Fulcrum’s sickle cell hold resolved, and trial will now focus on more severe patients

Fulcrum Therapeutics can resume testing its oral capsule in a Phase Ib study in patients with sickle cell disease, the biotech said Tuesday morning.

The FDA lifted the full clinical hold on FTX-6058, with trial revisions to focus on sicker patients after the small molecule spent six months in the waiting zone. The study protocol now stipulates patients must have severe cases of the red blood cell disorder or lack access to advanced therapies, either due to availability limitations or insurance hindrances. The trial was originally designed as an all-comers study.

Investors welcomed the trial clearance with open arms. Fulcrum’s stock $FULC price climbed 45% in early-morning trading.

Fulcrum estimates about 7,500 to 10,000 people in the US would meet the inclusion and exclusion criteria for the adjusted trial, the Cambridge, MA-based biotech said in an investor presentation. The CDC estimates about 100,000 people in the US are affected by sickle cell, with a disproportionate impact on Black people.

The move comes as two new sickle cell treatments could be approved by the FDA later this year. The agency is expected to decide on CRISPR Therapeutics and Vertex’s gene-editing program exa-cel by Dec. 8 and bluebird bio’s gene therapy lovo-cel by Dec. 20. CRISPR has said the FDA plans to seek the advice of its outside expert panel before making its decision.

Iain Fraser

Fulcrum’s interim chief medical officer Iain Fraser said it was too early to ascertain when the trial would resume because of the steps necessary to get clinical sites up to speed on the new protocol, as well as bring new sites into the study. In an interview, he said the biotech will resume by restarting a 12 mg cohort with about 10 patients and then enroll another 10 patients in a 20 mg cohort. Patients will undergo a 12-week treatment period.

“We’ve amended the informed consent and the investigators brochure. Those are going out to the sites for their [institutional review boards] to review and approve, so that’s the first step prior to re-initiating the study,” Fraser said.

A data monitoring committee will meet after the eighth patient in the 12 mg cohort completes four weeks of therapy, Fraser said.

For patients to get into the study, they must have certain frequencies of vaso-occlusive events, or pain crises, or end-organ disease due to chronic manifestations, Fraser said. Patients must have tried the sickle cell anemia “mainstay” drug hydroxyurea and second-line treatments like Pfizer’s Oxbryta, Novartis’ Adakveo or L-glutamine. Or, they must have previously been on hydroxyurea and not received those second-line treatments because of availability or insurance hurdles.

The regulator had halted the trial in February because of findings from preclinical data submitted in April, October and December of 2022, as well as “non-clinical and clinical evidence of hematological malignancies observed with other inhibitors of polycomb repressive complex 2,” Fulcrum said Tuesday. The hold occurred during a rough week for the sickle cell community when a trio of biotechs upended their development plans.

On an Aug. 3 earnings call, Fulcrum CEO Alex Sapir said the company expected a trial hold resolution either in the fourth quarter of this year or the first quarter of 2024.

Stifel analyst Dae Gon Ha wrote in a Tuesday morning note that “today’s announcement marks an important ‘win’ for the new management team instilling some confidence that they can help right the ship that has undergone a series of mishaps/adversities.” Sapir was appointed CEO in May, and Alan Musso was named CFO earlier this month after Esther Rajavelu resigned from the role in April.

If FTX-6058 succeeds, Stifel predicts a commercial launch in 2028. Before then, other drug developers could have sickle cell treatments on the market. Agios is taking its pill Pyrukynd into a Phase III trial this year for the condition. Editas Medicine also anticipates more data on its program by year’s end, but the biotech has said it might search for a partner. Beam, Scribe and other companies are also looking to create potential treatments.

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