FDA Places Clinical Hold on Two Intellia CRISPR Trials After Life-Threatening Liver Toxicity Case

The FDA has put a clinical hold on two phase 3 Intellia Therapeutics trials (MAGNITUDE and MAGNITUDE-2), which investigate the in vivo CRISPR-based therapy nexiguran ziclumeran (nex-z) for transthyretin amyloidosis with cardiomyopathy (ATTR-CM) and polyneuropathy (ATTR-PN).12

The clinical hold followed a report of grade 4 (life-threatening) liver transaminases and increased total bilirubin in a patient dosed with nex-z on September 30, 2025, in the MAGNITUDE trial; the patient was hospitalized and is receiving medical care.126

Intellia had already voluntarily paused patient dosing and screening in the affected studies before the FDA's action in response to the safety signal.26

The FDA's communication of the clinical hold was initially verbal, with a formal letter expected within 30 days.12

Nexiguran ziclumeran is a CRISPR/Cas9-based gene therapy designed to inactivate the TTR gene, addressing hereditary ATTR amyloidosis by preventing the production of misfolded transthyretin protein.14

Although liver toxicity is a known risk for CRISPR therapies targeting liver cells, this is the most severe liver event reported in Intellia's trials to date; previous incidents did not trigger a similar trial pause.46

Intellia's CEO stated the combination of elevated liver enzymes and bilirubin exceeded standard safety thresholds and met the trial's protocol-defined pausing criteria—known as 'Hy's law' for drug-induced liver injury.6

Sources:

1. https://www.cellgenetherapyreview.com/3972-News/622452-FDA-puts-clinical-hold-on-Intellia-CRISPR-therapy-trials/

2. https://www.biospace.com/fda/life-threatening-liver-toxicity-triggers-fda-freeze-on-two-intellia-gene-therapy-studies

4. https://www.statnews.com/2025/10/27/intellia-gene-editing-trial-pause/

6. https://www.fiercebiotech.com/biotech/intellia-pauses-phase-3-crispr-trials-after-patient-hospitalized