FDA placed hold on Fulcrum's sickle cell therapy over hematological malignancy concerns

The FDA’s ongoing clinical hold on Fulcrum’s sickle cell disease therapy was sparked by concerns about potential hematological malignancies, the biotech has revealed.

The agency placed the candidate, dubbed FDX-6058, on hold on February 23. Details were sparse while the company waited for the FDA’s hold letter, with Fulcrum only saying that the decision related to preclinical data. At the time, interim CEO Robert Gould, Ph.D., suggested the hold was linked to “modulation of the PRC2 complex,” a system involved in gene expression.

With the letter now received, Fulcrum has been able to shed light on the FDA’s decision-making. The agency used the letter to make note of preclinical data submitted in April, October and December 2022, as well as wider clinical evidence of hematological malignancies observed in trials of other polycomb repressive complex 2 (PRC2) inhibitors.

“The clinical hold noted that the profile of hematological malignancies observed in the non-clinical studies of FTX-6058 is similar to that observed with other inhibitors of PRC2, and that hematological malignancies have been reported clinically with other PRC2 inhibitors,” the company explained in its fourth-quarter earnings report this morning.

“The agency requested that Fulcrum further define the population where the potential benefit of continued treatment with FTX-6058 outweighs potential risk,” the biotech added.

Fulcrum said it was confident in its ability to address the agency’s feedback and “looks forward to providing further updates as the process unfolds.”

A small phase 1 study of FTX-6058 was generally well tolerated with no drug-related treatment-emergent serious adverse events or discontinuations due to treatment-related emergent adverse events to date, the company noted.

According to Oric Pharmaceuticals, which is working on a PRC2 inhibitor program to target cancer rather than sickle cell disease, dysregulation of PRC2 can “lead to tumorigenesis in a wide range of cancers including prostate cancer, breast cancer and hematological malignancies.”

The EZH2 protein is the enzymatic component of PRC2, and various EZH inhibitors are in development for cancer. Only one, Epizyme’s Tazverik, has been approved so far, although a number of players—including Pfizer—want in.

While most PRC2 inhibitors—including Tazverik—target the EZH2 subunit of the complex, FTX-6058 selectively modulates the EED subunit and is thus "mechanistically distinct" from both Oric's and Epizyme's drugs, Fulcrum explained to Fierce Biotech. 

While Fulcrum’s phase 1b study of FTX-6058 remains on pause, the company remains on track to complete enrollment in the second half of the year for the late-stage trial of its mitogen-activated protein kinase (MAPK) inhibitor losmapimod in facioscapulohumeral muscular dystrophy.

The hold on FDX-6058 came in the same week that three different sickle cell therapies were discontinued across the industry. Novartis cut an Intellia-partnered ex vivo therapy, Graphite Bio ended development of nulabeglogene autogedtemcel (nula-cel) after the first patient dosed experienced an adverse event of low blood cell counts, and Sangamo shelved its phase 3 asset to focus on Fabry disease.

This article was amended on March. 13, 2023 with further information from Fulcrum on FTX-6058's mechanism of action.