Intellia Therapeutics announced that the U.S. Food and Drug Administration (FDA) has lifted the clinical hold on the Investigational New Drug (IND) application for the MAGNITUDE phase III clinical trial evaluating nexiguran ziclumeran (nex-z) for patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM).

The decision allows the company to resume patient enrollment in the global phase III study after implementing additional safety monitoring measures agreed upon with the FDA. The clinical hold was initially imposed on October 29, 2025, following the observation of severe liver enzyme elevations and increased bilirubin levels in a patient who had received nex-z during the MAGNITUDE trial.

According to the company, mitigation measures now include enhanced monitoring of liver laboratory tests, guidance for short-term steroid treatment in cases of elevated liver enzymes shortly after dosing, and exclusion of patients with certain liver abnormalities. For the MAGNITUDE trial, additional exclusion criteria will also apply to patients with recent cardiovascular instability or an ejection fraction below 25 percent at the time of screening.

The MAGNITUDE trial is a randomised, double-blind, placebo-controlled phase III study designed to evaluate the efficacy and safety of nex-z in approximately 1,200 patients with ATTR-CM. Participants are randomizsed in a 2:1 ratio to receive either a single 55 mg infusion of nex-z or placebo, with the primary endpoint based on a composite of cardiovascular-related outcomes including mortality.

In parallel, the company is also advancing the MAGNITUDE-2 phase III trial for hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN), a randomised placebo-controlled study involving around 60 patients. The primary endpoints of this trial include changes in modified neuropathy impairment score and serum transthyretin levels.

Nexiguran ziclumeran is based on CRISPR/Cas9 gene-editing technology and is designed to inactivate the transthyretin (TTR) gene responsible for producing the disease-causing protein. Early clinical data have shown that a single administration of the therapy can lead to deep and sustained reductions in TTR levels.

The therapy has received Orphan Drug designation and Regenerative Medicine Advanced Therapy (RMAT) designation from the FDA, as well as Orphan Drug designation from the European Commission. Intellia is developing nex-z in collaboration with Regeneron Pharmaceuticals as part of a multi-target gene-editing partnership.