a study of etavopivat in patients with thalassemia or sickle cell disease

Conditions: Sickle Cell Disease; Thalassemia

Summary: this clinical trial is a phase 2 study that will evaluate the safety and clinical activity of etavopivat in patients with thalassemia or sickle cell disease and test how well etavopivat works to lower the number of red blood cell transfusions required and increase hemoglobin.

etavopivat is a potent, selective, orally bioavailable, small-molecule activator of pyruvate kinase red blood cell (pkr) being developed by forma therapeutics, inc and is intended for use as a treatment for patients with sickle cell disease (scd) or other inherited hemoglobinopathies or refractory anemias. this study is a multicenter, phase 2, open-label, multiple-cohort study examining the safety and efficacy of etavopivat for the treatment of patients, age 12 to 65 years, with scd or thalassemia. three treatment cohorts based on the patients hemoglobinopathy (scd or thalassemia) and transfusion requirements will be evaluated.

Eligibility criteria:
inclusion criteria: * provision of consent * female patients of childbearing potential must use acceptable methods of contraception, male patients are willing to use barrier methods of contraception cohort a (sickle cell disease transfusion cohort) * confirmed diagnosis of sickle cell disease * chronically red blood cell transfused (sample or exchange \[manual or via electrophoresis\]) for primary stroke prevention or due to previous stroke. chronic red blood cell transfusion is defined as: ≥ 6 red blood cell units in the previous 24 weeks before the first dose of study treatment and no transfusion-free period for \> 35 days during that period * at least 24 months of chronic monthly red blood cell transfusions for secondary stroke prevention/treatment of primary stroke (initial completed overt clinical stroke with documented infarction on brain computed tomography \[ct\] or magnetic resonance imaging \[mri\]) * prior to screening or at least 12 months of chronic rbc transfusions for primary stroke prevention (abnormal tcd) prior to screening * documented adequate monthly transfusions with average hbs ≤ 45% (the upper limit of the established academic community standard) for the previous 12 weeks of red blood cell transfusions before the first dose of study treatment cohort b (thalassemia transfusion cohort) * documented diagnosis of β-thalassemia, hemoglobin e/ β-thalassemia or hemoglobin h (α-thalassemia), or other thalassemia variant * chronically transfused, defined as: ≥ 6 red blood cell units in the previous 24 weeks before the first dose of study treatment and no transfusion-free period for \> 35 days during that period cohort c (thalassemia non-transfused cohort) * documented diagnosis of β-thalassemia, hemoglobin e/ β-thalassemia or hemoglobin h (α-thalassemia), or other thalassemia variant * hemoglobin ≤ 10 g/dl exclusion criteria: * female who is breast feeding or pregnant * hepatic dysfunction characterized by: * alanine aminotransferase (alt) \> 4.0 × upper limit of normal (uln) * direct bilirubin \> 3.0 × uln * history of cirrhosis * known human immunodeficiency virus (hiv) positivity * active hepatitis b or hepatitis c infection * severe renal dysfunction or on chronic dialysis * history of malignancy within the past 2 years prior to treatment day 1 requiring systemic chemotherapy and/or radiation. * patients with malignancy considered surgically cured are eligible (eg, non- melanoma skin cancer, cancer of the cervix in-situ, ductal carcinoma in situ \[stage 1\], grade 1 endometrial cancer) * history of unstable or deteriorating cardiac or pulmonary disease within 6 months prior to consent including but not limited to the following: * unstable angina pectoris or myocardial infarction or elective coronary intervention * congestive heart failure requiring hospitalization * uncontrolled clinically significant arrhythmias * symptomatic pulmonary hypertension

Keywords: scd sickle cell disease sickle cell anemia sickle cell anemia hemolytic hemoglobin vaso-occlusive crisis voc vaso-occlusive events sickle cell crisis pain crisis pain episode congenital anemia hemolytic anemia hematologic disease hemoglobinopathy hemoglobinopathies genetic disease inborn disease sickle cell trait pyruvate kinase pkr thalassemia beta-thalassemia alpha-thalassemia transfusions hemoglobin h transfusion transfusion-dependent non-transfusion dependent hemoglobin e