Sickle Cell Disease

Sickle Cell Disease | Altemia

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 resulting 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 tissues fo the body 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 these losses, 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 SCD 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:

Signs and Symptoms

Signs and symptoms of SCD 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.

Altemia Solution for Sickle Cell Disease

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. SC411 (Altemia™) is our proprietary product candidate that is being developed for the treatment of SCD. 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 adminstration. Based on research performed by Micelle BioPharma and others, the specific lipids contained in Altemia, may restore balance and fluidity to red blood cells and other cells impacted by the disease. We believe that Altemia will treat sickle cell disease by decreasing blood cell adhesion, chronic inflammation and red blood cell hemolysis, the factors that lead to reduction in pain episodes, vaso-occlusive crisis (VOC) crises and organ damage. Based on its formulation and mechanism of action, we believe that 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. We also believe that Altemia has the potential to address the inflammatory symptoms of SCD and to assist in reducing sickle cell events in general. By minimizing damage, Altemia may be able to reduce sickle cell crisis events and related mortality.

Phase II Clinical Trial of Altemia™

Micelle BioPharma is excited about the very promising results from a recent double blind, randomized, multicenter phase 2 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. The primary endpoint was the percentage change in the total blood cell membrane DHA and EPA concentration from baseline after 4 weeks of treatment. Following the duration of treatment, blood cell membrane DHA and EPA levels increased significantly from baseline levels in response to all three different doses of Altemia (P < 0.001); 36 mg/kg, 60 mg/kg, and pooled treatments also increased significantly compared to placebo (P < 0.01) (Figure 1). Furthermore, Altemia significantly reduced electronic diary (eDiary) recorded sickle cell pain crises, non-opioid and opioid analgesic use at home for sickle cell pain and days absent from school due to sickle cell pain. The lower rate of clinical SCC observed in the pooled active groups versus placebo did not reach statistical significance (rate ratio, 0.47; 95% confidence interval [CI]: 0.20 to 1.11; p=0.07) (Figure 2). All tested doses were safe and well tolerated. ClinicalTrials.gov: NCT02973360

    

Subjects who consented to the open label extension (OLE) period of the Phase 2 study were rolled into the lowest dose level (20 mg/kg) and subsequently to the middle dose (36 mg/kg). Forty-one subjects (66%) opted into the OLE. Of all subjects in the OLE, seven (17.07%) received placebo during the blinded part of the study. At the time of this analysis, thirty-seven subjects had completed at least 370 days in the study. The results show evidence of sustained therapeutic benefits of Altemia in reducing the incidence of SCC without unexpected or treatment-related adverse events (Figure 3).