Sickle Cell Disease – SC411

Sickle Cell Disease | SC411
Sickle Cell Disease (SCD) is a group of hereditary blood disorders caused by a genetic mutation that affects hemoglobin, the molecule that delivers oxygen throughout the body via red blood cells. SCD is caused by a genetic mutation in the beta-chain of hemoglobin, which results in mutant hemoglobin known as sickle hemoglobin, or HbS. Hemoglobin is a protein in red blood cells that carries oxygen from the lungs to the body’s tissues and returns carbon dioxide from the tissues back to the lungs. Hemoglobin accomplishes this diametric function by binding and then releasing oxygen through allosterism, a process by which the hemoglobin molecule changes its shape to have a high affinity for oxygen in the lungs, where oxygen is abundant, and low affinity for oxygen in the tissues, where oxygen must be released. Oxyhemoglobin, the high oxygen affinity form of hemoglobin, is formed in the lungs during respiration, when oxygen binds to the hemoglobin molecule, while deoxygenated hemoglobin, the low oxygen affinity form of hemoglobin, is formed when oxygen molecules are removed from the binding site as blood flows from the lungs to the body. In patients with sickle cell disease, deoxygenated HbS molecules polymerize, under very low oxygen, and form long, rigid rods within a red blood cell, much like a “sword within a balloon.” Another anomaly of these red blood cells is a unique fatty acid profile in their cell membranes, resulting in a pro-inflammatory condition and less overall fluidity of the cell membrane. As a consequence, the normally round and flexible red blood cell becomes rigid and elongated into a “sickled” shape. Sickled red blood cells do not flow properly in the bloodstream; they clog small blood vessels and reduce blood flow to the organs. Sickled red blood cells also die earlier than normal red blood cells and the bone marrow cannot make enough new red blood cells to replenish the dying ones, which causes a constant shortage of red blood cells. This results in inadequate oxygen delivery, or hypoxia, to all body tissues, which can lead to multi-organ failure and premature death.

 

How SCD Works in Comparison to Normal Red Blood Cells
The following graphic illustrates the process by which sickling occurs in sickle cell disease patients as a result of the fatty acid imbalance and polymerization of deoxygenated HbS in a red blood cell, leading to occluded blood flow, in contrast to a normal red blood cell:

 

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Signs and Symptoms
Signs and symptoms of sickle cell disease usually begin in early childhood. The severity of symptoms varies from person to person and it has been postulated that clinical manifestations result from complex combinations of genetic, cellular and environmental factors. Some people have mild symptoms, while others are frequently hospitalized for more serious complications. Beginning in childhood, patients suffer unpredictable and recurrent episodes or crises of severe pain due to blocked blood flow to organs and extremities, which often lead to psycho-social and physical disability. The constant destruction of red blood cells with the release of their contents into the blood often leads to damaged or diseased blood vessels, which further exacerbate blood flow obstruction and multi-organ damage. SCD can lead to hemolytic anemia (the destruction of red blood cells within blood vessels), vaso-occlusion (blocked blood flow to tissues), progressive multi-organ damage and early death. Patients with anemia experience fatigue, weakness, shortness of breath, dizziness, headaches, and coldness in the hands and feet. Anemia can also cause delayed growth and development in children. Deprivation of oxygen-rich blood is especially deleterious to the lungs, kidneys, spleen, and brain. A particularly serious complication of SCD is pulmonary hypertension linked to blockages in the blood vessels that supply the lungs. Pulmonary hypertension occurs in about one-third of adults with SCD and can lead to heart failure. Other serious consequences of the blocked blood vessels are strokes, cognitive impairment, autosplenectomy (disappearance of the spleen), ulcers of the lower extremities, impaired vision and hearing, and priapism. Blockage of the blood vessels supplying the spleen may lead to failure of that organ, which results in serious infectious conditions such as osteomyelitis (a bone infection), cholecystitis (inflammation of the gall bladder), pneumonia and urinary tract infection. Infections in sickle cell disease may also be linked to effects of the disease on other components of the immune system, such as white blood cells. As a result of the fatty acid imbalance, vaso-occlusion and organ damage, sickle cell patients are often in a near-continuous state of inflammation. They have elevated states of certain proteins that are markers of inflammation. Sickle cell patients also often have near continuous obstructive blood clotting activity inside the blood vessels, low level most of the time but spiking during crises. Ultimately, SCD causes multi-organ dysfunction and early death in affected individuals. Many succumb to complications of chronic organ dysfunction and eventual organ failure.

