FDA Lifts Clinical Hold on Fulcrum’s FTX-6058 for Sickle Cell Disease

Rare Daily Staff

The U.S. Food and Drug Administration has lifted the clinical hold on Fulcrum Therapeutics’ Investigational New Drug application for FTX-6058 for the potential treatment of sickle-cell disease.

On February 23, 2023, the FDA placed the IND for FTX-6058 on clinical hold. In its communication, the Agency noted preclinical data previously submitted in April, October and December 2022, and non-clinical and clinical evidence of hematological malignancies observed with other inhibitors of polycomb repressive complex 2. In connection with the clinical hold, Fulcrum suspended dosing in the phase 1b trial of FTX-6058 and worked with the FDA to resolve the hold.

Sickle cell disease (SCD) is a genetic disorder of the red blood cells caused by a mutation in the HBB gene. This gene encodes a protein that is a key component of hemoglobin, a protein complex whose function is to transport oxygen in the body. The result of the mutation is less efficient oxygen transport and the formation of red blood cells that have a sickle shape. These sickle shaped cells are much less flexible than healthy cells and can block blood vessels or rupture cells. People with SCD typically suffer from serious clinical consequences, which may include anemia, pain, infections, stroke, heart disease, pulmonary hypertension, kidney failure, liver disease, and reduced life expectancy.

FTX-6058 is an investigational oral small-molecule inhibitor of Embryonic Ectoderm Development (EED) that was discovered using FulcrumSeek, Fulcrum’s proprietary discovery engine. Inhibition of EED leads to potent downregulation of key fetal globin repressors, including BCL11A, thereby causing an increase in fetal hemoglobin (HbF). FTX-6058 is being developed for the treatment of sickle cell disease and other hemoglobinopathies.

Initial data in SCD demonstrated proof-of-concept and achieved absolute levels of HbF increases associated with potential overall patient benefit. In clinical trials conducted prior to the clinical hold, FTX-6058 was generally well-tolerated in people with SCD with up to three months of exposure, with no serious treatment-related adverse events reported. FTX-6058 has been granted FDA Fast Track and Orphan Drug designations for the treatment of SCD.

“Based on the initial data from the phase 1b trial, which showed increasing levels of fetal hemoglobin 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,” said Alex Sapir, president and CEO of Fulcrum.

Photo: Alex Sapir, president and CEO of Fulcrum.