Investigating Gene Therapy Nexiguran Ziclumeran for ATTRv-PN: Phase 3 MAGNITUDE-2 Trial

Welcome to NeurologyLive^®'s Clinical Trial in Focus. Every month, an ongoing clinical trial in the landscape of neurology is featured, highlighting the design of the study, the targeted patient population, the enrollment criteria, the primary and secondary end points, and its potential implications for clinical care. This month’s spotlight is the phase 3 MAGNITUDE-2 trial (NCT06672237), assessing investigational gene therapy nexiguran ziclumeran (Intellia Therapeutics) for patients with hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN), a rare genetic neuromuscular condition.

Study Design

This multinational, multicenter, double-blind, placebo-controlled phase 3 study will assess the efficacy and safety of a single dose of nexiguran ziclumeran compared with placebo in approximately 60 adult participants with ATTRv-PN aged 18 to 85 years.¹ Spanning 16 global site locations, participants will be randomized 1:1 to receive a single infusion of either nexiguran ziclumeran or placebo. To ensure all participants have the opportunity to receive the investigational therapy, an option to cross over to the alternative study arm will be available at 12 months or 18 months, contingent upon meeting specific study criteria.

In an April 2025 company update, Intellia Therapeutics announced that the first patient had been dosed. “We are pleased to have dosed the first patient with a treatment that has such strong potential to redefine the treatment paradigm for those living with ATTR with polyneuropathy. This is a debilitating, progressive disease that leaves people feeling increasingly helpless,” Paulo Sgobbi, MD, PhD, medical director of the PSEG Clinical Research Center in Brazil, said in a statement.¹ “Through nex-z’s potential to favorably impact disease progression, patients living with ATTR polyneuropathy could experience life-changing benefit while being freed from the existing chronic treatment regimen of pills, injections and infusions.”

“This milestone marks important progress toward our goal of completing the MAGNITUDE-2 clinical program and we are optimistic the study will enable us to demonstrate nex-z’s potential to be the first to halt or reverse disease progression with a single dose in hereditary ATTR with polyneuropathy,” John Leonard, MD, president and chief executive officer at Intellia, said in a statement.¹

Primary and Secondary Outcomes

Participants in the treatment arm will receive a single 55-mg intravenous (IV) infusion of nexiguran ziclumeran, and those in the placebo arm will receive a single IV infusion of normal saline (0.9% NaCl). The primary end points are the change from baseline in the Modified Neuropathy Impairment Score +7 (mNIS+7) at 18 months and serum transthyretin (TTR) levels at 29 days. Secondary outcomes include the Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) questionnaire score, modified body mass index (mBMI), and serum TTR levels, all assessed at 18 months.

Study Criteria

Eligible participants had a diagnosis of ATTRv-PN and a Karnofsky Performance Status score of 60 or higher. Patients were excluded if they have amyloidosis caused by non-TTR proteins or other known causes of sensorimotor or autonomic neuropathy, including diabetes mellitus. Additional exclusion criteria included New York Heart Association Class III or IV heart failure, liver failure, or infection with hepatitis B, hepatitis C, or human immunodeficiency virus. Patients with an estimated glomerular filtration rate less than 30 mL/min/1.73 m² or those unable or unwilling to comply with vitamin A supplementation were also ineligible. Finally, patients were excluded if they had prior treatment with TTR silencers, such as small interfering RNA or antisense oligonucleotides.

FDA Clinical Hold

Nexiguran ziclumeran is an investigational CRISPR/Cas9 gene editing therapy delivered via a lipid nanoparticle nonviral system designed to inactivate the TTR gene that encodes for the TTR protein. In October 2025, the FDA placed a clinical hold on MAGNITUDE-2 after a patient being treated in the MAGNITUDE trial (NCT06128629) experienced a grade 4 cases of liver transaminases and increased total bilirubin.² For context, the MAGNITUDE study is a separate phase 3 study assessing nexiguran ziclumeran among patients living with ATTR with cardiomyopathy.

On October 29, 2025, the FDA placed clinical holds on both the MAGNITUDE and MAGNITUDE-2 trials. The hold on MAGNITUDE-2 was lifted on January 27, 2026; however, the MAGNITUDE study remains on hold.^3,4 Intellia later reported that the patient who experienced a grade 4 adverse event in MAGNITUDE was hospitalized and died on November 5, 2025.

