Forma Therapeutics, Inc. (the Sponsor) is developing a drug called Etavopivat(FT-4202), for the treatment of sickle cell disease (SCD). Sickle Cell Disease, SCD is one of the most common blood disorders in the world passed from one generation to another. It is characterized by painful episodes, low blood level, and multiple organ damage. Painful episodes are the most common manifestation of the disease. Sickle cell disease commonness is seen to be 1.6% in children 6-35 months (Suchdev PS 2012). In addition to the widespread presence of SCD patients in this area, the outpatient and inpatient at the Siaya Referral Hospital shows over 400 sickle cell disease patients within the eligible age bracket are attended to. As there is no systematic screening program for young children less than 1 month in most public and private facilities, there are no data of sickle cell commonness in this age group. Sickle Cell Disease affects 20-25 million of people globally, of which 12-15 million live in Africa. The natural distribution covers a broad belt, including the Mediterranean, western, parts of East and Central Africa, the Middle East, India and South East Asia. It is estimated that 75-85% are children born in Africa where 50-80% of children born with the disease die before the age of 5 years. The Cooperative Study of Sickle Cell Disease study (CSSD) identified that most of the children with sickle cell disease died before their second birthday due to infection and anemia hence the need to identify these patients even before they shown signs of disease. In Sub-Saharan Africa, approximately 240,000 children are born with Sickle Cell. There is paucity of population level data but in general, based on model projections it is estimated that almost 6,000 newborns (one in every 150 newborns) had Sickle Cell in 2010 and this number could rise to over 10,000 (one in every 100 newborns) per year by 2050. In Kenyasickle cell disease commonness varies in regions and imitates malaria commonness. In the Western region it is estimated that as high as 18% of children are born with a Sickle Cell Trait and 4.5% will end up developing SCD. In the lake region, it is estimated that about 17% children are carriers of the trait with 0.6% having SCD while in the coastal region, using data of the admitted patients, almost 1% of children have SCD and are almost 20 times likely to die compared to admissions of other illnesses. Movement in search of better livelihoods leads to a wider spread of the areas previously considered zones with high sickle cell disease burden. (Source; National Guidelines for control and management of SCD in Kenya, April 2020) Despite current standards of medical care of sickle cell patients, including hydroxyurea (HU), blood transfusion, and Immunization against infection relevant to SCD like ‘Streptococcal pneumonia, Hemophilus influenza type B and Hepatitis B’ and supportive care with painkillers, mental and social support and malaria prevention medications, patients with SCD continue to suffer and some die prematurely. The clinical speculation is that ‘PKR activation’ will reduce the rate of sickle cell chain formation and improve red blood cell (RBC) membrane function, thereby reducing the change of red cell to look like sickle and break down that lead to low blood level and blockage of blood vessel, two hallmarks of Sickle Cell disease. By addressing this, FT-4202 has the potential to be an illness-modifying medication, leading to improved blood level, reduced red cell break down and the potential to reduce the organ damage resulting from longstanding low blood level. This study is a randomized, placebo-controlled, double-blind, multicenter Phase 2/3 study of patients, age 12 to 65 years, with Sickle Cell Disease. Initially, participants will be randomized 1:1:1 to one of two dose levels of FT-4202 or placebo (dose determination portion) and one of the two FT-4202 dose levels will be selected for the Phase 3 portion of the study, and randomization of patients becomes 1:1, the selected FT-4202 dose or placebo (effectiveness continuation portion) The main purpose is to assess the effectiveness of FT-4202 in adolescents and adults with SCD as compared to an inactive drug(Placebo) as measured by improvement in blood level and the rate of pain episodes in a year. This study will enroll up to approximately 344 adult and adolescent patients with Sickle Cell Disease, SCD. It will be conducted at KEMRI-CRDR Siaya. Siaya is expected to enroll a minimum of 30 participants. Enrolment will be on a competitive basis. The results of this study will form a basis for further studies on the usefulness of Etavopivat for SCD treatment. In addition, the results of this study will be important in defining new treatments for management of sickle cell disease. This could have a significant impact on the quality of life of these patients and their caregivers.

