The US Food and Drug Administration (FDA) has released the clinical hold on a second trial evaluating Intellia Therapeutics’ transthyretin amyloidosis with cardiomyopathy (ATTR-CM) gene therapy.
The agency placed the MAGNITUDE and MAGNITUDE 2 trials (NCT06128629; NCT06672237) on hold in October 2025 after a case of Grade 4 liver transaminases and increased total bilirubin in a patient dosed with Intellia’s gene therapy nexiguran ziclumeran (nex-z), being developed in partnership with Regeneron.
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In November 2025, Intellia announced that in the MAGNITUDE trial of nex-z, an in vivo CRISPR therapy, a male patient in his 80s died after receiving the study drug. Investigation following the death confirmed it was not related to the liver event, and instead was due to infection, CEO John Leonard explained during the JP Morgan Healthcare Conference 2026.
The hold was lifted on MAGNITUDE 2 in January 2026, after Intellia aligned with the FDA on certain study modifications and mitigation measures, including enhanced safety monitoring of liver laboratory tests.
MAGNITUDE has now been lifted after it was agreed that Intellia would include enhanced monitoring of liver laboratory tests, guidance for short-term steroid treatment if elevated liver transaminases are observed in the initial period following dosing and the exclusion of patients with certain liver abnormalities.
The trial now also includes additional exclusion criteria for patients with a recent history of cardiovascular instability and those with an ejection fraction <25% at the time of screening.
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By GlobalDataLeonard said: “We are very pleased to have aligned with the FDA on the path forward for our MAGNITUDE clinical trial, with measures designed to further enhance patient safety and allow us to continue to investigate nex-z in a broad ATTR-CM population. With the resolution in January of the clinical hold on our MAGNITUDE-2 Phase III trial for patients with hereditary ATTR with polyneuropathy, our attention now turns to completing enrollment in both ongoing trials. We appreciate the FDA’s responsiveness throughout this process and thank the many investigators and patients who are participating in these trials.”
Intellia’s stock, listed on the Nasdaq exchange, rose 12% after the lift was announced, from a 27 February close of $13.78 to a 2 March close of $15.44. The company has a market cap of $1.78bn.
Liver issues a known problem with gene therapy
Liver toxicity has been a significant barrier for gene therapies. As well as Intellia’s troubles, uniQure paused dosing in its Phase I/II Fabry disease trial after two patients experienced elevated liver enzymes.
Sarepta Therapeutics navigated a safety controversy in 2025 after its approved AAV-based Duchenne muscular dystrophy (DMD) drug, Elevidys (delandistrogene moxeparvovec-rokl), caused two liver-related patient deaths, one in April 2025 and one in June 2025. These led to a label change and the removal of non-ambulatory DMD patients from the label.
Sarepta suffered a third patient death in an early-stage trial of another muscular dystrophy gene therapy candidate.
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