Intellia Puts Phase 3 Trials for Transthyretin Amyloidosis Gene Editing Therapy Nex-Z on Hold Following Grade 4 Liver AE

Intellia has temporarily paused dosing and screening of patients for both the phase 3 MAGNITUDE clinical trial (NCT06128629) and the phase 3 MAGNITUDE-2 clinical trial (NCT06672237), which are respectively evaluating the gene editing therapy nexiguran ziclumeran (nex-z, also known as NTLA-2001) for transthyretin amyloidosis with cardiomyopathy (ATTR-CM) and polyneuropathy (ATTR-PN), after a patient in MAGNITUDE experienced a grade 4 liver adverse event (AE).¹

Specifically, the patient, who was dosed with the therapy on September 30 of this year, showed grade 4 liver transaminases and increased total bilirubin and was hospitalized as of October 24. This event met criteria for pausing the trials as per predefined protocol. According to Intellia, the patient is being closely monitored, the company is considering risk mitigation strategies, and engagement with experts and regulatory authorities is underway.

“In line with our commitment to patient safety, we have taken immediate action to temporarily pause enrollment in MAGNITUDE and MAGNITUDE-2 as we investigate this recent event,” John Leonard, MD, the president and chief executive officer of Intellia, said in a statement.¹ “As we focus on ensuring the health of this patient, we also are engaging with regulatory authorities and other stakeholders globally to develop a strategy to resume enrollment as soon as appropriate.”

Intellia noted that over 450 of the more than 650 patients enrolled in MAGNITUDE and the 47 patients entrolled in MAGNITUDE-2 have been dosed with nex-z. Nex-z is a CRISPR/Cas9 gene editing therapy delivered via a lipid nanoparticle (LNP) nonviral system designed to inactivate the TTR gene that encodes for the TTR protein.²

The therapy has previously been evaluated in a phase 1 trial (NCT04601051) for ATTR amyloidosis. Notably, in 2024, it was demonstrated that the therapy could be safely redosed, according to data that were presented at the 2024 Peripheral Nerve Society (PNS) Annual Meeting, held June 22-25, in Montreal, Canada.³ The follow-on data were from the 3 initial patients enrolled in the dose-escalation portion of the phase 1 trial, who initially received 0.1 mg/kg of NTLA-2001 and then opted to receive a 55 mg dose after 2 years of observation as per the study protocol.

“Today’s data showcase an exciting new platform advancement for Intellia and the field of gene editing,” Leonard said in a statement at the time.² “For the first time ever, we demonstrated that redosing with CRISPR, utilizing our proprietary, nonviral LNP-based delivery platform, enabled an additive pharmacodynamic effect on the target protein.”

CGTLive® has previously spoken to Ahmad Masri, MD, MS, a cardiologist at the Center for Hypertrophic Cardiomyopathy at Oregon Health & Science University, about the current landscape of care for ATTR amyloidosis and how a therapy like nex-z could potentially transform this landscape. In the interview, held for World Amyloidosis Day in 2023, Masri encouraged the healthcare community to think more closely about amyloidosis indications.

“I encourage everyone to continue to learn about amyloidosis: systemic amyloidosis, ATTR amyloidosis, light chain amyloidosis, as well as other types of amyloidosis,” Masri told CGTLive. “These are not ultra-rare diseases like people used to think. These are patients in our clinics not infrequently. I encourage everybody to continue to think about this, read about it, and use it as a case study for how things evolve over time... the whole landscape looks very different in 2023, compared to just 10 years ago.”

REFERENCES
1. Intellia Therapeutics provides update on MAGNITUDE clinical trials of nexiguranziclumeran (nex-z). News release. Intellia Therapeutics, Inc. October 27, 2025. Accessed October 28, 2025. https://ir.intelliatx.com/news-releases/news-release-details/intellia-therapeutics-provides-update-magnitude-clinical-trials
2. Intellia Announces Positive Clinical Proof-of-Concept Data for Redosing a CRISPR-Based Therapy with its Proprietary LNP-Based Delivery Platform. News release. Intellia Therapeutics. June 25, 2024. Accessed October 28, 2025. https://www.globenewswire.com/news-release/2024/06/25/2904115/0/en/Intellia-Announces-Positive-Clinical-Proof-of-Concept-Data-for-Redosing-a-CRISPR-Based-Therapy-with-its-Proprietary-LNP-Based-Delivery-Platform.html
3. Taubel J, Gane E, Fontana M, et al. Activity Of Follow-on Dosing ForAn Investigational In Vivo CRISPR-Based LNP Therapy In Transthyretin Amyloidosis. Presented at: 2024 PNS Annual Meeting, June 22-25; Montreal, Canada. Poster #O435