pociredir (FTX-6058) / Fulcrum Therap - LARVOL DELTA

Regulation of BCL11A DNA binding and expression in human erythrocyte precursor HUDEP-2 cells. (PubMed, bioRxiv) - "Notably, FTX6058 markedly reduced BCL11A transcription and translation (likely via effects on LIN28B), while EML741 caused a partial reduction. Third, we screened 213 pomalidomide- and lenalidomide-derived compounds and quantified proportions of HbF+ cells by flow cytometry...Although BCL11A levels themselves were unchanged, all four compounds selectively decreased levels of known pomalidomide targets, with consistently decreased levels of the zinc-finger proteins IKZF1 and ZFP91. Together, our studies clarify how BCL11A recognizes DNA, how its expression can be modulated epigenetically, and how small-molecule degraders influence its regulatory network, providing new avenues for HbF reactivation therapies."

Journal • Beta-Thalassemia • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • BCL11A • EML4 • IKZF1 • LIN28B

Single-dose Pharmacokinetics of Pociredir in Participants With Sickle Cell Disease (clinicaltrials.gov) - P1 | N=24 | Recruiting | Sponsor: Fulcrum Therapeutics

New P1 trial • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

PIONEER: Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Pociredir (clinicaltrials.gov) - P1 | N=45 | Completed | Sponsor: Fulcrum Therapeutics | Recruiting ➔ Completed | N=70 ➔ 45

Enrollment change • Trial completion • Anemia • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Open-Label Extension Study to Pioneer Study 6058-SCD-101 (clinicaltrials.gov) - P2 | N=50 | Not yet recruiting | Sponsor: Fulcrum Therapeutics

New P2 trial • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • HP

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 (ASH 2025) - "Taken together, these results highlight the transformative potential of oral HbF induction and position pociredir as a breakthrough candidate that could reshape the approach to disease modification in sickle cell disease. This session will focus on the underlying science, clinical data, and the future potential of this therapeutic strategy."

Clinical • P1 data • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

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 (ASH 2025) - P1 | "Preliminary data for VOCs follow a similar trend. Updates from this cohort andCohort 4 will be presented."

Clinical • P1 data • Anemia • Genetic Disorders • Glomerulonephritis • Hematological Disorders • Musculoskeletal Pain • Nephrology • Renal Disease • Sickle Cell Disease • BCL11A

HbF Inducing Eed Inhibitor Ftx-6058 Selectively and Reversibly Impacts Bone Marrow in Wild-Type Mice (ASH 2023) - "These findings demonstrate that inhibition of EED through FTX-6058 leads to a minimal, transient impact on the bone marrow in mice, and any transcriptional changes are rapidly reversible following cessation of dosing. A small molecule EED inhibitor has the potential to provide a new treatment for sickle cell disease without irreversibly altering the bone marrow."

Preclinical • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • HBB

Rap-536, a Murine Luspatercept Analog Ameliorates Anemia and Vaso-Occlusion in Experimental Model of Sickle Cell Disease (ASH 2024) - "Here we investigate the expression of GDF-11 in SCD patients and the role of RAP-536, a murine analog of luspatercept, in modulating anemia and VOC in SCD models, alone and/or in combination with hydroxyurea (HU) and epigenetic modulators Tazemetostat (TZM) and FTX6058, inducers of fetal hemoglobin (HbF). The observed synergy with HbF inducers like HU, TZM and FTX6058 suggests potential combination strategies to enhance therapeutic outcomes. These findings warrant clinical evaluation of luspatercept in SCD patients, aiming to address both anemia and vaso-occlusive complications in this patient population with high unmet medical need."

