Unique oral drug candidate designed to overcome sickle cell disease


Progress is being made in the quest for an oral treatment for sickle cell disease. In preclinical trials, a new drug has shown the ability to induce blood cells to produce fetal hemoglobin at levels predicted to prevent sickling. The new small-molecule drug could be formulated into a convenient daily oral dosage, according to researchers who presented their results at the spring meeting of the American Chemical Society, which was held virtually.

The new drug candidate, designated FTX-6058 by Fulcrum Therapeutics, was developed using a proprietary small-molecule probe and CRISPR guide RNA libraries to screen “a disease-relevant cell model that allowed us to pinpoint a treatment target,” said Ivan V. Efremov, PhD, senior director, head of medicinal chemistry at the company, who presented the research.

Even though sickle cell patients carry genes leading to defective adult hemoglobin, they still carry stem cells in their bone marrow with the potential to produce fetal hemoglobin. FTX-6058 attaches to a protein inside these bone marrow stem cells destined to become mature red blood cells and reinstates their fetal hemoglobin expression, according to Dr. Efremov.

“What is really key is FTX-6058 upregulates fetal hemoglobin across all red blood cells, a pancellular distribution,” he explained, adding that if “some red blood cells did not express this, they could still sickle and cause disease symptoms.”

The premise behind the development of the drug evolved from the example of patients with sickle cell genes who also have a mutation that causes fetal hemoglobin production. The presence of fetal hemoglobin provides significant benefits to patients with sickle cell disease. At around 5%-10% levels of fetal hemoglobin expression, mortality is reduced. By 10%-25% levels of fetal hemoglobin, recurring events including vaso-occlusive crises, acute chest syndrome, and hospitalization are reduced. When fetal hemoglobin levels reaches around 25%-30%, enough red blood cell function is restored so that these patients become asymptomatic, Dr. Efremov said.

FTX-6058 was designed to mimic this effect.

FTX-6058 inhibits the action of the polycomb repressive complex 2 (PRC2) via binding to the EED subunit. PRC2 acts as a histone methyltransferase to control gene expression. Inhibition of PRC2 leads to significant fetal hemoglobin protein expression in both cell and mouse models. Other such inhibitors are under study for the suppression of cancer progression.

Preclinical experiments comparing FTX-6058 with the fetal hemoglobin booster, hydroxyurea, approved in the 1990s, showed the new drug candidate outperforms the current treatment, Christopher Moxham, PhD, chief scientific officer of Fulcrum Therapeutics, said in a company press release. The company began a phase 1 safety trial in healthy adult volunteers last year after preclinical experiments with FTX-6058 in human-derived cell assay systems and mouse models also showed an increase in fetal hemoglobin to meet the 25%-30% asymptomatic symptom threshold level.

Ongoing studies

The researchers plan to launch phase 2 clinical trial enrolling patients with sickle cell disease by end of 2021. In addition, further characterization of the therapeutic molecule is continuing, using genomics and additional cell assay systems to expand details FTX-6058’s mode of action.

The company also is looking to explore the use of FTX-6058 in patients with beta-thalassemia to supplement their reduced hemoglobin production.

The pharmacologic profile of FTX-6058 indicates that the drug has the potential to be administered as a once-a-day oral formulation, Dr. Efremov stated. Both the preclinical PK [pharmacokinetic] data and “the emerging PK from the human clinical study supports once-a-day oral administration, which obviously offers significant convenience to patients,” he added.

Fulcrum Therapeutics is funding the studies.

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