FTX-6058 shown to raise fetal hemoglobin in SCD patient in trial

Positive finding not yet reported at time FDA issued clinical hold

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by Steve Bryson, PhD |

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The investigational oral treatment FTX-6058 effectively raised the level of fetal hemoglobin in a sickle cell disease (SCD) patient to 24.9% in a clinical trial that’s now been placed on hold by regulators.

According to the therapy’s developer, Fulcrum Therapeutics, these initial data had been obtained but not yet reported when the U.S. Food and Drug Administration (FDA) placed the clinical hold on the trial in February. That ongoing Phase 1b study (NCT05169580) is testing different doses of FTX-6058 in SCD patients.

In a communication to Fulcrum regarding the hold, the agency noted non-clinical and clinical evidence of blood-related cancers associated with medicines that block the polycomb repressive complex 2 (PRC2) — FTX-6058’s therapeutic target. It also mentioned previously submitted preclinical data and a response to an early request for information.

Active discussions between the company and the FDA regarding the hold are ongoing, per Fulcrum.

“We continue to engage in productive dialogue with the FDA, as we work diligently to address the clinical hold for FTX-6058,” Robert J. Gould, PhD, Fulcrum’s interim president and CEO, said in a company press release.

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Higher FTX-6058 Doses Raise Hemoglobin in Healthy Adults in Trial

Fetal hemoglobin levels in one sickle cell patient increased over 24%

SCD is caused by inherited defects in the adult version of hemoglobin — the protein in red blood cells that carries oxygen throughout the body.

During fetal development, another version of the protein, called fetal hemoglobin (HbF), is produced. This version of hemoglobin transports oxygen more efficiently than its adult counterpart. But after birth, HbF is gradually replaced by adult hemoglobin.

FTX-6058 is designed to block PRC2, a group of proteins that normally suppresses the activity of HbF-encoding genes. By removing the blockade and activating these genes, the therapy aims to switch HbF production back on, improving oxygen transport, and easing SCD symptoms.

Early data from a double-blind Phase 1 trial (NCT04586985), completed in late 2022, demonstrated that FTX-6058 could safely boost HbF production as intended in healthy volunteers. In a double-blind trial, neither participants nor researchers know which individuals are receiving the treatment being tested and who is given the placebo.

The open-label Phase 1b trial was launched to explore FTX-6058’s safety, pharmacological properties, and preliminary efficacy. As its name suggests, both health providers and participants in an open-label trial are aware of the treatment being given. This trial was expected to involve 40 SCD patients, ages 18-65.

Enrolled participants receive different daily doses of FTX-6058. After four weeks, patients are given the opportunity to continue treatment in an extension study for an additional eight weeks.

Initial data obtained before the clinical hold showed that in one participant receiving 12 mg of FTX-6058 daily, absolute HbF increased by 10% from the study’s start. This represented a total HbF level of 24.9% after 42 days of treatment. According to Fulcrum, that new data was reported in March.

So far, the therapy was generally well-tolerated in SCD patients with up to three months of exposure. No treatment-emergent serious adverse events and no discontinuations were reported.

The FDA has previously granted FTX-6058 both fast track and orphan drug designations for SCD. Both are intended to speed a therapy’s development and review; orphan drug status is specifically awarded to medications that aim to treat rare diseases.

The company also is investigating the therapy’s potential to treat beta-thalassemia, a blood disorder caused by genetic mutations that disrupt or lower the production of hemoglobin.