Fulcrum Therapeutics has begun a strategic review that may result in it getting sold, a move made after the company’s main medicine hit a possibly insurmountable obstacle.
On Tuesday, Fulcrum disclosed that, late last month, it received the official record from a recent meeting with the Food and Drug Administration. The meeting revolved around next steps for pociredir, an experimental treatment for sickle cell disease that Fulcrum had ushered through early-stage human testing.
According to the company, FDA staff were worried about pociredir’s safety, given emerging data that showed higher-than-expected rates of “secondary” blood cancers in patients who had received an Ipsen drug, Tazverik, which was pulled from the market in March. Fulcrum’s drug works in a similar-but-different way, and the company tried to make the case that these differences are important to assessing overall benefits and risks. The FDA, though, still concluded the potential hazards were too great and “left no viable regulatory path forward.”
Fulcrum has therefore made the “very difficult decision to discontinue development of pociredir,” said CEO Alex Sapir. The company is now exploring strategic alternatives, including potentially merging or selling either assets or the entire business. It’s also started efforts to “significantly reduce” operating expenses and preserve capital, though specific details weren’t provided. Fulcrum had a third of a billion dollars in cash, cash equivalents, and marketable securities as of March 31.
Fulcrum’s stock price, which had already fallen significantly since late last year, cratered following Tuesday’s update. Shares were down more than 50%, to just above $3 apiece.
“With limited visibility into future value creation beyond strategic alternatives and cost-cutting initiatives, we are moving to the sidelines,” wrote Leerink Partners analyst Joseph Schwartz, who also downgraded his rating on Fulcrum’s stock to “Market Perform.”
Schwartz noted, however, that his team was “surprised by this outcome” due to the effects pociredir demonstrated in that early-stage study. There, the drug boosted fetal hemoglobin levels — one of the most proven methods for treating sickle cell — and improved red blood cell health in adults with severe disease. Schwartz highlighted how the trial also hadn’t reported any new clinical safety signals.
Pociredir is designed to inhibit a large protein complex, “PRC2,” that helps turn off fetal hemoglobin production. It does this by latching onto a specific piece of the protein that, notably, is distinct from where Tazverik binds. Recent clinical data pointing to an increased incidence of hematologic malignancies among patients given Tazverik appears to have led the FDA to draw a “hard line regarding the risk/benefit profile of all PRC2 inhibitors regardless of mechanistic differences,” Schwartz wrote.
The FDA previously put a so-called full clinical hold on Fulcrum’s program in early 2023, in part because of concerns with the wider class of PRC2-targeting drugs. The hold was lifted that summer, with Fulcrum agreeing to tailor the type of patients who were eligible to participate in its Phase 1 study. Schwartz argues the FDA position regarding pociredir “seems to have been biased” by malignancy observations seen in preclinical testing.
Luca Issi, an analyst at RBC Capital Markets, claims his team wasn’t entirely surprised by this outcome. While it’s “unfortunate for the many [sickle cell] patients looking for therapeutic alternatives, we do believe that discontinuing the program is the right pragmatic decision given the FDA clearly believes that this is a class effect,” Issi wrote in his own note to clients.
Fulcrum’s is the latest in a string of setbacks for sickle cell drugmakers. In 2023, development was discontinued for three experimental treatments from Intellia Therapeutics, Sangamo Therapeutics and Graphite Bio. Two years later, Pfizer and Agios Pharmaceuticals each delivered disappointing clinical results.
Pfizer’s study was for a drug that the pharmaceutical giant picked up through the $5.4 billion acquisition of Global Blood Therapeutics. In 2024, Pfizer removed from the market another asset from that deal, the approved sickle cell therapy Oxbryta, because of safety concerns.
The year prior, Novartis withdrew Adakveo from the European market after authorities there formally revoked the sickle cell disease drug’s authorization.
The World Health Organization estimates that, as of 2021, close to 8 million people had sickle cell. The disease causes "vaso-occlusive crises," a sudden, brutal wave of pain brought on by the crescent-shaped blood cells block small blood vessels. It can also make patients more vulnerable to infections and trigger chronic damage. Often, the life expectancy for people with sickle is 20 or so years less than their peers.
