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

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

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

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

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

INTERIM RESULTS OF SAFETY, TOLERABILITY, PHARMACOKINETICS, AND PHARMACODYNAMICS FROM AN ONGOING OPEN-LABEL STUDY INVESTIGATING FTX-6058 IN ADULTS LIVING WITH SICKLE CELL DISEASE (EHA 2022) - "Methods The ongoing Phase 1b open-label study investigating FTX-6058 is a multiple cohort trial that is being conducted in adults with SCD +/- hydroxyurea. Conclusion FTX-6058 is an investigational, potential first-in-class oral HbF inducer. To date, FTX-6058 has demonstrated favorable safety and tolerability profile, with PK linearity and time- and dose-dependent increases in HBG mRNA that support longer term dosing in people living with SCD."

Clinical • PK/PD data • Genetic Disorders • Hematological Disorders • Pain • Sickle Cell Disease

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

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

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

Clinical • New P1 trial • Anemia • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • PCR

Measuring H3K27me3 Reduction after in-Vivo Administration of Ftx-6058; A Potent Polycomb Repressive Complex 2 (PRC2) Inhibitor (ASH 2021) - "Research use only (RUO) validation was completed by Q2 Solutions Laboratories. The monocyte FTX-6058 TE assay is currently being evaluated as an exploratory biomarker in Fulcrum Therapeutics' phase 1 clinical trial FIS 002-2020."

Preclinical • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Development and Validation of a Gamma Globin RT-Ddpcr Exploratory Biomarker for Sickle Cell Phase 1 Clinical Trial Fis 002-2020 (ASH 2021) - "FTX-6058, a selective and potent binder of embryonic ectoderm development protein (EED), is being investigated in Sickle Cell Disease (SCD)...doi:10.1371/journal.pone.0159004 2 Taylor SC, Laperriere G, Germain H (2017), Droplet Digital PCR versus qPCR for gene expression analysis with low abundant targets: from variable nonsense to publication quality data. Scientific Reports 7(2409): DOI:10.1038/s41598-017-02217-x"

Biomarker • Clinical • P1 data • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • OAZ1

Ftx-6058 Induces Fetal Hemoglobin Production and Ameliorates Disease Pathology in Sickle Cell Mice (ASH 2021) - "Compared with untreated and hydroxyurea treated animals, FTX-6058 (QD, 5mg/kg) exhibits potent target engagement as evidenced by ~70% reduction in H3K27me3 levels, the key epigenetic mark catalyzed by PRC2. Taken together, these studies further support the therapeutic rationale of PRC2 modulation in SCD. The fetal hemoglobin induction and effects on hematological parameters and pathophysiologic symptoms observed with FTX-6058 have the potential to translate to meaningful clinical benefits in SCD and other hemoglobinopathies."

Preclinical • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Safety, Tolerability and Pharmacokinetics of FTX-6058 (clinicaltrials.gov) - P1; N=164; Recruiting; Sponsor: Fulcrum Therapeutics; N=96 ➔ 164

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

Fulcrum Therapeutics Reports Recent Business Highlights and Second Quarter 2021 Financial Results (GlobeNewswire) - "Presented the medicinal chemistry strategy for FTX-6058 at the First Time Disclosure Session at the American Chemical Society (ACS) Spring 2021 National Meeting. The presentation included initial pharmacokinetic data from the SAD cohort of the Phase 1 trial in healthy adult volunteers."

P1 data • PK/PD data • Hematological Disorders • Sickle Cell Disease

Fulcrum Therapeutics Announces Positive Interim Results from Phase 1 Healthy Adult Volunteer Trial of FTX-6058 for Sickle Cell Disease (GlobeNewswire) - P1, N=96; NCT04586985; Sponsor: Fulcrum Therapeutics; "Results from the MAD portion of the trial demonstrated proof of biology as evidenced by a dose proportional induction in HBG mRNA and accompanying increases in HbF-containing reticulocytes (F-reticulocytes). At 10mg, the highest dose studied to date, the mean changes were 4.5-fold and 4.2-fold, respectively....Results from the MAD cohorts showed maximal target engagement as evidenced by 70% – 80% reduction in baseline H3K27me3 levels....Fulcrum anticipates presenting additional results from all Phase 1 dose cohorts at an upcoming medical meeting in the fourth quarter of 2021...Based on the results reported today, Fulcrum anticipates initiating enrollment in a clinical trial in sickle cell patients in the fourth quarter of 2021....This trial could provide the opportunity to demonstrate HbF protein induction in people living with sickle cell disease and will be used to help inform a potential Phase 2/3 trial."

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

Fulcrum Therapeutics Presents Published Structure of Investigational Small Molecule FTX-6058 at the American Chemical Society (ACS) Spring 2021 Virtual Conference (GlobeNewswire) - "Fulcrum Therapeutics... presented the medicinal chemistry strategy for FTX-6058 at the First Time Disclosure Session at the American Chemical Society (ACS) Spring 2021 National Meeting. FTX-6058 is a highly potent orally bioavailable small molecule EED inhibitor for the potential treatment of select hemoglobinopathies, including sickle cell disease and β-thalassemia....The company anticipates sharing data from this Phase 1 trial in mid-2021 and initiating a clinical trial in sickle cell patients by the end of 2021."

Clinical • P1 data • Beta-Thalassemia • Hematological Disorders • Sickle Cell Disease

"FTX-6058 #ACSSpring2021" (@cenmag)

"Researchers saw 2-3 fold increases in fetal hemoglobin (HbF) when treated with FTX-6058 #ACSSpring2021" (@cenmag)

"FTX-6058 binds EED, ligands bind site contains electron deficient Arg, plus 3 electron rich aromatic rings, on Phe97, Tyr148, and Tyr365 #ACSSpring2021" (@cenmag)