FDA Places Clinical Hold on Fulcrum’s FTX-6058 in Sickle Cell Disease

Rare Daily Staff

The U.S. Food and Drug Administration verbally informed Fulcrum Therapeutics that it has issued a full clinical hold regarding the Investigational New Drug application for FTX-6058 for the potential treatment of sickle-cell disease.

The Agency indicated that it would provide a formal Clinical Hold Letter to the company within 30 days.

The clinical hold was initiated by the FDA due to previously reported preclinical data. Fulcrum will suspend dosing in the phase 1b trial of FTX-6058 and intends to work diligently with the Agency to resolve the hold as soon as possible.

It hasn’t been a good week for sickle cell therapeutics development as three companies said they were discontinuing development of their experimental therapies to treat the disease. Graphite Bio is discontinuing development of its experiment sickle cell disease gene-edited stem cell therapy; Intellia Therapeutics said its partner Novartis chose to discontinue the development of its autologous ex-vivo CRISPR-edited hematopoietic stem cell program targeting fetal hemoglobin for the treatment of SCD; and Sangamo Therapeutics said it made a strategic decision to halt further investments in its zinc finger nuclease gene-edited cell therapy program for SCD beyond completion of the phase 1/2 study.

Sickle cell disease 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 sickle cell disease 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 (SCD) and other hemoglobinopathies. FTX-6058 is currently being evaluated in a phase 1b multi-center open-label trial in people with SCD. Initial data demonstrated proof-of-concept and achieved absolute levels of HbF increases associated with potential overall patient benefit. To date, FTX-6058 has been generally well-tolerated in people with SCD with up to three months of exposure, with no drug-related serious adverse events reported. FTX-6058 has been granted FDA Fast Track and Orphan Drug designations for the treatment of SCD.

“Patient safety remains paramount to me. I am encouraged by the Agency’s willingness to work with us to clarify the therapeutic potential of FTX-6058. Fulcrum intends to address questions related to modulation of the PRC2 complex and the preclinical data,” said Robert Gould, Fulcrum’s interim president and CEO. “We continue to have confidence in the benefit-risk profile of FTX-6058 and remain committed to our goal of providing a differentiated therapeutic option for people living with sickle cell disease.”

Photo: Robert Gould, Fulcrum’s interim president and CEO