Sickle cell disease (SCD) is an blood disease that causes the Red blood cells in blood to (RBCs) to change to sickle shape. Sickled cells do not flow easily through small blood vessels and may cause obstruction resulting in recurrent episodes of pain. These episodes are referred to as vaso-occlusive events (VOC). The sickled cells have a shorter life span than the non sickled cells and this results in low blood levels (anaemia). SCD affects about 100,000 patients in the United States, up to 164,000 patients in Europe, and millions more in the rest of the world. In Kenya, the Ministry of Health estimates that at least 6000 children are born with SCD every year. Sickle Cell disease patients are found in larger numbers in areas with where Malaria common than in areas where malaria is less common in Kenya (Williams et al., 2005). Kombewa lies in an area where Malaria is common. Cure for SCD can be achieved by procedures called bone marrow transplant or gene therapies, but these are not available or possible for all patients and are also expensive. For most patients treatment is mainly supportive; pain control, blood transfusions or the use of hydroxyurea (HU). Newer treatments have been developed that increase blood level or reduce frequency of VOCs but none of the treatments does both. The search for other treatmentsis on going. The study drug, Etavopivat (FT-4202) is a potent activator of a protein called Pyruvate kinase R (PKR), which is key in the process of generating energy in the body. It is that PKR activation will reduce the rate of RBC sickling and RBC destruction leading to less frequent episodes of pain(VOC) and increased blood levels. This study is designed to take place in phases among patients with SCD, aged 12 to 65 years. The phase 2 is the dose determination portion when patients will receive one of two dose levels of study drug or placebo (a placebo is a substance that looks like the study drug but has no effects on the body). The selected dose will be assessed for efficacy (effectiveness) in Phase 3, for increasing blood level and reducing episodes of VOC, over 52 weeks, when compared to a placebo (). After the 52 week follow up period the patients may enter 52 weeks period in which all patients receive the study drug. This study will enroll up to about 344 patients with SCD (60 to 90 patients in the Dose Determination Group and 274 patients in the Phase 3). The Kombewa Clinical Research Centre targets to enroll about 25 Subjects in the dose determination group and about 40 subjects in the efficacy continuation group. At study pre-determined time points, the participants will undergo heath assessments; physical examinations, taking of vital signs (e.g. temperature, Blood pressure, heart rate, respiratory rate), recording heart activity using an electrocardiogram (ECG), and various laboratory assessments as part of follow up safety assessments. All the information will be recorded and then analyzed. Ethical approvals will be sought from the relevant authorities prior to study start. Results from the overall study will inform on the potential usefulness of the study drug (FT-4202) in the treatment of patients with SCD

Sickle cell disease is a chronic hemolytic anemia caused by inheritance of a mutated form of hemoglobin (Hb), sickle Hb (HbS). The disease is characterized by polymerization of HbS in RBCs when in the deoxygenated state, resulting in a sickle-shaped deformation of RBCs. Sickled cells aggregate in capillaries precipitating vaso-occlusive events that generally present as acute and painful crises (VOC) resulting in tissue ischemia, infarction, and long-term tissue damage, that underlies the significant morbidity and increased mortality associated with this disease. Red blood cells in SCD patients tend to be fragile due to sickling and other factors, and the mechanical trauma of circulation causes hemolysis and chronic anemia. Sickle cell disease is the most common inherited hemolytic anemia, affecting approximately 100,000 individuals in the United States (US) (CDC 2020), approximately 35,000 to 164,000 individuals in Europe, and millions more worldwide (Hassell, 2010; Lobitz et al, 2018). In Kenya, Ministry of Heath estimates that at least 6000 children are born annually with SCD. The paediatric to adult ratio stands at 3:1 and Sickle Cell disease has been found to be more prevalent in areas with high prevalence of Malaria in Kenya (Williams et al., 2005). Kombewa lies in the area with high prevalence of Malaria. Therapeutic treatment of SCD remains inadequate. Potentially curative therapies, such as bone marrow transplant or gene therapies are invasive and such high-risk procedures are available to only a limited number of patients. For most patients, treatment involves supportive care for management of vaso-occlusive crisis (VOC) or the use of hydroxyurea (HU), to stimulate production of fetal Hb (HbF) and reduce Hb polymerization. However, the myelosuppressive and teratogen effects of HU limit its effectiveness. More recently other therapies have been approved; L-Glutamine to reduce the acute complications of SCD, Volexotor, indicated to reduce hemolysis and improve hemoglobin levels, and Crizanlizumab to reduce the incidence of VOCs. None of these therapies results in both improvement of anemia and a reduction in the frequency of VOCs. Additional therapies that target the underlying physiology are needed. Pyruvate kinase R (PKR) is the isoform of Pyruvate kinase expressed in RBCs and its activation is proposed to directly target both sickling by reducing deoxy-HbS and Hemolysis by improving RBC membrane integrity. The study drug, Etavopivat (FT-4202) is a potent selective activator of PKR. This is a randomized, placebo-controlled, double-blind, multicenter Phase 2/3 study among SCD patients, aged 12 to 65 years. The primary objective is to assess the efficacy of FT-4202 in adolescents and adults with SCD as compared to placebo as measured by improvement in hemoglobin (Hb) and annualized vaso-occlusive crisis (VOC) rate. The Phase 2, is the dose determination portion and the selected dose will be assessed in Phase 3, the efficacy portion against placebo. Following a double blind period of 52 weeks, all patients may enter a 52-week open-label extension period. The study will enroll approximately 344 adult and adolescent patients with SCD, who fulfill the eligibility criteria (60 to 90 patients in the Dose Determination Group and approximately 274 patients in the Efficacy Continuation Group). The Kombewa Clinical Research Centre targets to enroll about 25 Subjects in the dose determination group and about 40 subjects in the efficacy continuation group. Study activities during visits will include but not limited to a physical, vital signs, randomization, 12-Lead ECG, and various laboratory assessments at screening and as part of efficacy and safety assessments at time points as per the protocol Schedule. Patients will be evaluated for safety by collection of adverse events (AEs)/serious adverse events (SAEs), laboratory tests and vital signs. Serious adverse events will be collected from the time of signature of informed consent throughout the dosingperiod and including the follow-up period. Ethical approvals will be sought from the relevant authorities prior to study implementation. Results from the overall study will inform the potential usefulness of FT-4202 in the treatment of patients with SCD.