FDA lifts second clinical hold on Intellia's MAGNITUDE Phase 3 trial

The U.S. Food and Drug Administration removed the second of two clinical holds on Intellia Therapeutics’ investigational CRISPR gene‑editing therapy, clearing the way for the MAGNITUDE Phase 3 trial in transthyretin amyloidosis with cardiomyopathy to proceed under tightened safety conditions, the company said March 2. The action follows an earlier January lift on MAGNITUDE‑2, the sister Phase 3 study in hereditary ATTR with polyneuropathy.

The holds were first imposed after a serious liver toxicity event in late October 2025. Intellia has acknowledged that a patient dosed with nexiguran ziclumeran, known as nex‑z or NTLA‑2001, experienced Grade 4 elevations in liver transaminases and increased total bilirubin that met the trial’s protocol‑defined pausing criteria and later resulted in death. The initial regulatory pause was announced Oct. 29, 2025, and Intellia notified investigators and stakeholders as it developed revised risk mitigation measures.

Under the FDA’s conditions for allowing MAGNITUDE to restart, Intellia said it will exclude patients with certain liver issues, patients with a cardiac ejection fraction below 25 percent, and patients with a recent history of cardiovascular instability from enrollment in the cardiomyopathy trial. Both MAGNITUDE and MAGNITUDE‑2 will adopt closer liver enzyme monitoring and new guidance on short‑term steroid treatment for patients who develop concerning elevations in liver tests. The company has said it has “aligned with the FDA on the path forward” for the trial.

John Leonard, M.D., Intellia’s president and chief executive officer, framed the regulatory agreement as a safety‑focused path forward. “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,” he said. He added that “our attention now turns to completing enrollment in both ongoing trials,” and in a separate release thanked investigators and patients for their continued participation.

Investors responded to the sequence of regulatory moves. Intellia shares climbed about 10 percent after the company said regulators had cleared the restart of one of the two Phase 3 trials, reflecting market relief that setbacks may not materially delay development timelines. Evercore ISI analysts described the safety adjustments as “modest” and said the lift “probably comes with minimal disruption to the clinical timeline.”

The clinical holds and their lifting highlight broader public health and policy tensions as powerful new technologies move from early studies into large, late‑stage trials. Gene editing interventions, particularly those delivered systemically with lipid nanoparticles, can present unpredictable organ toxicities that demand stringent monitoring and transparent reporting. For patients with rare, progressive diseases such as ATTR, delays in trials translate directly into postponed access to potential one‑time therapies, raising equity concerns for communities that have often lacked resources to pursue alternative care.

Key questions remain unanswered by the releases: the precise list of liver conditions that will trigger exclusion, the detailed monitoring schedule and thresholds for action, and the clinical adjudication of the fatal liver event. Regulators, Intellia and partners such as Regeneron will face continued scrutiny as enrollment resumes and as clinicians and patient groups seek clear information about risk management and equitable trial access.