A Phase 1b, Open-label, Multiple-Dose Study Evaluating Safety, Pharmacokinetics (PK), and Pharmacodynamics (PD) of Pociredir in Patients With Sickle Cell Disease (SCD): Trial Design

Abstract

Abstract Background SCD is the most common inherited blood disorder caused by a mutation in the β - globin (HBB) gene, resulting in dysfunctional hemoglobin S (HbS) that polymerizes under hypoxic conditions with consequent characteristic and pathogenic dysmorphic erythrocytes. Increased expression of fetal hemoglobin (HbF) can counteract this process, ameliorating clinical manifestations and symptoms of SCD and reducing morbidity and mortality. Pociredir, a novel, oral HbF inducer in development for the treatment of SCD, targets the embryonic ectoderm development subunit of polycomb repressive complex 2, inhibiting trimethylation of lysine 27 on histone H3, decreasing BCL11A expression and increasing HbF. We report on an ongoing phase 1b, open-label, multicenter, international study evaluating the safety, PK, and PD of oral pociredir in patients with SCD (PIONEER; ClinicalTrials.gov ID: NCT05169580). Methods The study was approved by regulatory authorities and ethics committees of participating sites. All participants provided written informed consent prior to their inclusion. PIONEER will enroll up to 70 patients 18-65 years of age with SCD (genotypes: S/S, S/β0, S/β+, and S/C). Current key inclusion criteria are poor response or intolerance of hydroxy urea (HU) and severe sickle cell disease. Exclusion criteria include prior hematopoietic stem cell transplant, or gene therapies; receiving scheduled transfusions; having known chromosomal abnormality or genetic mutation that may put the patient at increased risk of myelodysplastic syndrome or acute myeloid leukemia. Pociredir will be administered orally once daily for 12 weeks. Patients will be followed post dosing for 4 weeks. Primary endpoints are safety and tolerability and PK of pociredir. Secondary endpoints are changes from baseline in HbF and other SCD relevant biomarkers. Before a significant study amendment, patients enrolled across 3 cohorts. Cohort 1 enrolled 10 adults who received pociredir at a dose of 6 mg once daily (QD) for 4 weeks, with an option to continue for 8 more weeks. Cohorts 2 and 3 enrolled 2 adults (2 mg QD for 12 weeks) and 4 adults (12 mg QD), respectively. Concurrent hydroxyurea (HU) was allowed for patients included in the analysis. Results As of data cut off, 16 patients with HbSS genotype have been included in the analysis. Their mean age was 30.3 years (range, 21-48), and most participants were female (69%). Baseline mean HbF was 9.3% (range, 3.2-19.9%) and 5 patients were on HU. Ten patients had 23 adverse events (AEs), with 8 AEs deemed possibly related to pociredir, including headache (n = 2), lip numbness, diarrhea, tinnitus, fatigue, drowsiness, and nausea. All related AEs were mild, nonserious, resolved quickly, and did not lead to drug discontinuation. Four AEs were vaso-occlusive crises (VOCs); 1 was a serious AE involving ACS, unrelated to the drug, in a nonadherent patient. Other VOCs were mild to moderate and managed as outpatients. No laboratory-related AEs, deaths, or discontinuations occurred. Maximum HbF increase from baseline was 9.8% points at 12 weeks (Cohort 1) and 10.0% points at 6 weeks (Cohort 3). Most patients showed improved hemolysis biomarkers. Conclusions Preliminary safety, PK, and efficacy results demonstrate a favorable safety profile, a dose-dependent increase in HbF, and a reduction in hemolysis, supporting further investigation. PIONEER is currently enrolling in Nigeria, South Africa, and the United States.