FTX-6058, an investigational treatment for sickle cell disease (SCD) and beta-thalassemia being developed by Fulcrum Therapeutics, showed efficacy at raising the levels of fetal hemoglobin in cellular and animal models of the diseases, according to new preclinical data announced by the company.
Fulcrum also stated that it remains on track to initiate a Phase 1 trial before the end of the year to assess the safety of FTX-6058 in healthy volunteers.
“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. We believe FTX-6058 has the potential to offer a durable and transformative therapy for people living with sickle cell disease,” Owen Wallace, chief scientific officer of Fulcrum, said in a press release.
New preclinical findings were presented by the company in a presentation titled “FTX-6058, a novel HbF-inducing agent for the treatment of Sickle Cell Disease and β-Thalassemia,” at The 14th Annual Sickle Cell Disease Research & Educational Symposium and 43rd National Sickle Cell Disease Scientific Meeting, recently held online.
SCD and beta-thalassemia are both hemoglobinopathies, that is, genetic disorders in which the function of hemoglobin — the protein in red blood cells responsible for transporting oxygen in the body — is compromised.
As its name suggests, fetal hemoglobin (HbF) is a form of hemoglobin that is usually only produced during fetal development. It is more effective at transporting oxygen throughout the body than its adult counterpart.
Since HbF can functionally compensate for the adult form of hemoglobin, which is faulty in patients with hemoglobinopathies, therapies that increase its levels have started to be explored as new treatment candidates for these disorders.
FTX-6058 is a small molecule that increases HbF levels by blocking the activity of a protein called embryonic ectoderm development (EED).
“An orally available small molecule therapeutic acting through a novel mechanism to induce increased pancellular [affecting all cell types] HbF should be an important disease-modifying agent [for SCD],” said Martin H. Steinberg, MD, professor of Medicine at Boston University School of Medicine.
Data from in vitro experiments — tests in a dish conducted using lab-cultured cells — showed that treating red blood cells derived from healthy donors and SCD patients with FTX-6058 increased the production of HbF to up to 30% of the total hemoglobin found in these cells.
Moreover, absolute HbF levels in these cells increased by 8–18% following treatment with FTX-6058, which may potentially lead to clinically meaningful benefits for SCD patients. For reference, increases of 5% or even less in HbF levels are thought to be clinically beneficial to those with SCD.
In vivo or in-the-body experiments in a mouse model of SCD also showed that treatment with FTX-6058 was able to increase both the RNA and protein levels of HbF, even more than hydroxyurea, an approved medication currently used to treat sickle cell disease. Of note, RNA is the molecule cells use as a template to produce proteins.
Treatment with FTX-6058 also was found to be specific and selectively increase the levels of HbF, without affecting other components of hemoglobin. Additionally, its pharmacological profile when given orally, once per day, to mice supported its use as a potential treatment for humans.
“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,” Wallace said.
“In addition to achieving robust fetal hemoglobin levels in cell and murine [animal] models, an extensive nonclinical safety package and off-target profile has been established for FTX-6058,” he added.
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