Intellia pauses Nex‑Z Phase 3 trials, places program on clinical hold

Intellia Therapeutics halted late-stage testing of its CRISPR therapy nexiguran ziclumeran, or nex-z, in October 2025 after a patient in the MAGNITUDE study developed severe liver abnormalities and was hospitalized. The pause covered both MAGNITUDE, a Phase 3 trial in transthyretin amyloidosis with cardiomyopathy, and MAGNITUDE-2, a Phase 3 trial in hereditary transthyretin amyloidosis with polyneuropathy, the company said. (fiercebiotech.com) Two days later, on October 29, 2025, the U.S. Food and Drug Administration imposed a formal clinical hold on both studies. Intellia said at the time it was working with regulators, investigators and outside experts on a path to resume enrollment. (cgtlive.com) ### Which trials were stopped, and who was affected? (ir.intelliatx.com) MAGNITUDE and MAGNITUDE-2 are Intellia’s registrational studies for nex-z, an in vivo CRISPR treatment designed to inactivate the TTR gene in the liver. MAGNITUDE is testing the therapy in patients with transthyretin amyloidosis with cardiomyopathy, while MAGNITUDE-2 is studying hereditary transthyretin amyloidosis with polyneuropathy. More than 650 patients had been enrolled in MAGNITUDE before the pause, and 47 patients had been enrolled in MAGNITUDE-2, according to company statements reported in October 2025. CGTLive reported that more than 450 of the patients in MAGNITUDE and the 47 patients in MAGNITUDE-2 had already received nex-z. (fiercebiotech.com) ### What exactly happened to the patient in MAGNITUDE? Intellia said the affected patient in MAGNITUDE received nex-z on September 30, 2025 and was hospitalized as of October 24, 2025 after showing grade 4 liver transaminases and increased total bilirubin. The company said the event met predefined protocol criteria requiring the studies to pause. (cgtlive.com) John Leonard, Intellia’s president and chief executive officer, said on an October 2025 call that the combination of elevated liver enzymes and bilirubin crossed the threshold that triggered the stop. Leonard said the findings “would meet the traditional definition of Hy’s law,” referring to a rule of thumb used to assess the risk of drug-induced liver injury. (cgtlive.com) ### Why did the FDA step in after Intellia had already paused enrollment? The FDA on October 29, 2025 formally placed both studies on clinical hold, turning Intellia’s voluntary pause into a regulatory stop. BioPharma Dive reported that the agency was expected to provide Intellia with a formal letter within 30 days, after which the company would need to respond before the trials could restart. (cgtlive.com) William Blair analyst Myles Minter said in a research note cited by BioPharma Dive that an FDA hold creates “a higher level of scrutiny” than a sponsor-led pause. Leerink Partners analyst Mani Foroohar said the hold likely delayed study readouts by several quarters, according to the same report. (fiercebiotech.com) ### What did Intellia say about the possible cause? Leonard said in October 2025 that the company was still early in its review and it was “premature” to identify predictors or patient groups at risk. He said the patient’s liver abnormalities appeared more than three weeks after dosing, a timing pattern that he said resembled an earlier asymptomatic liver-enzyme event seen in the program. (biopharmadive.com) Fierce Biotech reported that Leonard said the lag made the lipid nanoparticles used to deliver the therapy an unlikely cause, because those particles are more typically associated with small liver-enzyme increases in the day or two after dosing. Leonard said he believed the issue was limited to Intellia’s TTR program, while studies of lonvoguran ziclumeran, its hereditary angioedema candidate, were continuing. (biopharmadive.com) ### How did the company get the program moving again? Intellia said on January 27, 2026 that the FDA lifted the clinical hold on MAGNITUDE-2, the polyneuropathy study, while discussions continued for MAGNITUDE, the cardiomyopathy trial. On March 2, 2026, the company said the FDA had also removed the hold on MAGNITUDE. (fiercebiotech.com) The March 2 company statement said Intellia and the FDA agreed on added safeguards, including enhanced liver laboratory monitoring, guidance for short-term steroid treatment if liver transaminases rise soon after dosing, and exclusion of patients with certain liver abnormalities. For MAGNITUDE, Intellia also added exclusion criteria for patients with recent cardiovascular instability and those with ejection fraction below 25% at screening. (fiercebiotech.com) ### What comes next for Intellia’s broader pipeline? Intellia said in March 2026 that it was working with investigators, ethics committees, international regulators and other stakeholders to resume enrollment in both studies. MAGNITUDE is designed to enroll about 1,200 patients and uses a composite endpoint based on cardiovascular-related events, including mortality; patients are randomized 2:1 to receive a single 55 mg infusion of nex-z or placebo. (drugs.com) As of December 31, 2025, Intellia had about $605.1 million in cash, cash equivalents and marketable securities and said that balance was expected to fund operations into the second half of 2027. The company has also said it expects top-line data from its HAELO Phase 3 study of lonvo-z by mid-2026 and plans a biologics license application submission in the second half of 2026 if those data support it. (ir.intelliatx.com) (stocktitan.net)