Safety and efficacy of pociredir in adults with severe sickle cell disease and hydroxyurea intolerance or unresponsiveness: results from the phase 1b PIONEER study

Abstract

Abstract Background Higher levels of fetal hemoglobin (HbF) have been shown to improve clinical outcomes in sickle cell disease (SCD). Pociredir is a novel, once-daily, oral small molecule that increases HbF expression. Here, we report safety and efficacy results for cohorts 3b (12 mg) and 4 (20 mg) from the ongoing phase 1b PIONEER (NCT05169580) dose-escalation study of pociredir. Methods Patients with severe SCD (≥4 vaso-occlusive crises [VOCs] over 12 months, ≥2 VOCs over 6 months, or documented SCD-related end organ disease) who were ineligible for or unresponsive to hydroxyurea were enrolled in cohorts 3b (12 mg) and 4 (20 mg) and treated for 12 weeks with safety monitoring for an additional 4 weeks after treatment completion. Primary endpoints were safety and tolerability. Secondary and exploratory endpoints included HbF induction; markers of anemia, hemolysis, and erythropoiesis; and % F cells. Results A total of 16 patients were enrolled in the 12-mg cohort (56% female; mean age, 34.3 years) and 13 patients in the 20-mg cohort (per statistical analysis protocol, analysis set excludes 1 patient who received only 1 dose: 83% female; mean age, 32.3 years). As of the data cutoff date (November 11, 2025), all 16 patients in the 12-mg cohort and 6 of 12 in the 20-mg cohort had completed 12 weeks of treatment. Pociredir was generally well tolerated, with no dose-limiting toxicities, no discontinuations due to treatment-related adverse events (AEs), and no treatment-related serious AEs. Treatment-related AEs (including headache, nausea, paresthesia, diarrhea, rhinorrhea, reticulocytopenia, and insomnia) were reported for 3 patients in each cohort. HbF increased from baseline in all patients (12 mg: mean increase, 8.6% [P < 0.0001] through week 12; 20 mg: mean increase, 9.9% [P < 0.0001] through week 6; Figure 1). An absolute HbF level of ≥ 20% was achieved by 7 of 16 (44%) patients in the 12-mg cohort at week 12 and 7 of 12 (58%) patients in the 20-mg cohort as of their latest study visit (Figure 2). Hemoglobin (in non-transfused patients) increased significantly from baseline to week 12 in cohort 3b (mean change from baseline [CFB]: 0.9 g/dL [P = 0.0004]) and to week 6 in cohort 4 (mean CFB: 0.7 g/dL [P = 0.0005]). Fewer patients in the 20-mg cohort vs the 12-mg cohort required transfusions during the treatment period (n = 0 vs n = 2, respectively) despite the cohorts having similar mean hemoglobin levels at baseline (7.3 g/dL vs 7.8 g/dL). Hemolysis/erythropoiesis markers showed significant improvement in both cohorts. In cohort 3b at week 12, mean CFB for lactate dehydrogenase, indirect bilirubin, absolute reticulocyte count, and red cell distribution width was −171.5 IU/L (P = 0.0001), −20.9 μmol/L (P = 0.0005), −121.8 x 10³ cells/μL (P = 0.002), and −5.6% (P < 0.0001), respectively. Similarly, in cohort 4 at week 6, mean CFB for these markers was −238.2 IU/L (P = 0.03), −24.2 μmol/L (P = 0.01), −127.9 x 10³ cells/μL (P = 0.03), and −4.7% (P = 0.0001), respectively. The F-cell percentage reached 65% at week 12 in the 12-mg cohort and 58% at week 6 in the 20-mg cohort. Conclusions Pociredir 12 mg and 20 mg had a favorable safety profile, with no dose-limiting toxicities or treatment-related serious AEs. Preliminary efficacy analysis showed a dose-dependent increase in HbF, reduction of hemolysis markers, and improved anemia in patients with severe SCD and limited treatment options.