Preclinical • Anemia • Genetic Disorders • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Sickle Cell Disease • GATA1 • GDF11 • TFRC • TGFB1

Fulcrum Therapeutics…announced that new data from the Phase 1b PIONEER trial of pociredir in sickle cell disease (SCD) will be presented at the 67th American Society of Hematology (ASH) Annual Meeting (GlobeNewswire)

P1 data • Sickle Cell Disease

Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Pociredir (clinicaltrials.gov) - P1 | N=70 | Recruiting | Sponsor: Fulcrum Therapeutics | Trial primary completion date: Sep 2025 ➔ Dec 2025

Trial primary completion date • Anemia • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Fulcrum Therapeutics to Present Results from the 12 mg Dose Cohort of the Phase 1b PIONEER Trial of Pociredir in Sickle Cell Disease (GlobeNewswire) - "Fulcrum Therapeutics...will host a conference call and webcast on Tuesday, July 29, 2025 beginning at 8:00 a.m. ET to present topline results from the 12 mg dose cohort of the Phase 1b PIONEER trial of pociredir in sickle cell disease."

P1 data • Sickle Cell Disease

POCIREDIR, A POTENT AND SELECTIVE EED INHIBITOR FOR THE TREATMENT OF SICKLE CELL DISEASE, INDUCES TARGET ENGAGEMENT AND GENE EXPRESSION CHANGES THAT ARE SPECIFIC AND REVERSIBLE IN WILD-TYPE MICE (EHA 2025) - "Short-term dosing of pociredir in wild-type mice demonstrated significant on-target activity, robust induction of Hbb-bh1 (mouse embryonic globin mRNA) and did not significantly alter the transcriptional profile of either bone marrow or the inguinal lymph node (an "off-target" organ). After cessation of dosing, on-target activity ceased, H3K27me3/H3 ratios returned to basal levels, and transcriptional profiles remained unchanged. In summary, complete reversibility of PRC2 inhibition was observed after the cessation of dosing."

Preclinical • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • HBB • PTPRC

PHARMACOKINETICS (PK), PHARMACODYNAMICS (PD), AND SAFETY OF THE NOVEL ORAL FETAL HEMOGLOBIN (HBF) INDUCER POCIREDIR IN HEALTHY ADULTS IN A PHASE 1 STUDY (EHA 2025) - P1 | "Pociredir shows favorable PK in healthy adults and no clinically relevant AEs, supporting once-daily oral dosing. Together with the observed dose-dependent induction of HBG mRNA, further investigation is warranted in patients who would benefit from induction of HbF, such as those with SCD. The ongoing PIONEER clinical trial, an open-label, multicenter, international study evaluating the safety, PK, and PD of oral pociredir in SCD, is currently enrolling patients (ClinicalTrials.gov ID: NCT05169580)."

Clinical • P1 data • PK/PD data • Genetic Disorders • Hematological Disorders • Leukopenia • Sickle Cell Disease • HBB

Fulcrum Therapeutics Announces Recent Business Highlights and Financial Results for Fourth Quarter and Full Year 2024 (GlobeNewswire) - "Patient enrollment and site activation continues to progress in the Phase 1b PIONEER trial evaluating pociredir in patients with SCD. Fulcrum has enrolled 10 patients in the 12 mg dose cohort, and plans to share data from the 12 mg dose cohort in mid-2025 and from the 20 mg dose cohort by the end of 2025. Fulcrum continues to advance its program for the potential treatment of inherited aplastic anemias, such as Diamond-Blackfan anemia (DBA), Shwachman-Diamond syndrome, and Fanconi anemia, and plans to submit an IND for DBA during the fourth quarter of 2025. Consistent with our commitment to share full trial results with patients, study investigators, and the broader FSHD community, data from the Phase 3 REACH trial evaluating losmapimod in patients with Facioscapulohumeral Muscular Dystrophy will be presented on March 19th at the 2025 MDA Conference being held in Dallas, Texas."

IND • P1 data • P3 data • Trial status • Aplastic Anemia • Muscular Dystrophy • Sickle Cell Disease

Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Pociredir (clinicaltrials.gov) - P1 | N=70 | Recruiting | Sponsor: Fulcrum Therapeutics | Trial completion date: Apr 2025 ➔ Dec 2025 | Trial primary completion date: Apr 2025 ➔ Sep 2025

Trial completion date • Trial primary completion date • Anemia • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

INTERIM RESULTS OF A PHASE 1B STUDY (PIONEER) OF AN ORAL HBF INDUCER, POCIREDIR, IN SICKLE CELL DISEASE (EHA 2024) - P1 | "Pociredir was generally well tolerated with eight mild and non-serious drug-related TEAEs and no TEAEsresulted in drug discontinuations. All adherent participants in the 2, 6 and 12 mg cohorts showed consistentincreases in HbF. The study is currently enrolling in the 12 mg dose cohort."