Forma Therapeutics, Inc. (the Sponsor) is developing FT-4202, an oral Pyruvate Kinase Activator for the treatment of sickle cell disease (SCD). SCD 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 are the most common presentation of SCD. Vaso-occlusive crises are caused by activation of the endothelial cells, neutrophils, monocytes and platelets by the sickled red blood cells leading to aggregation and adhesion of these cells to one another and to the endothelial cells leading to clot formation and blockage of the microvascular channels. HbSS prevalence is seen to be 1.6% in children 6-35 months (Suchdev PS 2012). In addition to the high prevalence of SCD patients in this area, outpatient and inpatient at the Siaya Referral Hospital shows over 400 sickle cell disease patients within the eligible age bracket are reviewed. As there is no systematic neonatal screening program in most public and private facilities, there are no neonatal prevalence data. Sickle Cell Disease affects 20-25 million of people globally, of which 12-15 million live in Africa. The natural distribution covers a broad belt, including the Mediterranean, western, parts of East and Central Africa, the Middle East, India and South East Asia. It is estimated that 75-85% are children born in Africa where 50-80% of children born with the disease die before the age of 5 years. The Cooperative Study of Sickle Cell Disease study (CSSD) identified that most of the children with sickle cell disease died before their second birthday due to infection and anemia hence the need to identify these patients even before they shown signs of disease. In Sub-Saharan Africa, approximately 240,000 children are born with Sickle Cell. There is paucity of population level data but in general, based on model projections it is estimated that almost 6,000 newborns (one in every 150 newborns) had Sickle Cell in 2010 and this number could rise to over 10,000 (one in every 100 newborns) per year by 2050. In Kenya, the prevalence varies in regions and mimics the malaria endemicity. In the western region it is estimated that as high as 18% of children are born with a Sickle Cell Trait and 4.5% will end up developing SCD7. In the lake region, it is estimated that about 17% children are carriers of the trait with 0.6% having SCD8 while in the coastal region, using inpatient data, almost 1% of inpatient children have SCD and are almost 20 times likely to die compared to admissions of other morbidities9. Movement in search of better livelihoods leads to a wider spread of the areas previously considered endemic zones. (National Guidelines for control and management of SCD in Kenya, April 2020) Despite current standards of care, including hydroxyurea (HU), blood transfusion, and Immunization against infection relevant to SCD like Streptococcal pneumonia, Hemophilus influenza type B and Hepatitis B and supportive care with analgesia, psychosocial support and malaria prophylaxis, patients with SCD continue to suffer serious morbidity and premature mortality. The clinical hypothesis is that PKR activation will reduce the rate of sickle cell polymerization and improve red blood cell (RBC) membrane function, thereby reducing RBC sickling and RBC hemolysis that lead to vascular obstruction and anemia, two hallmarks of SCD pathology. By addressing this underlying mechanism of SCD, FT-4202 has the potential to be a disease-modifying therapy, leading to improved anemia, reduced hemolysis and the potential to reduce the end-organ damage resulting from chronic hemolytic anemia. This study is a randomized, placebo-controlled, double-blind, multicenter Phase 2/3 study of patients, age 12 to 65 years, with SCD. Initially, participants will be randomized 1:1:1 to one of two dose levels of FT-4202 or placebo (dose determination portion) and one of the two FT-4202 dose levels will be selected for the Phase 3 portion of the study, and randomization of patients becomes 1:1, the selected FT-4202 dose or placebo (efficacy continuation portion). 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 the efficacy of FT-4202 as compared to placebo on the annualized vaso-occlusive crisis (VOC) rate. This study will enroll up to approximately 344 adult and adolescent patients with SCD. It will be conducted at KEMRI-CRDR Siaya.Siaya is expected to enroll a minimum of 30 participants. Enrolment will be on a competitive basis. The results of this study will form a basis for further studies on the usefulness of Etavopivat for SCD treatment. In addition, the results of this study will be important in defining new treatments for management of sickle cell disease. This could have a significant impact on the quality of life of these patients and their caregivers.