The company previously reported that of the over 450 of the more than 650 patients enrolled in MAGNITUDE dosed with nexiguran ziclumeran, less than 1% have experienced grade 4 liver transaminase elevations and that of the 47 patients enrolled in MAGNITUDE-2 dosed with the gene therapy, no grade 4 liver transaminase elevations have been reported to date.

Intellia also 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. 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. 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,” Leonard, said in a statement.³

Phase 1 Data

The phase 3 MAGNITUDE-2 trial was designed based on findings from Intellia’s open-label phase 1 study (NCT04601051), which evaluated a single-dose administration of nexiguran ziclumeran in patients withATTRv-PN. In the phase 1 study, the primary objectives were to assess safety and pharmacodynamics. Secondary end points included changes in familial amyloid polyneuropathy stage, polyneuropathy disability score, serum neurofilament light chain (NfL) levels, mBMI, and mNIS+7.^5,6

A total of 36 patients received nexiguran ziclumeran in the phase 1 study; the mean follow-up was 27 months. Researchers reported that the mean percent change from baseline in the serum TTR level was -90% at 28 days, which was sustained through 24 months (-92%). Treatment-related AEs included transient infusion-related reactions (n = 21), decreased thyroxine level without hypothyroidism or elevated thyrotropin level (n = 8), and headache (n = 4). Notably, 1 participant died from cardiac amyloidosis, and 1 other patient withdrew owing to progressive decline in motor function.

Researchers observed that serious AEs were reported in 11 participants. At 24 months, the familial amyloid polyneuropathy stage and polyneuropathy disability score remained stable in 29 and 27 patients, respectively; improved in 2 and 5, respectively; and worsened in 2 and 2, respectively. Moreover, the mean change in the serum NfL level was -9.0 pg per milliliter, and the change in the modified BMI was 24.7. Authors noted that the mean change from baseline in the mNIS+7 was -8.5.

“ATTR amyloidosis is a progressive and fatal disease, often leaving patients with shortened lifespans and poor quality of life,” lead study author Julian Gillmore, MD, PhD, professor of medicine, National Amyloidosis Center, UCL Division of Medicine, Royal Free Hospital, UK, said in a statement.⁵ “Today’s data support the potential benefit of nex-z and how persistently low levels of serum TTR may translate to improved outcomes and lowered rates of mortality.”

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REFERENCES
1. Intellia Therapeutics Announces First Patient Dosed in the MAGNITUDE-2 Phase 3 Study of Nexiguran Ziclumeran (nex-z), a One-Time Gene Editing-Based Treatment for Transthyretin (ATTR) Amyloidosis with Polyneuropathy. News release. Intellia Therapeutics. April 3, 2025. Accessed February 26, 2026. https://ir.intelliatx.com/news-releases/news-release-details/intellia-therapeutics-announces-first-patient-dosed-magnitude-2
2. Intellia Therapeutics Provides Update on MAGNITUDE Clinical Trials of Nexiguran Ziclumeran (nex-z). News release. Intellia Therapeutics. October 27, 2025. Accessed February 26, 2026. https://ir.intelliatx.com/news-releases/news-release-details/intellia-therapeutics-provides-update-magnitude-clinical-trials
3. Intellia Therapeutics Announces FDA Lift of Clinical Hold on MAGNITUDE-2 Phase 3 Clinical Trial in ATTRv-PN. News release. Intellia Therapeutics. January 27, 2026. Accessed February 26, 2026. https://ir.intelliatx.com/news-releases/news-release-details/intellia-therapeutics-announces-fda-lift-clinical-hold-magnitude
4. Intellia Therapeutics Announces Fourth Quarter and Full-Year 2025 Financial Results and Business Updates. News release. Intellia Therapeutics. February 26, 2026. Accessed February 26, 2026. https://ir.intelliatx.com/news-releases/news-release-details/intellia-therapeutics-announces-fourth-quarter-and-full-year-8
5. Intellia Therapeutics Presents Positive Longer-Term Phase 1 Data of Nexiguran Ziclumeran (nex-z) in Patients with Transthyretin (ATTR) Amyloidosis with Cardiomyopathy. News release. Intellia Therapeutics. November 10, 2025. Accessed February 26, 2026. https://ir.intelliatx.com/news-releases/news-release-details/intellia-therapeutics-presents-positive-longer-term-phase-1-data
6. Gillmore JD, Gane E, Täubel J, et al. Nexiguran Ziclumeran Gene Editing in Hereditary ATTR with Polyneuropathy. N Engl J Med. 2025;393(14):1375-1386. doi:10.1056/NEJMoa25102