FDA lifts the clinical hold on Intellia’s MAGNITUDE-2 Phase 3 trial of nex-z, allowing enrollment to resume in patients with hereditary ATTR polyneuropathy
Written By: Pharmacally Medical News Desk
Intellia Therapeutics, Inc. has received a key regulatory green light after the U.S. Food and Drug Administration lifted the clinical hold on the Investigational New Drug application for the MAGNITUDE-2 Phase 3 trial of Nexiguran Ziclumeran (nex-z) in patients with hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN).
Although the safety event occurred in the MAGNITUDE trial, the FDA placed clinical holds on both MAGNITUDE and MAGNITUDE-2 trials; the hold has now been lifted only for MAGNITUDE-2, while discussions for MAGNITUDE are ongoing.
The decision allows Intellia to resume patient enrollment in MAGNITUDE-2, a late-stage study evaluating nex-z as a potential one-time gene-editing treatment for this progressive and debilitating rare disease. According to the company, preparations are already underway to restart enrollment as quickly as possible across participating sites.
John Leonard, M.D., president and chief executive officer of Intellia, said the company appreciated the FDA’s prompt review and continued engagement. He emphasized that the team is focused on advancing nex-z for people living with ATTRv-PN following the removal of the hold.
Background on the Clinical Hold
The FDA imposed clinical holds on both the MAGNITUDE trial (NCT06128629) and MAGNITUDE-2 (NCT06672237) Phase 3 trials on October 29, 2025. The action followed the observation of Grade 4 elevations in liver transaminases along with increased total bilirubin in a patient dosed with nex-z in the MAGNITUDE study, which is evaluating the therapy in transthyretin amyloidosis with cardiomyopathy (ATTR-CM). These findings met protocol-defined pausing criteria and triggered a comprehensive safety review.
For MAGNITUDE-2, Intellia has now aligned with the FDA on specific protocol amendments and risk-mitigation measures. These include enhanced monitoring of liver laboratory parameters to strengthen patient safety oversight as the trial resumes.
Engagement with the FDA remains ongoing for the MAGNITUDE Phase 3 trial in ATTR-CM. Intellia stated that it plans to provide an update on the path forward for that program once regulatory alignment is achieved.
Updated MAGNITUDE-2 Trial Design
MAGNITUDE-2 is a randomized, double-blind, placebo-controlled Phase 3 study designed to assess the efficacy and safety of nex-z in adults with ATTRv-PN. Following the protocol amendment, the target enrollment has been increased from approximately 50 to about 60 patients.
Participants are randomized 1:1 to receive a single intravenous infusion of nex-z at a dose of 55 mg or placebo. The study’s primary endpoints are changes in the modified neuropathy impairment score and reductions in serum transthyretin (TTR) levels, both of which are clinically relevant measures of disease progression and treatment effect.
About Nexiguran Ziclumeran (Nex-z)
Nex-z is an investigational in vivo CRISPR/Cas9-based gene-editing therapy designed to inactivate the TTR gene in the liver, thereby reducing production of the transthyretin protein that drives ATTR amyloidosis. The therapy has the potential to become the first one-time treatment option for patients with ATTR-CM and hereditary ATTR with polyneuropathy.
Interim Phase 1 data previously showed that a single administration of nex-z resulted in deep, consistent, and durable reductions in circulating TTR levels. The program has received Orphan Drug and Regenerative Medicine Advanced Therapy (RMAT) designations from the FDA, as well as Orphan Drug Designation from the European Commission.
Intellia is developing and commercializing nex-z in collaboration with Regeneron Pharmaceuticals, Inc., as part of a broader multi-target research and development alliance.
With the MAGNITUDE-2 hold lifted, the resumption of this Phase 3 trial marks an important step forward for Intellia’s lead in vivo gene-editing program and for patients awaiting new disease-modifying options in ATTRv-PN.
Reference
Intellia Therapeutics Announces FDA Lift of Clinical Hold on MAGNITUDE-2 Phase 3 Clinical Trial in ATTRv-PN, 27 January 2026, https://ir.intelliatx.com/news-releases/news-release-details/intellia-therapeutics-announces-fda-lift-clinical-hold-magnitude
MAGNITUDE: A Phase 3 Study of NTLA-2001 in Participants with Transthyretin Amyloidosis with Cardiomyopathy (ATTR-CM), ClinicalTrials.gov ID NCT06128629, https://clinicaltrials.gov/study/NCT06128629
A Phase 3 Study of NTLA-2001 in ATTRv-PN, ClinicalTrials.gov ID NCT06672237, https://clinicaltrials.gov/study/NCT06672237
