Fulcrum scraps sickle cell drug after FDA raises safety concerns
Agency cited concerns about potential blood cancer risk from pociredir
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Fulcrum Therapeutics said it is discontinuing development of pociredir, its experimental oral treatment for sickle cell disease (SCD), after the U.S. Food and Drug Administration (FDA) raised concerns that the therapy may increase the risk of certain blood cancers.
The concerns stem from the unexpectedly high rate of secondary blood cancers observed with Tazverik (tazemetostat), a cancer therapy that targets the same protein complex as pociredir, which led to the therapy’s withdrawal from all markets earlier this year.
Although the two drugs act on different parts of that protein complex and clinical trials have supported pociredir’s therapeutic potential in people with SCD, the FDA “left no viable regulatory path forward for further clinical development of pociredir,” Fulcrum said in a company press release.
“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,” said Alex C. Sapir, Fulcrum’s president and CEO. “We know the SCD community has faced many disappointments and setbacks related to innovation for this devastating disease, and we are not only humbled but forever grateful to the SCD warriors, investigators, and broader SCD community who have worked tirelessly alongside Fulcrum to evaluate new treatment options for this devastating disease.”
SCD is caused by mutations that lead to the production of a faulty form of hemoglobin, the protein that enables red blood cells to carry oxygen throughout the body. As a result, red blood cells take on a sickle shape, making them prone to breaking apart and getting trapped in blood vessels, where they can block blood flow. This can cause anemia (red blood cell shortage), episodes of severe pain known as vaso-occlusive crises (VOCs), and progressive organ damage.
Once-daily pill showed promise in trial
Pociredir, formerly known as FTX-6058, was designed to increase production of fetal hemoglobin (HbF), which is normally made before birth and largely replaced by adult hemoglobin later.
The once-daily pill aimed to block embryonic ectoderm development (EED), part of a protein complex, PRC2, that keeps the genes that regulate HbF production turned off. By suppressing EED, the therapy sought to restart fetal hemoglobin production, potentially easing anemia, VOCs, and other sickle cell symptoms.
In a Phase 1 study (NCT04586985) completed in 2022, pociredir safely increased HbF levels in healthy adults. Those findings supported the launch of the Phase 1b PIONEER trial (NCT05169580) in adults with SCD, ages 18 to 65. Participants were assigned to receive one of four daily pociredir doses, ranging from 2 to 20 mg, for up to 12 weeks (about three months).
In 2023, the FDA placed a clinical hold on the study over concerns that therapies targeting the PRC2 complex could increase the risk of certain blood cancers. The agency lifted the hold later that year after Fulcrum introduced stricter enrollment criteria, allowing the study to continue.
Data from the first 16 participants who completed 12 weeks of treatment with the 12 mg dose showed that mean HbF levels rose from 7.6% before pociredir to 16.2% after 12 weeks. Seven participants (44%) achieved HbF levels above 20%, a threshold Fulcrum has said is associated with a substantially lower risk of VOCs based on real-world data. Eight participants (50%) reported no VOCs during the treatment period.
Additional results announced earlier this year showed that, among the 12 evaluable participants treated with the 20 mg dose, HbF levels increased from 7.1% before treatment to 19.3% after 12 weeks — a greater increase than with the 12 mg dose. More than half (58%) achieved HbF levels of at least 20%.
Pociredir was also associated with reductions in markers of red blood cell destruction and increases in hemoglobin.
The therapy was generally safe and well tolerated, without reports of treatment-related serious adverse events or discontinuations.
Despite these encouraging findings and the absence of new safety concerns observed with pociredir to date, “the FDA raised concerns regarding the potential malignancy risk associated with pociredir’s [blockage] of the PRC2 complex given the experience with Tazverik that was recently withdrawn from the market,” Sapir said.
Both therapies target the PRC2 complex, but they act on different parts of it. Pociredir targets EED, while tazemetostat targets EZH2.
Fulcrum provided the FDA with data supporting the view that the mechanistic differences between EED and EZH are relevant for the assessment of the pociredir’s risks and benefits. However, the agency ultimately concluded that therapies targeting any component of the PRC2 complex may carry similar risks.
“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,” Sapir said.
