Fulcrum Therapeutics has scrapped its sole clinical-stage program after the FDA took a hard line on the modality following the recent withdrawal of Ipsen’s Tazverik from the U.S. market.
Ipsen withdrew Tazverik in March across all indications and in all markets after a data monitoring committee observed “adverse events of secondary hematologic malignancies” in a phase 1b/3 trial.
France’s Ipsen had acquired the rights to Tazverik, an inhibitor of polycomb repressive complex 2 (PRC2), when it bought Epizyme in 2022. By that point, Tazverik had already been on the U.S. market for two years as both an epithelioid sarcoma and a follicular lymphoma treatment.
Fulcrum’s lead asset pociredir is also a PRC2 inhibitor, which the company had been evaluating in a phase 1b study for sickle cell disease (SCD). The biotech said it had been in discussions with the FDA to reassure the agency that there are “mechanistic differences” between pociredir’s target of the regulatory protein EED and Tazverik’s target of the EZH2 enzyme.
These targets “perform different biological roles,” which is “relevant to the benefit-risk assessment,” Fulcrum argued in a June 1 post-market release. Unfortunately for Fulcrum, the FDA wasn’t convinced.
“[The] FDA considered this position but concluded that any pharmacological intervention targeting the PRC2 complex carries equivalent malignancy risk regardless of the specific subunit engaged,” Fulcrum explained. The agency’s position is “informed by pociredir’s previously disclosed preclinical malignancy observations and left no viable regulatory path forward for further clinical development of pociredir,” the biotech added.
It’s a significant setback for Fulcrum, which as recently as late April reaffirmed its “conviction in pociredir’s potential to address the underlying biology” of SCD, while highlighting a “strong balance sheet” of $333 million to fund the drug’s development through 2029.
Instead, Fulcrum has been left with no option but to abandon its ambitions for pociredir in SCD and “explore strategic alternatives.”
Those alternatives could range from a merger or sale of the company or its assets. Fulcrum’s preclinical pipeline consists of HbF inducers being developed for SCD and prostate cancer.
In the meantime, the biotech has already “initiated efforts to significantly reduce its operating expenses and preserve capital.” Fierce has asked the company whether these efforts are likely to include laying off employees.
“Following a thorough review of regulatory feedback, the totality of available data, and the implications for a viable regulatory path, we have made the very difficult decision to discontinue development of pociredir,” CEO Alex Sapir said in the release.
“While no new safety signals have been observed to date with pociredir, the FDA raised concerns regarding the potential malignancy risk associated with pociredir’s inhibition of the PRC2 complex given the experience with Tazverik that was recently withdrawn from the market,” Sapir added. “We arrived at this decision after discussion with the FDA, and despite robust elevations in fetal hemoglobin seen with pociredir and the potential for clinical benefit, we do not see a path forward with pociredir.”
Unsurprisingly, investors took fright at the abrupt turn in events, sending Fulcrum’s stock down 51% to $3.10 in pre-market trading Tuesday from a Monday closing price of $6.42.
