Fulcrum Therapeutics Announces Preclinical Proof-of-Concept Data for FTX-6058 at the Virtual 14th Annual Sickle Cell Disease Research & Educational Symposium and 43rd National Sickle Cell Disease Scientific Meeting - Seite 2

The validation of EED as a target for sickle cell disease and the discovery of FTX-6058 as a novel HbF-inducing small molecule were conducted using Fulcrum’s Product Engine. Through inhibition of EED, Fulcrum has demonstrated the ability to modulate the activity of the Polycomb Repressive Complex 2 (PRC2), a key regulator of HbF expression, in preclinical studies. Fulcrum validated the role between EED binding/PRC2 modulation and HbF induction utilizing its proprietary CRISPR and chemical probe screening platform. Treatment of human CD34⁺-derived erythroid cells from healthy and sickle cell disease donors with FTX-6058 resulted in clinically desirable fetal hemoglobin levels (up to ~30% of total hemoglobin), demonstrating a superior globin profile relative to hydroxyurea and other small molecule compounds or mechanisms currently under development. In these preclinical studies, FTX-6058 also induced pancellular distribution of HbF similar to hereditary persistence of fetal hemoglobin.

In vivo preclinical studies showed elevation of HbF at the mRNA and protein levels at plasma concentrations predicted by Fulcrum to be achievable in patients. FTX-6058 treatment led to, elevation of the human HBG1 mRNA and HbF protein in the Townes SCD mouse model. In a head-to-head in-vivo preclinical study, FTX-6058 demonstrated superior HbF induction over hydroxyurea in the Townes SCD mouse model.

“We continue to demonstrate important progress with our Product Engine, developing a robust pipeline focused on treatments for rare diseases and areas of significant unmet need,” said Owen Wallace, Fulcrum’s chief scientific officer. “We are very encouraged by these in vitro and in vivo findings, as the preclinical data support our novel approach to treating hemoglobinopathies, such as sickle cell disease and beta-thalassemia. In addition to achieving robust fetal hemoglobin levels in cell and murine models, an extensive nonclinical safety package and off-target profile has been established for FTX-6058. We believe FTX-6058 has the potential to offer a durable and transformative therapy for people living with sickle cell disease.”

Fulcrum completed a comprehensive IND-enabling package, including preclinical safety studies and up to 28-day Good Laboratory Practices (GLP) toxicology studies, as well as Good Manufacturing Practices (GMP) material scale-up for its planned Phase 1 clinical trial. The Company remains on track to initiate a Phase 1 clinical trial by year-end. In addition, Fulcrum’s non-provisional composition of matter patent application covering FTX-6058 and related structures has published.