FDA Lifts Clinical Hold on Intellia’s Trial for Gene Editing Therapy Nex-Z in ATTRv-PN, Places Holds on REGENXBIO MPS Trials

The FDA has lifted a clinical hold it had previously placed on Intellia Therapeutics’ phase 3 MAGNITUDE-2 clinical trial (NCT06672237), which is evaluating gene editing therapy nexiguran ziclumeran (nex-z, also known as NTLA-2001) for transthyretin amyloidosis with polyneuropathy (ATTR-PN).¹

The hold was placed in October 2025 after a patient being treated in the separate phase 3 MAGNITUDE clinical trial (NCT06128629), which is evaluating nex-z for ATTR with cardiomyopathy (ATTR-CM), experienced a grade 4 cases of liver transaminases and increased total bilirubin. Clinical holds were placed on both MAGNITUDE and MAGNITUDE-2 simultaneously on October 29, 2025, and the clinical hold on MAGNITUDE remains in effect. On November 5, 2025, the patient who experienced the grade 4 adverse event (AE) died, after having been hospitalized.²

Intellia noted that it has since aligned with the FDA on modifications to MAGNITUDE-2, including enhanced safety monitoring of liver laboratory tests, and that engagement with the agency aimed at finding a roadway forward for MAGNITUDE is ongoing.¹ The company also stated that it is working with stakeholders such as trial investigators, ethics committees, and international regulatory bodies, to continue enrolling patients in MAGNITUDE-2 as soon as is possible, and that the target enrollment for MAGNITUDE-2 has been increased from about 50 patients to about 60 patients.

“We appreciate the FDA’s expeditious review of our submission and ongoing engagement and thank our study investigators and patients for their continued participation,” John Leonard, MD, the president and chief executive officer of Intellia, said in a statement.¹ “With the clinical hold for MAGNITUDE-2 lifted, our team is focused on resuming patient enrollment as quickly as possible as we seek to advance this potential one-time treatment option for people living with ATTRv-PN.”

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.^2,3 Intellia has previously 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 and that 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.^2,4

Also this week, the FDA placed clinical holds on REGENXBIO’s clinical trials for RGX-111, an investigational adeno-associated virus (AAV) vector-based gene therapy intended to treat severe mucopolysaccharidosis Type I (MPS I, also known as Hurler syndrome), and clemidsogene lanparvovec (RGX-121), an investigational AAV vector-based gene therapy intended to treat mucopolysaccharidosis type 2 (MPSII, also known as Hunter syndrome).⁵ The holds are related to an intraventricular central nervous system tumor that occurred in 1 patient who was treated with RGX-111 in a phase 1/2 clinical trial. The patient has not experienced symptoms, but the neoplasm was identified on a routine brain MRI 4 years after the patient was treated with the gene therapy product, and preliminary analysis indicated an AAV vector genome integration event associated with overexpression of PLAG1, a protooncogene. REGENXBIO noted that the tumor was resected, that the patient has shown positive developmental advancements, and that whether the serious AE was related to RGX-111 has not yet been determined.

According to REGENXBIO, although the event occurred in the RGX-111 trial, the FDA also placed a hold on RGX-121 because of “similarities in products, study populations, and shared risk between the clinical studies”.⁵ The company noted that it has not yet received the full clinical hold letter from the agency and that it expects additional details to come later on.

"We are surprised by FDA's decision to place our RGX-121 program on hold while the investigation of this single, inconclusive incident in RGX-111 continues," Curran M. Simpson, the president and chief executive officer of REGENXBIO, said in a statement.⁵ "These are separate therapies, and the positive safety profile of RGX-121 in more than 30 patients treated, including those dosed nearly 7 years ago, remains unchanged. Patient safety is our top priority, and we, our investigators, and the patient community remain confident in the benefit-risk ratio of RGX-121 and are highly encouraged by the meaningful efficacy profile demonstrated in the pivotal trial. RGX-121 presents an opportunity to address the urgent, significant unmet medical need in this ultrarare disease community, and continued delay means continued neurodevelopmental decline in boys with MPS II."

REFERENCES
1. Intellia Therapeutics announces FDA lift of clinical hold on MAGNITUDE-2 phase 3 clinical trial in ATTRv-PN. News release. Intellia Therapeutics, Inc. January 27, 2026. Accessed January 28, 2026. https://ir.intelliatx.com/news-releases/news-release-details/intellia-therapeutics-announces-fda-lift-clinical-hold-magnitude
2. Intellia Therapeutics Announces Third Quarter 2025 Financial Results and Recent Updates. News release. Intellia Therapeutics, Inc. November 6, 2025. Accessed January 28, 2026. https://ir.intelliatx.com/news-releases/news-release-details/intellia-therapeutics-announces-third-quarter-2025-financial
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 January 28, 2026. 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. Intellia Therapeutics provides update on MAGNITUDE clinical trials of nexiguranziclumeran (nex-z). News release. Intellia Therapeutics, Inc. October 27, 2025. Accessed January 28, 2026. https://ir.intelliatx.com/news-releases/news-release-details/intellia-therapeutics-provides-update-magnitude-clinical-trials
5. REGENXBIO announces regulatory update on ultra rare MPS programs. News release. REGENXBIO Inc. January 28, 2026. Accessed January 28, 2026. https://ir.regenxbio.com/news-releases/news-release-details/regenxbio-announces-regulatory-update-ultra-rare-mps-programs/