Intellia’s CRISPR therapy Phase III to continue after FDA lifts clinical hold

Intellia Therapeutics revealed that the US FDA has lifted the clinical hold on its MAGNITUDE-2 Phase III trial for nexiguran ziclumeran (nex-z), a one-time CRISPR-based gene-editing therapy for hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN). Intellia will now restart patient enrollment and dosing after agreeing with the agency on risk mitigation measures.

In October 2025, the FDA placed a hold on the investigational new drug (IND) filings for two Phase III trials: the MAGNITUDE-2, designed to evaluate safety and efficacy of nex-z in adults living with the rare nerve-damaging ATTRv-PN, and MAGNITUDE for the cardiomyopathy form (ATTR-CM). That followed a reported serious liver toxicity in the MAGNITUDE study, meeting pausing criteria under the protocol. Enhanced liver safety monitoring and other study modifications agreed with the FDA underpinned the decision to lift the hold for MAGNITUDE-2. Intellia plans to resume MAGNITUDE-2 enrollment as quickly as possible, with the trial’s target population increased modestly from 50 to 60 patients to improve statistical robustness. The company’s engagement with regulators on the MAGNITUDE trial for ATTR-CM remains ongoing, with updates expected once a path forward is aligned.

“Nex-z” is a first-in-class, in vivo CRISPR/Cas9-based gene-editing therapy developed by Intellia in collaboration with Regeneron Pharmaceuticals. It targets transthyretin (TTR) amyloidosis, a rare and progressive disease caused by misfolding of the TTR protein, leading to amyloid deposits in tissues.

The drug candidate is designed to introduce targeted double-strand breaks in the TTR gene within hepatocytes (liver cells). This gene disruption leads to permanent inactivation of TTR gene expression, resulting in a marked reduction of circulating TTR protein. By lowering both mutant and wild-type TTR, the therapy aims to halt or reverse the progression of amyloid deposition in affected tissues (nerves, heart, etc.).

Regeneron and Intellia partnered on development of multiple CRISPR gene therapies in 2023, with Intellia leading development of Nex-z, while Regneron is leading early stage trials for a hemophilia B candidate. Intellia is also developing the Phase III stage lonvoguran ziclumeran for hereditary angioedema independently.