P1 data • Fatigue • Genetic Disorders • Hematological Disorders • Otorhinolaryngology • Pain • Sickle Cell Disease • TINCR

Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of FTX-6058 (clinicaltrials.gov) - P1 | N=70 | Recruiting | Sponsor: Fulcrum Therapeutics | Active, not recruiting ➔ Recruiting

Enrollment open • Anemia • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of FTX-6058 (clinicaltrials.gov) - P1 | N=70 | Active, not recruiting | Sponsor: Fulcrum Therapeutics | Suspended ➔ Active, not recruiting | N=40 ➔ 70 | Trial completion date: Mar 2023 ➔ Apr 2025 | Trial primary completion date: Mar 2023 ➔ Apr 2025

Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • Anemia • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

FDA Lifts Clinical Hold on Fulcrum Therapeutics’ FTX-6058 for Sickle Cell Disease (GlobeNewswire) - "Fulcrum Therapeutics, Inc...today announced that the U.S. Food and Drug Administration (FDA) has lifted the clinical hold on the Investigational New Drug (IND) application for FTX-6058 for the potential treatment of sickle-cell disease (SCD)....Based on the initial data from the Phase 1b trial, which showed increasing levels of HbF with each dose escalation, we believe in the potential of FTX-6058 to not only shift the current standard of care but importantly, offer these patients a differentiated oral option."

FDA event • Anemia • Hematological Disorders • Sickle Cell Disease

INHIBITION OF POLYCOMB REPRESSIVE COMPLEX 2 THROUGH EED INDUCES FETAL HEMOGLOBIN IN HEALTHY AND SICKLE CELL DISEASE MODELS (EHA 2022) - P1 | "Downregulation of BCL11A is mechanistically distinct from the current standard of care, Hydroxyurea, and pre-clinical HbF induction via FTX-6058 exceeds that observed with Hydroxyurea. Conclusion These novel findings further elucidate the regulatory network that underlies fetal hemoglobin gene expression and has important implications for the use of inhibitors of PRC2 as potential therapies for SCD and β-thalassemia. The translation of these findings is underway as FTX-6058, an investigational, novel and potent inhibitor of Embryonic Ectoderm Development (EED), is currently being evaluated in clinical studies as a potential treatment for select hemoglobinopathies (NCT04586985, NCT05169580 )."

Clinical • Beta-Thalassemia • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • CD34

Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of FTX-6058 (clinicaltrials.gov) - P1 | N=40 | Suspended | Sponsor: Fulcrum Therapeutics | Recruiting ➔ Suspended

Trial suspension • Anemia • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Safety, Tolerability and Pharmacokinetics of FTX-6058 (clinicaltrials.gov) - P1 | N=109 | Completed | Sponsor: Fulcrum Therapeutics | Recruiting ➔ Completed | N=164 ➔ 109

Enrollment change • Trial completion • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of FTX-6058 (clinicaltrials.gov) - P1 | N=40 | Recruiting | Sponsor: Fulcrum Therapeutics | Trial completion date: Nov 2022 ➔ Mar 2023 | Trial primary completion date: Nov 2022 ➔ Mar 2023

Trial completion date • Trial primary completion date • Anemia • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of FTX-6058 (clinicaltrials.gov) - P1 | N=40 | Recruiting | Sponsor: Fulcrum Therapeutics | N=20 ➔ 40

Enrollment change • Anemia • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Safety, Tolerability and Pharmacokinetics of FTX-6058 (clinicaltrials.gov) - P1 | N=164 | Recruiting | Sponsor: Fulcrum Therapeutics | Trial completion date: Jun 2022 ➔ Dec 2022 | Trial primary completion date: Jun 2022 ➔ Dec 2022

Trial completion date • Trial primary completion date • Genetic Disorders • Hematological Disorders • Sickle Cell Disease