S103: TRIAL IN PROGRESS: A PHASE 2, OPEN-LABEL STUDY EVALUATING THE SAFETY AND EFFICACY OF THE PKR ACTIVATOR ETAVOPIVAT (FT-4202) IN PATIENTS WITH THALASSEMIA OR SICKLE CELL DISEASE

Abstract

Background: Sickle cell disease (SCD) and thalassemia are hemoglobinopathies characterized by lifelong anemia. In SCD, a single β-globin gene mutation results in sickle hemoglobin (HbS) that polymerizes upon deoxygenation, causes RBCs to sickle and leads to various complications. In thalassemia, α- and/or β-globin gene mutation(s) result in reduced or absent adult Hb, ineffective erythropoiesis, and downstream complications. The resultant anemias, exacerbated by impaired RBC health, are associated with lower ATP levels than in healthy RBCs. Supportive care and agents like hydroxyurea are used most in SCD, with some patients (pts) on regular transfusions. Regular or episodic transfusions, with their own set of complications, are the mainstay of treatment for thalassemia. Etavopivat, an investigational, once-daily, selective, erythrocyte pyruvate kinase (PKR) activator increases ATP and decreases 2,3 diphosphoglycerate (2,3-DPG). In a Phase 1 study, etavopivat 300–600 mg once daily in pts with SCD not regularly transfused was well-tolerated, improved hematologic markers, decreased hemolysis, and improved markers of RBC health [1,2]. Etavopivat 200 and 400 mg once daily (dose levels predicted to provide the desired PD response profiles) are being evaluated in a Phase 2/3 study of pts with SCD not on chronic transfusions (The Hibiscus Study, NCT04624659). Aims: Describe the design of a Phase 2, open-label, multicenter study (NCT04987489) evaluating the efficacy and safety of etavopivat in pts with: SCD on chronic transfusions (Cohort A), transfusion-dependent thalassemia (Cohort B), and non–transfusion-dependent thalassemia (Cohort C). Methods: Up to 20 pts (12–65 y) will be enrolled in each of the 3 cohorts described above. Key eligibility criteria are outlined in the Table. Pts will receive etavopivat 400 mg once daily for 48-wks (Figure). Pts will provide written informed consent. Baseline assessments will include medical, disease, transfusion, and medication histories. Transfusions received during the study (every ~3–5 wks) will be recorded and include Hb values before and ≥15 min after transfusion, transfusion dates, number of RBC units, volume of packed RBCs, and hematocrit of the transfused unit (if available). If a pt has an increase in pre-transfusion Hb of ≥1.0 g/dL versus their baseline pre-transfusion Hb, the investigator may delay transfusion 1 wk or reduce the number of RBC units transfused. In pts with SCD, RBC exchange transfusions may also be performed. The primary endpoints are outlined in the Figure. Secondary and exploratory endpoints include the proportion of pts with a reduction in transfusions over 12 wks of ≥33% and ≥50%, respectively, and a reduction in transfusions over 12, 24, and 48 wks (Cohorts A/B); and Hb response at Wks 24 and 48, and changes from baseline in Hb over 12, 24, and 48 wks (Cohort C). The following additional endpoints will be assessed (all cohorts): changes from baseline in quality of life (using the SF-36 and PROMIS); changes from baseline in serum ferritin levels at 12, 24, and 48 wks; liver iron at 48 wks; 2,3-DPG and ATP; PK; and safety. All primary endpoints will be analyzed using a 1-sided test at α=0.025.Summary: Etavopivat is a novel, investigational, once-daily, selective PKR activator with potential to improve RBC health and lifespan. This Phase 2 study will assess the safety of etavopivat and its impact on Hb levels and transfusion burden in pts (12–65 y) with SCD or thalassemia.