The FDA has lifted the clinical hold it had placed on the Phase Ib study following the occurrence of hematological malignancies.
Photo of FDA sign under blue sky/courtesy of Sarah Silbiger/Getty Images
Fulcrum Therapeutics will continue testing FTX-6058 as a treatment for sickle-cell disease now that the FDA has lifted a clinical hold placed on the candidate in February, the company announced today.
“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,” Alex Sapir, Fulcrum’s president and chief executive officer, said in the release.
Fulcrum shares rose 30% in the hours following the announcement.
Original story posted March 10:
Clinical Hold on Fulcrum’s Sickle Cell Hopeful Triggered by Hematologic Malignancies Profile
In its decision to put Fulcrum Therapeutics’ sickle cell disease (SCD) candidate under full clinical hold, the FDA cited non-clinical instances of hematological malignancies associated with the drug, the company revealed in its 2022 financial report.
The FDA noted that “the profile of hematologic malignancies observed in the non-clinical studies of FTX-6058 is similar to that observed with other inhibitors of PRC2,” Robert Gould, Ph.D., interim president and CEO, Fulcrum, said during an investor call Thursday.
The regulator is asking Fulcrum to further define the population where FTX-6058’s benefits would clearly outweigh its potential risks.
FTX-6058 is a potent and orally available small molecule inhibitor of the Embryonic Ectoderm Development (EED), a subunit of the PRC2 protein complex. In preclinical studies, Fulcrum has shown that using FTX-6058 to target EED induces an increase in fetal hemoglobin. In December 2022, the FDA granted the candidate Fast Track designation for SCD.
In February, flagging issues with “previously reported preclinical data,” the FDA placed FTX-6058 under full clinical hold. At the time, no specific reason was given for the hold.
Prior to the clinical hold, FTX-6058 was in a Phase Ib study, in which a 6-mg dose of the candidate elicited a 9.5% increase in absolute fetal hemoglobin levels from baseline.
Gould said the hold was not the result of any clinical finding in that trial.
Also during its financial report, Fulcrum announced that Santiago Arroyo has resigned as the company’s chief medical officer, effective March 7. Iain Fraser will fill the post on an interim basis.
The company will continue working with the FDA to address all of the regulator’s concerns regarding FTX-6058, Gould said during the call. Still, in view of the clinical hold, Fulcrum is suspending its guidance to complete the Phase Ib study and to arrive at a registration-enabling dose by the fourth quarter of 2023.
The Problem with PRC2
The clinical hold on FTX-6058 highlights the difficulty of targeting the PRC2 complex.
Epizyme has seen such a drug through to the market. In January 2020, the biotech won FDA accelerated approval for Tazverik (tazemetostat), an orally available and potent first-in-class inhibitor of the EZH2 sub-unit of the PRC2 complex, for use in patients with metastatic or locally advanced epithelioid sarcoma who are ineligible for resection.
Later that year, in June, Tazverik’s indication was expanded to include two specific follicular lymphomas. Ipsen now owns the rights to Tazverik after it bought Epizyme in June 2022 for $247 million.
While Tazverik made it through regulatory rigor, the drug carries a warning for secondary malignancies. Patients treated with Tazverik are at a higher risk of developing T-cell lymphoblastic lymphoma, myelodysplastic syndrome and acute myeloid leukemia.
