Introduction. Increased expression of fetal hemoglobin (HbF) can counteract hemoglobin S polymer formation in sickle cell disease (SCD), reducing symptoms and improving clinical outcomes. Pociredir is a novel, once-daily, oral agent that binds the embryonic ectoderm development (EED) subunit of the polycomb repressive complex 2 (PRC2), inhibiting trimethylation of histone H3 at lysine 27 (H3K27me3), resulting in downregulation of BCL11A and MYB and inducing HbF expression. Here, we report safety and efficacy results for Cohort 3b (12 mg; n=16) from the ongoing PIONEER dose-escalation study.

Methods. PIONEER (ClinicalTrials.gov ID: NCT05169580) is an open-label, Phase 1b study evaluating pociredir in adults. Previously, participants (with no requirement for disease severity) were enrolled in three dose cohorts, 2 mg (n=2), 6 mg (n=10), and 12 mg (n=4), treated for a 4-week period, with an option to be treated for up to 12 weeks, and monitored for safety for 4 weeks after treatment completion. Following a protocol amendment, participants with severe SCD (≥4 vaso-occlusive crises [VOCs] over 12 months, ≥2 VOCs over 6 months, or documented SCD-related organ damage, and not receiving hydroxyurea (HU) or any other disease modifier, due to ineligibility or prior unresponsiveness, were then enrolled in Cohort 3b (12 mg) and Cohort 4 (20mg) and treated for 12 weeks. Primary endpoints include safety, tolerability, and pharmacokinetics. Secondary and exploratory endpoints include changes in %HbF, %F-cells, hemolytic markers, biomarkers of erythropoiesis, and incidence of VOC. Changes from baseline were analyzed using a paired t-test.

Results. All 16 participants in Cohort 3b (12 mg) completed the 12-week treatment period. At the time of the data cut, 7 participants remained on study in the safety follow-up. Mean age was 34.3 years (range, 18-60), and 56% were female. Genotypes included HbSS (n=14) and HbS/β⁰ (n=2). Six participants had ≥2 VOCs in the prior 6 months and 10 had ≥4 VOCs in the prior 12 months, with a mean number of baseline VOCs of 2.83 and 5.20, for the respective observation period.

At week 12, all participants demonstrated an increase in HbF, which increased from 7.6% (SE 1.2%) at baseline to 16.3% (SE 2.1%; mean increase of 8.6%, P<0.0001) with 44% (7/16) of patients achieving HbF levels of >20%. Two patients received multiple transfusions due to SCD-related complications. For non-transfused patients (n=14), mean absolute increase in HbF from baseline was 9.5% with 50% (7/14) of achieving levels >20% at week 12. For 8 participants for whom F-cell data at 12 weeks were available, 75% (6/8) had F-cell% >70%. Both HbF and F-cell trajectories did not appear to plateau at week 12, suggesting maximal responses had not yet been reached.

Markers of hemolysis showed consistent improvement. At week 12, mean lactate dehydrogenase (LDH) levels decreased from 614.6 IU/L at baseline to 443.1 IU/L (D= -171.5, P < .001) and indirect bilirubin levels decreased from 56.4 µmol/L to 35.5 µmol/L (D= -20.9, P < .001). A similar trend was observed for absolute reticulocyte counts and red cell distribution width. Total

hemoglobin increased by an average of 1.0 g/dL (P < .001) in non-transfused patients. During the 12-week treatment, 0.56 VOCs per patient were observed, compared to an estimated 1.25 VOCs in the 12-week period prior to enrollment. Half of participants (8/16) did not experience a VOC.

Treatment-emergent adverse events (TEAEs) were reported in 15 of 16 patients, regardless of causality, during the study period. TEAEs occurring in > three participants included back or extremity pain (n=5, 31%), fatigue (n=4, 25%), and arthralgia (n=3, 19%). Five treatment-related TEAEs (headache, nausea, paresthesia, diarrhea, rhinorrhea) were reported in 3 participants: all were grade 1 and resolved without dose interruption. Five serious AEs were reported, all consistent with VOC or other SCD-related pre-existing conditions (nephrotic syndrome, severe anemia).

Conclusion. Pociredir continues to demonstrate a favorable safety profile in severe SCD, consistent with earlier cohorts and expectations. Treatment with 12 mg QD resulted in rapid, sustained, and clinically meaningful increases in HbF in the majority of red cells, along with reductions in hemolysis and improvements in anemia. Preliminary data for VOCs follow a similar trend. Updates from this cohort and Cohort 4 will be presented.

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2025
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