Trial of experimental treatment for hATTR-PN completes enrollment
Nex-z is a one-time gene-editing therapy targeting key protein
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Patient enrollment has been completed in a late-stage clinical trial testing nexiguran ziclumeran (nex-z), Intellia Therapeutics’ experimental one-time gene-editing therapy, in people with hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN).
The Phase 3 trial, dubbed MAGNITUDE-2 trial (NCT06672237), enrolled 67 adults at 14 locations in Mexico, Argentina, Brazil, Singapore, Taiwan, and Thailand. It will assess whether a single infusion of nex-z can reduce levels of disease-driving transthyretin (TTR) protein and reduce nerve damage over 18 months, or about 1.5 years.
“We are grateful to the patients, caregivers and investigators who are participating in MAGNITUDE-2,” John Leonard, MD, Intellia’s president and CEO, said in a company press release. “Completing enrollment in this trial is a pivotal step toward bringing a potentially transformative one-time treatment to people living with [hATTR-PN], a debilitating and life-threatening disease with significant unmet need.”
Therapy could potentially slow disease progression
In hATTR-PN, mutations in the TTR gene result in the production of abnormal TTR protein that can misfold and form toxic clumps, called amyloid deposits. These deposits primarily accumulate in peripheral nerves, or those outside the brain and spinal cord. This causes damage to several nerves, a condition known as polyneuropathy, and leads to hATTR-PN symptoms.
Developed by Intellia in collaboration with Regeneron Pharmaceuticals, nex-z, previously known as NTLA-2001, uses the CRISPR/Cas9 gene-editing technology to inactivate the TTR gene in liver cells, where most TTR protein is produced.
The treatment is expected to reduce TTR production after a single into-the-vein infusion, potentially limiting the formation of new amyloid deposits and slowing disease progression.
“While disease-modifying therapies have advanced the standard of care for [hATTR-PN], many patients continue to progress,” said John L. Berk, MD, professor emeritus at Boston University School of Medicine. “An agent that can quickly, substantially and consistently reduce TTR after a single dose would be a meaningful advancement for patients.”
In a previous Phase 1 clinical trial (NCT04601051), about 30 people with hATTR-PN who received a single nex-z infusion at doses of at least 0.3 mg/kg saw their blood TTR levels drop by an average of 92% after two years.
Clinical assessments also suggested that the treatment may stabilize or reduce disease-related impairment. Among 18 hATTR-PN participants with available two-year data, 13 showed clinically meaningful reductions in the modified Neuropathy Impairment Score plus 7 (mNIS+7), a measure of nerve damage and related function. The treatment was generally well tolerated, with infusion-related reactions among the most common side effects.
Nex-z also being evaluated as potential ATTR-CM treatment
In the ongoing MAGNITUDE-2 study, participants are randomly assigned to receive a single infusion of either nex-z (55 mg) or a placebo.
The main goal is to assess changes in blood TTR levels 29 days after nex-z infusion and in mNIS+7 after 18 months. Secondary outcomes include changes in blood TTR levels, quality of life, and modified body mass index (a measure of clinical frailty and nutritional status) 18 months after the infusion.
Intellia is also evaluating nex-z as a potential treatment for people with transthyretin amyloid cardiomyopathy (ATTR-CM), a disease related to hATTR-PN that primarily affects the heart. The global Phase 3 MAGNITUDE trial (NCT06128629) is testing the therapy against a placebo in up to 1,200 ATTR-CM patients. That study is still enrolling at sites around the world.
Both trials were temporarily placed on clinical hold by the U.S. Food and Drug Administration (FDA) in October 2025 after a participant in the MAGNITUDE trial developed severe liver abnormalities following treatment with nex-z and later died.
The FDA lifted the hold of the MAGNITUDE-2 study at the beginning of this year after Intellia agreed to protocol changes, including enhanced monitoring of liver function. The hold on MAGNITUDE was lifted about a month later.
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