The patient who was hospitalized after receiving Intellia Therapeutics’ CRISPR therapy nex-z has died. Both phase 3 studies of the candidate remain on hold as the biotech works to understand liver-related events seen in the trials and to develop a risk-mitigation plan.
Intellia paused dosing in studies of nex-z, a CRISPR therapy designed to inactivate the TTR gene, late last month. The pause was triggered by a transthyretin amyloidosis with cardiomyopathy (ATTR-CM) patient who had grade 4 liver enzymes and increased total bilirubin. The FDA put both trials on hold shortly after Intellia disclosed the safety signal.
The biotech provided an update after the market closed Thursday, telling investors the hospitalized patient died Wednesday night. Intellia CEO John Leonard, M.D., said on a call with investors that the patient was in his early 80s and had bilirubin and ALT—markers of liver health—that were, respectively, two and three times the upper limit of normal.
Questioned by analysts, Leonard declined to speculate about the drivers of the liver toxicity signal or provide more details on the patient’s comorbidities and location. The treating physician told Intellia that the patient had complicating comorbidities, but further details are yet to emerge.
Leonard said Intellia still believes in nex-z, pointing to the less than 1% rate of grade 4 elevated liver enzymes across the more than 650 patients enrolled in the ATTR-CM trial. There have been no grade 4 cases among the 47 patients enrolled in the ATTR with polyneuropathy trial. Leonard said most patients have passed the three- to five-week post-treatment window in which the liver cases have started.
Not everyone shares Leonard’s belief in nex-z. Late last month, Guggenheim Securities analysts wrote in a note to investors that the adverse events could “severely limit the commercial potential of nex-z.” The prediction reflected the uncertainty about the mechanism of the adverse events, which the analysts said suggests they could occur in commercial settings, and the availability of other treatments. Alnylam Pharmaceuticals, BridgeBio and Pfizer compete for the ATTR market.
Intellia is working on risk-mitigation measures. The biotech has already told sites to collect additional labs from patients in the initial weeks following dosing to detect potential liver enzyme elevation sooner, Leonard said. The CEO added that the ultimate goal is to find a way to exclude patients who may be at risk.
It is unclear how long it will take to resume the trials. While dosing of the one-time therapy is paused, Intellia is continuing to track patients who have already received the treatment. Edward Dulac, Intellia’s chief financial officer, told investors that he doesn’t “see a substantial shift in the operating needs or the cash needs of the company.” Intellia expects its $670 million to fund operations into mid-2027.
Shares in Intellia fell 24% to $9.33 in premarket trading Friday.