Fulcrum's sickle cell disease program is back in business after FDA lifts 6-month hold

After a six-month wait, Fulcrum Therapeutics’ sickle cell disease (SCD) plans are back on track after the FDA lifted a hold on the biotech’s candidate.

The regulator instigated the full clinical hold on the therapy, dubbed FDX-6058, back in February. Details were sparse at the time, with Fulcrum only able to say that the hold was initiated due to previously reported preclinical data.

The Cambridge, Massachusetts-based company was able to shed more light on the rationale behind the hold a month later, and, in its Tuesday morning release, Fulcrum reaffirmed that the FDA had “noted preclinical data previously submitted in April, October and December 2022, and non-clinical and clinical evidence of hematological malignancies observed with other inhibitors of polycomb repressive complex 2 (PRC2).”

SCD is a notoriously tricky indication, demonstrated by the fact that the original 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.

Since then, Fulcrum said it has “worked diligently” with the FDA to resolve the hold and is now “eager to advance FTX-6058 through clinical development” beginning with a phase 1b trial.

FTX-6058 is designed to inhibit a protein-encoding gene called embryonic ectoderm development, a subunit of PRC2, leading to the downregulation of key fetal globin repressors including BCL11A. According to the theory, this should lead to an increase in fetal hemoglobin (HbF).

“Based on the initial data from the phase 1b trial, which showed increasing levels of HbF with each dose escalation, we believe in the potential of FTX-6058 to not only shift the current standard of care but importantly, offer these patients a differentiated oral option,” CEO Alex Sapir said in the release. “We look forward to building on these results with plans to resume enrollment for patients with SCD.”

While Fulcrum’s own asset is now back in the race, it will be trailing behind bluebird bio and Vertex-CRISPR, which are awaiting FDA decisions for their respective gene therapies for SCD in December.

Investors were clearly enthused by the news, sending Fulcrum's stock jumping 49% to $5.86 in premarket trading Tuesday. Still, the company has a long way to go to reclaim the heights of over $12 that its share price was sitting at before the hold was placed in February.