a global Phase II study of sevuparin in hospitalized sickle cell disease (SCD) patients. The randomized, double-blinded study included 144 SCD-patients at clinical sites across Europe, the Middle East, and the Caribbean. The study compared intravenously (IV) administered sevuparin with a placebo in patients admitted to the hospital with an acute vaso-occlusive crisis (VOC) associated with SCD. The study also assessed several pain-related secondary endpoints.

Emerging Pipeline Landscape: Sickle Cell Disease

Company NameProduct NameMechanism Of ActionRoute Of AdministrationStage Of Development
Global Blood TherapeuticsVoxelotorInhibits sickle hemoglobin polymerizationOralPhase III
Bluebird bioLentiGlobin BB305Gene TransferenceIntravenousPhase II/III
Bluebird bioBCL11A shRNA (mir)RNA Interference to stimulate the gene expressionIntravenousPhase I
Micelle BioPharma IncSC411/ Docosahexaenoic AcidLipid ReplenishmentOralPhase II
Novartis PharmaceuticalsCrizanlizumab (SEG101)P-Selectin InhibitorIntravenousPhase III
Cyclerion TherapeuticsIW-1701/ OlinciguatSoluble Guanylyl Cyclase AgonistsOralPhase II
Imara, Inc.IMR-687PDE9 InhibitorOralPhase II
Modus Therapeutics ABSevuparinCell Adhesion Molecule InhibitorsIntravenousPhase II