 

SC411 Solution for Sickle Cell Disease
SC411 is our proprietary product candidate that is being developed for the treatment of sickle cell disease. SC411 consists of a complex proprietary mixture of various fatty acids, primarily in the form of Ethyl Cervonate™ (SCI’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 and intended to be taken orally. As early as 1991, it was suggested that certain fatty acids decrease the destruction of red blood cells in mammals. It also has been found that sickle cell patients have abnormal blood fatty acids in red blood cells, white blood cells, platelets and plasma. These findings led naturally to the hypothesis that certain fatty acids may be useful in the treatment of SCD. As early as 2001, small human clinical trials showed that certain fatty acids could reduce pain episodes in sickle cell patients, perhaps by reducing activity that leads to obstructive blood clotting. Other studies have shown that these fatty acids can increase hemoglobin levels and reduce pain episodes, vaso-occlusive episodes, anemia, organ damage and other disease complications in sickle cell patients. Our Clinical Research Director, Dr. Daak, conducted a study on the effect of a mixture of certain fatty acids in patients with sickle cell anemia. The Daak et al study was a randomized, double-blind, placebo-controlled, 12-month clinical trial of the effects of a fatty acid combination that was primarily DHA plus EPA (both omega-3 fatty acids) in SCD patients. The study was carried out at the University of Khartoum, Khartoum (Sudan) in collaboration with London Metropolitan University, London. Inclusion criteria for the study included patients in steady-state SCD for 4 weeks prior to start of the study. Exclusion criteria included presence of other chronic diseases, blood transfusion in the previous 4 months, hydroxyurea treatment, history of overt stroke, and pregnancy. There were 140 patients deemed eligible for randomization and they were distributed 1:1 between the omega-3 and placebo groups. A total of 113 patients completed the study (58 in the omega-3 group, 55 in the placebo group). The test medication (which is identified as Active in the graph below) was a capsule containing a blend of certain fatty acids (primarily omega-3 fatty acids). The placebo capsule contained a high oleic acid oil blend. Both medication and placebo capsules contained vitamin E to prevent oxidation. To maintain the blind study, the capsules were matched in appearance and flavor. The dosing was based on age and weight. The primary endpoint was the annualized rate of clinical vaso-occlusive crisis, defined as painful events that lead to hospitalization. The secondary endpoints included incidence of severe anemia (Hb concentration < 50 g/L); number of inpatient days due to clinical vaso-occlusive crisis; and rates of blood transfusion, school attendance, mean Hb concentration, and average cell volume. The patients in the study were stratified by age and sex and randomly assigned to the drug or placebo control group. Masking was maintained throughout the study. Patient information was captured at baseline on a questionnaire and in a monthly self-assessment health diary in which the patient recorded daily pain frequency/intensity, pain medication use, and hospitalizations. During the study period, in-clinic monthly follow-ups were conducted at which time the patient diaries were reviewed. Whole blood was collected at recruitment and after one year and analyzed for fatty acid composition.

 

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Based on the concentration of a specific fatty acid contained in SC411, we believe that SC411 may provide similar benefits as those observed in the Daak, et. al. study. We believe that SC411 will treat sickle cell disease by decreasing blood cell adhesion, chronic inflammation and red cell hemolysis, the factors that lead to reduction in pain episodes, vaso-occlusive crises and organ damage. Based on its formulation and mechanism of action, we believe that SC411 is well-positioned to deliver therapeutic amounts of certain fatty acids to sickle cell patients. We believe that SC411 has the potential to address the inflammatory symptoms (e.g., pain and fatigue) of SCD and to assist in reducing sickle cell crisis events. We believe that by consistently and reliably delivering omega-3 fatty acids into a patient’s bloodstream, the membrane of a sickle cell will become more fluid, which will prevent the cell from blocking the capillary veins. By minimizing damaged capillary veins, SC411 may be able to reduce sickle cell crisis events and related mortality.

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