Fulcrum Halts Development of SCD Candidate Pociredir, Sets Strategic Review

Fulcrum Therapeutics said today it is scrapping its lead pipeline program to develop pociredir as a treatment for sickle cell disease (SCD) and launching a “comprehensive” review of strategic alternatives, after the FDA told the company it had heightened concerns about the drug’s risks and benefits in fighting the disease.

Those concerns, which the agency raised with Fulcrum executives at a recent end-of-phase meeting, stemmed from an unexpectedly high rate of secondary blood cancers seen with another PRC2 inhibitor—Ipsen’s Tazverik^® (tazemetostat), indicated to treat follicular lymphoma and epithelioid sarcoma, the company disclosed, based on meeting minutes received May 28.

Ipsen voluntarily withdrew Tazverik from the market in March following adverse events of secondary blood cancers emerging from the ongoing Phase Ib/III SYMPHONY-1 trial (NCT04224493), which evaluated the drug in combination with lenalidomide plus rituximab (R²) vs R² in follicular lymphoma. Ipsen inherited the drug when it acquired its developer Epizyme in 2022 for $247 million. Tazverik last year generated €40.6 million ($47.2 million) for Ipsen and another $2.5 million for Hutchmed, which marketed the drug in China. The withdrawal also affected Eisai, since it marketed Tazverik in Japan and manufactured the drug there.

Pociredir is an oral small molecule polycomb repressive complex 2 (PRC2) inhibitor targeting embryonic ectoderm development (EED), and was discovered using Fulcrum’s discovery technology. Fulcrum has reasoned that inhibiting EED leads to potent downregulation of key fetal globin repressors including BCL11A, thereby causing an increase in fetal hemoglobin (HbF).

“Fulcrum submitted information to FDA supporting the position that mechanistic differences between EED (pociredir’s target) and EZH2 (tazemetostat’s target), which perform different biological roles, were relevant to the benefit-risk assessment,” Fulcrum said in a statement. “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.

The agency considered Fulcrum’s position before rebuffing the company, concluding that any drug intervention targeting the PRC2 complex carries equivalent malignancy risk “regardless of the specific subunit engaged,” Fulcrum continued, based on pociredir’s previously disclosed preclinical malignancy observations.

That left no viable regulatory path forward for further clinical development of pociredir, Fulcrum concluded.

No path forward

“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,” stated Alex C. Sapir, Fulcrum’s president and CEO. “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.”

“We know the SCD community has faced many disappointments and setbacks related to innovation for this devastating disease,” Sapir added. “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.”

Pociredir is not the first SCD therapy to be scrapped. In 2024, Pfizer withdrew Oxbryta^® (voxelotor) from the market, citing deaths and vaso-occlusive crises occurring in patients given Oxbryta in clinical studies. Hours before Pfizer’s announcement, the European Medicines Agency (EMA) disclosed findings from two Phase III trials of Oxbryta in which a total of 18 deaths occurred—all but two of them reported in patients who were dosed with the drug.

Pfizer inherited Oxbryta when it acquired the drug’s original developer, Global Blood Therapeutics (GBT), for $5.4 billion, a deal completed in 2022.

Vivien Sheehan, MD, PhD, director of Translational Sickle Cell Disease Research at Emory University School of Medicine, told GEN Fulcrum’s data was “reasonable, although not game changing.”

“I don’t take it [Fulcrum’s halt to pociredir development] as an abandonment of SCD,” said Sheehan, who is also a member of the Discovery and Developmental Therapeutics Research Program at Winship Cancer Institute of Emory University. “There may not have been a path forward, and more efficacious drugs in the pipeline may have also influenced the decision.”

She expressed greater enthusiasm for a potential SCD treatment being developed by Bristol Myers Squibb (BMS)—BMS-986470, an oral HbF-activating cereblon (CRBN) E3 ligase modulator (CELMoD) agent designed as a potential first-in-class degrader of both transcription factors zinc finger and BTB domain containing 7A (ZBTB7A) and widely interspaced zinc finger (WIZ).

BMS-986470 is now under study in an ongoing Phase I/II trial (NCT06481306) designed to evaluate the safety and tolerability, pharmacokinetics and pharmacodynamics, pH and food effect, and preliminary efficacy of BMS-986470 in healthy volunteers and participants with SCD. The study’s estimated primary completion date is January 6, 2027, according to ClinicalTrials.gov.

A 2024 preclinical study by a team of BMS researchers showed BMS-986470 to have generated “robust γ -globin induction activity leading to HbF levels predicted to significantly ameliorate SCD pathology.”

$1.5B peak sales forecast

In ending development of pociredir, Fulcrum has scrapped a drug that stood to generate as much as $1.5 billion in projected peak sales by 2038, according to BofA Securities, which predicted a 2029 commercial launch for the drug.

Investors responded to Fulcrum’s halt to development of pociredir with a stock selloff that sent shares of Fulcrum on the Nasdaq Global Market plummeting 51% Tuesday, to $3.13 from yesterday’s closing price of $6.42.

As a result of scraping development of pociredir, Fulcrum said, it will explore potential strategic alternatives, “including, but not limited to, a merger, acquisition, business combination, or other strategic transactions involving the company or its assets.”

Fulcrum said it has also begun efforts to “significantly” reduce its operating expenses and preserve capital. Fulcrum finished the first quarter with $333.3 million in cash, cash equivalents, and marketable securities.

“We believe that our existing cash, cash equivalents, and marketable securities as of March 31, 2026 will enable us to fund our operating expenses and capital expenditure requirements into 2029,” Fulcrum stated in its Form 10-Q regulatory filing for the first quarter.

“With a strong balance sheet extending our cash runway into 2029, we are well positioned to advance pociredir through the next phase of clinical development,” Fulcrum stated in its April 27 press release.

The company has not set a timeline for completing its strategic review, adding that it does not intend to provide further updates “unless and until the board of directors has approved a course of action, the review process is concluded, or other disclosure is otherwise determined to be appropriate.”

Positive interim data

As late as April 27, when it held its quarterly earnings call with analysts to discuss first quarter results, Fulcrum had conveyed optimism about pociredir’s clinical prospects.

During the call, Sapir cited Fulcrum’s announcement of positive interim data from its Phase Ib PIONEER trial (NCT05169580) in February, which showed:

• A mean absolute HbF increase of 12.2% at 12 weeks of treatment with pociredir, rising from a baseline of 7.1% to 19.3%—what the company said represented “a rapid, robust, and clinically relevant response,” with progression toward pan-cellular HbF induction as F-cells increased from 31% to 63%.
• Absolute HbF levels ≥20% in 7 of 12 patients (58%), with all patients achieving at least a 6.5% absolute increase in HbF.
• Improvements in markers of hemolysis, improved erythropoiesis, and a >1 g/dL increase in total hemoglobin.
• Zero vaso-occlusive crises (VOCs) during the treatment period reported in seven of 12 patients (58%).

“Importantly, pociredir has continued to be generally well tolerated with no treatment-related serious adverse events reported to date,” Sapir told analysts. “Taken together, these data reinforce our conviction in pociredir’s potential to address the underlying biology of sickle cell disease—and support our belief that pociredir has the potential to represent a differentiated, once-daily oral treatment option for patients.”

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