Pociredir

• Company has announced discontinuation due to FDA concerns regarding pociredir’s benefit-risk profile in SCD, stemming from an unexpectedly high rate of secondary hematologic malignancies observed with Tazverik® (tazemetostat), another PRC2 inhibitor, which was withdrawn from the global market in March 2026. Fulcrum submitted information to the FDA supporting the position that mechanistic differences between EED (pociredir’s target) and EZH2 (tazemetostat’s target), which perform different biological roles, were relevant to the benefit-risk assessment. FDA considered this position but concluded that any pharmacological intervention targeting the PRC2 complex carries equivalent malignancy risk regardless of the specific subunit engaged. FDA’s position is informed by pociredir’s previously disclosed preclinical malignancy observations and left no viable regulatory path forward for further clinical development of pociredir.
• Data presented at the EHA Annual Congress (11 – 14 June 2026) showed that:HbF increased from baseline by week 12 in all participants.
  – 8.6% increase in 12mg cohort (16 patients) and 12.2% in 20mg cohort (13 patients).
  – Haemoglobin increased significantly in non-transfused patients in both cohorts from baseline to week 12.
  -Haemolysis/erythropoiesis markers showed significant improvement in both cohorts from baseline to week 12.

Sources: Fulcrum Therapeutics Announces Discontinuation of Pociredir Program in Sickle Cell Disease and Initiation of Strategic Review 
Results of the Phase 1b Pioneer Study: Safety and Efficacy of Pociredir in Adults with Severe Sickle Cell Disease and Hydroxyurea Intolerance or Unresponsiveness

Update: 31 March 2026

Pociredir is a once daily oral HbF inducer. Results from the 12-week treatment period of the 20 mg dose cohort of the Phase 1b PIONEER trial (n=12) were announced:

• Mean absolute HbF increased by 12.2% at 12 weeks (vs. 8.6% at Week 12 in the 12 mg cohort)
• All patients demonstrated a clinically relevant HbF increase.
• Based on treating physician-documented medical records from the 6-12 months before enrollment, approximately 16 VOCs would have been expected during the 12-week treatment period. During the 12-week treatment period, six VOCs were reported. Seven of 12 patients (58%) reported no VOCs during the treatment period.

Source: https://ir.fulcrumtx.com/news-releases/news-release-details/fulcrum-therapeutics-announces-positive-12-week-results-20-mghttps://ir.fulcrumtx.com/static-files/ad8b1e95-b4be-4100-9815-4a90e0b93327
Corporate Presentation, March 2026

Update: 22 December 2025

Results from the Phase 1b study were presented at the 67^th ASH Annual Congress (6 – 9 December 2025) in Orlando (USA). The data showed that:

• Cohort 3b was created following a protocol amendment to allow patients with ≥ 4 VOCs per year, ≥ 2 VOCs over 6 months, or documented SCD-related organ damage and not receiving hydroxyurea to enroll.
• Sixteen patients were enrolled in Cohort 3b and administered a dose of 12mg, completing the 12-week treatment period.
• At week 12, all participants had an increase of HbF, with 44% of patients achieving levels of more than 20% – a threshold associated with reduced VOCs
• Markers of haemolysis showed improvements.

Sources: Pociredir, a novel oral once-daily fetal hemoglobin inducer: Results from the Phase 1b pioneer study in adult participants with severe sickle cell disease and hydroxyurea intolerance or unresponsiveness
https://www.fulcrumtx.com/wp-content/uploads/251206-PIONEER-PHASE-1B-ASH-POSTER-vF.pdf

Update: 30 September 2025

• Data to be shared from the 20mg dose cohort by year’s end.
• Interim results from 16 patients who completed a 12-week treatment period with 12mg pociredir showed:
  • A mean increase of 8.6% of fetal haemoglobin (HbF)
  • 7/16 (44%) participants saw HbF rise over 20% – a threshold associated with reduced VOCs
  • Mean total haemoglobin increased by 0.9 g/dL

Sources: https://www.rttnews.com/3577462/pociredir-trial-and-dba-ind-filing-put-fulcrum-therapeutics-on-watchlist.aspx
https://sicklecellanemianews.com/news/pociredir-well-tolerated-shows-promising-activity-scd-trial/

Update: 30 June 2025

Enrolment is complete for the groups receiving 2mg, 6mg, and 12mg. Begun enrolment for the 20mg dose group.

Source: https://sicklecellanemianews.com/news/sickle-cell-disease-patients-being-recruited-pioneer-trial-pociredir/

Update: 31 March 2025

No update available.

Update: 19 December 2024

No update available.

Update: 30 September 2024

No update available.

Update: 30 June 2024

Data presented at the 29^th EHA Annual Congress (13 – 16 June 2024) in Madrid (Spain) from 3 dose-finding cohorts (6mg, 2mg, and 12mg) to induce fetal haemoglobin (HbF) enrolled 10, 2 and 4 patients respectively, showed that:

• • All patients adherent to the once daily oral administration of pociredir had HbF induction with increases of 9.8% and 10% in the 6mg and 12mg cohorts, respectively.
  • Dose-dependent increases were not affected by hydroxyurea use.

Source: Interim Results of a Phase 1b Study (Pioneer) of an Oral HbF Inducer, Pociredir, in Sickle Cell Disease