Fulcrum's clinical hold caps off tough week for sickle cell drug development

Fulcrum Therapeutics’ sickle cell disease therapy has been placed on a clinical hold by the FDA, capping off a tough week for drug development for the condition that saw three separate treatments discontinued.

The Cambridge, Massachusetts-based company was informed verbally by the agency that the investigational new drug application for FDX-6058 has been placed on a full clinical hold. Fulcrum said in a Friday press release that the FDA has promised to provide a formal clinical hold letter within 30 days.

Details were slim, but Fulcrum said that the hold was initiated due to previously reported preclinical data. The company will suspend dosing in a phase 1b trial and “intends to work diligently with the agency to resolve the hold as soon as possible.”

Interim CEO Robert Gould, Ph.D., suggested the hold was related to “modulation of the PRC2 complex,” a system involved in gene expression.

“I am encouraged by the agency’s willingness to work with us to clarify the therapeutic potential of FTX-6058,” said Gould, who took over the CEO role temporarily in January. “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.”

FTX-6058 has previously been well tolerated in patients with sickle cell who were exposed for up to three months, with no drug-related adverse events, Fulcrum said. The trial was to enroll up to 40 participants, according to an entry in the U.S. National Library of Medicine’s clinical trials database.

Back in August 2021, Fulcrum trumpeted “proof of biology” for FDX-6058 based on an interim readout from a phase 1 trial of healthy volunteers. The company is testing the therapy for sickle cell and beta thalassemia. That interim readout gave Fulcrum the confidence to begin enrolling sickle cell patients in the open-label phase 1b portion of the trial.

Fulcrum’s stumble comes after three different sickle cell therapies were discontinued across the industry on Wednesday and Thursday. 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 and Sangamo shelved its phase 3 asset to focus on Fabry disease.

Meanwhile, Vertex Pharmaceuticals and CRISPR Therapeutics are finalizing regulatory filings for their partnered asset exa-cel, which is designed for both sickle cell and beta thalassemia. The FDA filing is expected to be completed in the first quarter.