The US Food and Drug Administration (FDA) has removed the clinical hold on the Investigational New Drug application (IND) for the MAGNITUDE Phase III clinical trial of nexiguran ziclumeran (nex-z) for patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM). 

The clinical holds on the INDs for MAGNITUDE and MAGNITUDE-2 were imposed by the FDA in October 2025, following the observation of Grade 4 liver transaminases and increased total bilirubin in a patient who was dosed with nex-z in MAGNITUDE.  

The company has aligned with the FDA on mitigation measures for MAGNITUDE and MAGNITUDE-2 that 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.  

For MAGNITUDE, additional exclusion criteria are being incorporated for patients with a recent history of cardiovascular instability and those with ejection fraction <25% at the time of screening. 

Based on CRISPR/Cas9 gene editing technology, Nex-z is designed to inactivate the TTR gene that encodes for the transthyretin (TTR) protein. Interim Phase I clinical data showed the administration of nex-z led to consistent, deep and long-lasting TTR reduction. 

“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,” said Intellia President and Chief Executive Officer John Leonard.  

“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.”