Purpose: In sickle cell disease (SCD), a single β-globin gene mutation results in sickle hemoglobin (HbS) that polymerizes upon deoxygenation, causing red blood cells (RBCs) to sickle leading to various complications. In thalassemia, RBCs have an imbalance in the ratio of α/β globin chains and aggregated, unpaired globin chains increase metabolic demands. These stresses result in ineffective erythropoiesis and shorten RBC lifespan, leading to chronic anemia. 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 treating SCD, with some patients 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-DPG.1,2 In a Phase 1 study, etavopivat 300-600 mg once daily in patients 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 (doses predicted to provide desired pharmacodynamic response profiles) are being evaluated in a Phase 2/3 study of patients with SCD not on chronic transfusions (The Hibiscus Study, NCT04624659). We describe the design of a Phase 2, open-label, multicenter study (NCT04987489) evaluating efficacy and safety of etavopivat in patients with SCD on chronic transfusions (Cohort A), transfusion-dependent thalassemia (Cohort B) and non–transfusion-dependent thalassemia (Cohort C).
Materials and methods: Key eligibility criteria are outlined in Figure 1. Patients will receive etavopivat 400 mg once daily for 48 wks (Figure 2). Patients will provide written informed consent.
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 patient has an increase ≥1.0 g/dL in pre-transfusion Hb vs baseline, the investigator may delay transfusion 1 wk or reduce the number of RBC units transfused. RBC exchange transfusions may also be performed in patients with SCD.
Primary, secondary and exploratory endpoints are outlined in Figure 2. The following additional endpoints will be assessed in all cohorts: change from baseline in quality of life (using SF-36 and PROMIS); change from baseline in serum ferritin levels at 12, 24 and 48 wks; liver iron at 48 wks; 2,3-DPG and ATP; pharmacokinetics; and safety. Primary endpoints will be analyzed using a 1-sided test at α=0.025.
Results: Results are not yet available for this trial in progress. Planned enrollment includes ≤20 patients (aged 12-65 y) in each of the 3 cohorts (Figure 2).
Conclusion: 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 patients (aged 12-65 y) with SCD or thalassemia.
Brown et al, Blood 2021.
Kalfa et al, Blood 2021.
Key eligibility criteria for patients 12–65 y of age.
Study Design.
R. BROWN declares a conflict of interest:
Consultancy, Expert: Global Blood Therapeutics; Novo Nordisk
Research support/Scientific studies: Doris Duke Foundation, Global Blood Therapeutics, Forma, Imara, Novartis
C. TRENOR declares a conflict of interest:
Consultancy, Expert: employment - Forma Therapeutics
K. WOOD declares a conflict of interest:
Stock shareholder: Forma Therapeutics Inc.
Other: Employee of Forma Therapeutics Inc.