Written By: Shreya Bendsure BPharm
Reviewed By: Pharmacally Editorial Team
Intellia Therapeutics headquarters at Cambridge, Massachusetts has paused its Phase 3 MAGNITUDE trials for the investigational CRISPR-based therapy NTLA-2001 (Nexiguran Ziclumeran) after a patient suffered a severe, life-threatening liver injury. This unprecedented event marks a significant setback for in vivo CRISPR therapeutics targeting transthyretin amyloidosis and raises broader questions about gene editing safety in late-stage trials.
On October 27, 2025, Intellia Therapeutics announced a temporary halt of patient dosing and screening in both its MAGNITUDE and MAGNITUDE-2 Phase 3 trials following a serious adverse event involving grade 4 liver toxicity and hyperbilirubinemia in a dosed ATTR-CM patient. The affected individual was hospitalized and is undergoing intense medical intervention, with Intellia working closely with global regulatory agencies to determine next steps.
About the Investigational Drug: NTLA-2001
NTLA-2001 (Nexiguran Ziclumeran) is an investigational, in vivo CRISPR-Cas9-based gene editing therapy designed to eliminate the production of transthyretin (TTR) in the liver using a lipid nanoparticle (LNP) delivery system. This advanced one-time infusion targets both wild-type and mutant TTR gene sequences, aiming to reduce the circulating amyloid-forming TTR protein, the pathogenic driver of transthyretin amyloidosis. NTLA-2001 is notable for being the first systemically administered CRISPR therapy in clinical development for hereditary and wild-type ATTR amyloidosis.
Disease Background: ATTR Amyloidosis
Transthyretin amyloidosis (ATTR) is a progressive, often fatal condition caused by misfolded TTR proteins forming amyloid fibrils that deposit in vital organs especially the heart called transthyretin amyloid cardiomyopathy (ATTR-CM) and peripheral nerves called transthyretin amyloid polyneuropathy (ATTR-PN). The disease manifests as heart failure, neuropathy, or both, with two primary subtypes: wild-type (age-related, typically cardiac) and hereditary (genetic mutations, systemic or neurologic manifestations). ATTR-CM is underdiagnosed due to its symptom overlap with more common cardiac conditions, contributing to substantial morbidity and delayed treatment.
Clinical Evidence
The MAGNITUDE Phase 3 clinical trial (NCT06128629) is a randomized, double-blind, placebo-controlled, multinational study designed to evaluate the efficacy and safety of NTLA-2001 for patients with ATTR-CM. Over 765 participants are randomized in a 2:1 ratio to receive a single 55 mg intravenous infusion of NTLA-2001 or placebo. Eligible patients must have documented ATTR diagnosis, significant heart involvement (NT-proBNP ≥ 600 pg/mL), and be clinically stable, while excluding those with advanced heart failure (New York Heart Association (NYHA) class IV) or hepatic impairment. The study follows patients for up to 48 months, aiming to capture both rapid and long-term effects. Primary endpoints focus on a composite of cardiovascular-related mortality and cardiovascular clinical events; secondary endpoints include change from baseline to month 18 in serum TTR, improvements in heart failure biomarkers, clinical symptoms, NYHA classification changes, and patient-related quality of life outcomes (KCCQ-OS, 6-minute walk test).
Interim and prior Phase 1 data support the rationale for this study: earlier dosing of NTLA-2001 in more than 60 patients achieved median serum TTR reductions of approximately 91% at day 28, with durable suppression persisting over 12 months or longer in most participants. Notably, infusion reactions were the most common adverse events, typically mild and transient. Polyneuropathy endpoints in MAGNITUDE-2 include changes in polyneuropathy disability scores, modified body mass index, and disease quality-of-life metrics. Together, these trial designs aim to conclusively determine whether NTLA-2001 offers a transformative, one-time therapy to halt or reverse ATTR amyloidosis progression by permanently suppressing the underlying genetic driver.
Safety Profile
The safety profile of NTLA-2001 in the MAGNITUDE program has undergone intense scrutiny following the recent Grade 4 liver toxicity incident that satisfied Hy’s Law criteria for serious, drug-induced liver injury. This event was characterized by biochemical laboratory findings of liver transaminases (ALT/AST) more than 3 times the upper limit of normal (ULN) and total bilirubin more than 2 times ULN in a dosed patient a constellation considered predictive of possible acute liver failure and severe adverse drug reactions. The affected patient required hospitalization when these markers rose dramatically, as per the established trial pausing protocol.
Prior safety data had shown NTLA-2001 to be generally well-tolerated in over 450 global trial participants, with most adverse events being mild or moderate, including transient infusion reactions, headache, and mild liver enzyme elevations typically not clinically significant and self-resolving.
The presentation of this adverse liver event involved both biochemical lab values (ALT/AST and bilirubin) and clinical symptoms, requiring supportive medical management; the patient is still undergoing follow-up and the severity is being closely monitored. Hy’s Law predicts a roughly 10% risk of acute liver failure in such cases. In response, Intellia immediately halted patient dosing and screening in both Phase 3 trials (MAGNITUDE and MAGNITUDE-2), pausing enrollment of new participants as well. This action was taken in consultation with regulatory authorities, including the FDA, and Intellia has committed to investigating the event thoroughly while keeping patient safety as their paramount concern.
Intellia plans to investigate possible risk factors such as dose, age, or comorbidities that could have contributed to the adverse event, and will explore additional hepatic safety measures and patient selection criteria before reinitiating trials.
Key Opinions
Dr. John Leonard, Intellia’s President and CEO, emphasized the company’s prioritization of patient safety following the adverse event:
“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. As we focus on ensuring the health of this patient, we are also engaging with regulatory authorities and other stakeholders globally to develop a strategy to resume enrollment as soon as appropriate.”
Analyst notes and industry reactions underscore the rarity and seriousness of grade 4 hepatic events in gene therapy programs, stressing the heightened regulatory scrutiny expected for all CRISPR trials moving forward.
Public Health Implications
The MAGNITUDE trial pause spotlights critical issues in gene editing safety, specifically for in vivo hepatic CRISPR interventions, and could slow near-term progress for rapid adoption of genome editing in systemic diseases.
ATTR amyloidosis remains a debilitating, underdiagnosed condition requiring novel therapeutic advances. The setback has direct implications for patients in need of new, potentially curative treatments.
The episode is likely to influence regulatory guidance, patient selection criteria, adverse event monitoring, and overall public health messaging around first-in-class genomic medicines.
Greater industry and clinical vigilance will be essential as in vivo editing platforms move toward broader applications.
References
Intellia Therapeutics Provides Update on MAGNITUDE Clinical Trials of Nexiguran Ziclumeran (nex-z), 27 October 2025, Intellia Therapeutics, https://ir.intelliatx.com/news-releases/news-release-details/intellia-therapeutics-provides-update-magnitude-clinical-trials
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
MAGNITUDE: A Phase 3 Study of NTLA-2001 in Participants With Transthyretin Amyloidosis With Cardiomyopathy (ATTR-CM), Stanford Medicine, Health Care, https://stanfordhealthcare.org/trials/m/NCT06128629.html
Patel AGM, Li P, Badrish N, Kesari A, Shah KB. Transthyretin Cardiac Amyloidosis: Current and Emerging Therapies. Curr Cardiol Rep. 2025 Jan 22;27(1):33. doi: 10.1007/s11886-024-02172-w. PMID: 39841315; PMCID: PMC11754378.