Intellia Therapeutics has temporarily paused dosing and patient enrollment in two pivotal Phase III trials of its investigational CRISPR-based gene therapy for transthyretin amyloidosis (ATTR) following a serious liver safety event in a study participant. The affected volunteer, treated with Intellia’s lead candidate nexiguran ziclumeran (“nex-z”), was hospitalized with a “grade 4” spike in liver enzymes and bilirubin levels, both of which indicate a high risk for drug-induced liver injury. This event triggered Intellia’s protocol-mandated stopping criteria and led the FDA to place both studies—MAGNITUDE and MAGNITUDE-2—under official clinical hold.
The ongoing trials are evaluating nex-z in patients with ATTR cardiomyopathy and polyneuropathy, rare diseases caused by abnormal protein buildup that can affect the heart and nerves. Intellia is collaborating with regulators and independent experts to identify the root cause of the adverse event and establish enhanced patient monitoring and risk mitigation measures. Initial indications suggest the issue may be linked to the gene target itself rather than the lipid nanoparticle delivery system commonly used in gene editing therapies, although investigations are ongoing.
Intellia’s CEO, John Leonard, stated that while previous mild liver enzyme elevations had been observed, this was the first incident that met Hy’s law criteria for severe drug-induced liver injury.
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