Patient Treated in Trial for Intellia’s Transthyretin Amyloidosis Gene Editing Therapy Nex-Z Dies

A patient treated with Intellia Therapeutics’ gene editing therapy nexiguran ziclumeran (nex-z, also known as NTLA-2001) for transthyretin amyloidosis with cardiomyopathy (ATTR-CM) in the context of the phase 3 MAGNITUDE clinical trial(NCT06128629) has died, after being hospitalized following a grade 4 liver adverse event (AE).¹

MAGNITUDE had already been temporarily paused by Intellia as of the initial announcement of the AE on October 27, 2025, along with the phase 3 MAGNITUDE-2 clinical trial (NCT06672237), which is evaluating nex-z for ATTR with polyneuropathy (ATTR-PN).² According to Intellia, the FDA placed clinical holds on both MAGNITUDE and MAGNITUDE-2 on October 29, 2025.¹ The patient’s death occurred on the night of November 5, 2025.

“We were deeply saddened to learn that the patient who experienced grade 4 liver transaminase elevations and increased total bilirubin following a dose of nex-z in the MAGNITUDE phase 3 clinical trial, as reported on October 27, 2025, passed away last night,” John Leonard, MD, the president and chief executive officer of Intellia, said in a November 6, 2025, statement.¹ “We have been advised by the treating physician that this is a case with complicating comorbidities, and it is being further evaluated. As we await the FDA’s clinical hold letter, we are working with clinical investigators and external experts to better understand the liver-related events that have been observed within MAGNITUDE and to develop our risk mitigation plan. We continue to believe in nex-z’s potential to address important unmet needs for patients with ATTR amyloidosis.”

Nex-z, which Intellia is collaborating with Regeneron on with regard to development and commercialization, is an investigational 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.^1,3 Intellia has pointed out that of the over 450 of the more than 650 patients enrolled in MAGNITUDE that have been dosed with nex-z, less than 1% have experienced grade 4 liver transaminase elevations.^1,2 Furthermore, of the 47 patients enrolled in MAGNITUDE-2 who have been dosed with nex-z, no grade 4 liver transaminase elevations have been reported to date.

Intellia also noted that it has recently put in place increased monitoring requirements during the weeks after dosingfor laboratory values of patients treated in MAGNITUDE and MAGNITUDE-2. The company also stated that while it awaits the clinical hold letter from the FDA, it is consulting with clinical investigators and other experts about other potential risk mitigation strategies. Once a plan has been finalized with regulatory bodies, Intellia plans to provide an update about its currently suspended milestone guidance for nex-z.

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.⁴ Intellia plans to present new longer-term data from the phase 1 trial at the 2025 American Heart Association (AHA) Scientific Sessions on November 10, 2025.¹

REFERENCES
1. Intellia Therapeutics Announces Third Quarter 2025 Financial Results and Recent Updates. News release. Intellia Therapeutics, Inc. November 6, 2025. Accessed November 7, 2025. https://ir.intelliatx.com/news-releases/news-release-details/intellia-therapeutics-announces-third-quarter-2025-financial
2. Intellia Therapeutics provides update on MAGNITUDE clinical trials of nexiguranziclumeran (nex-z). News release. Intellia Therapeutics, Inc. October 27, 2025. Accessed November 7, 2025. https://ir.intelliatx.com/news-releases/news-release-details/intellia-therapeutics-provides-update-magnitude-clinical-trials
3. 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 November 7, 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
4. 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