Gene therapy study placed on hold after elderly man passes away
Fatal case under review after severe liver event in ATTR amyloidosis study
An elderly man who developed life-threatening liver damage after receiving nexiguran ziclumeran (nex-z), an experimental gene-editing therapy, has died. The treatment was being tested for familial amyloid polyneuropathy (FAP) and the related condition ATTR amyloidosis with cardiomyopathy (ATTR-CM).
The announcement came from Intellia Therapeutics, the therapy’s developer, less than two weeks after the company reported the Grade 4, life-threatening liver event. The reaction, marked by high liver transaminases and bilirubin, occurred in the Phase 3 MAGNITUDE clinical trial (NCT06128629), which is testing nex-z against a placebo in adults with ATTR-CM.
“We were deeply saddened to learn that the patient who experienced [life-threatening] 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, Intellia’s president and CEO, said in a company press release. “We have been advised by the treating physician that this is a case with complicating [simultaneous health conditions], and it is being further evaluated.”
Screening and dosing paused as safety review gets underway
Reporting of the life-threatening liver event led Intellia to pause screening and dosing in both the MAGNITUDE trial and its parallel MAGNITUDE-2 study (NCT06672237) in people with FAP. The U.S. Food and Drug Administration (FDA) subsequently placed both trials on clinical hold, with a formal letter to follow within a month.
“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,” Leonard said.
Despite the setback, Intellia, which is developing nex-z in collaboration with Regeneron Pharmaceuticals, continues “to believe in nex-z’s potential to address important unmet needs,” Leonard said.
Transthyretin amyloidosis, or ATTR amyloidosis, is a group of conditions caused by the buildup of toxic clumps made up of unstable transthyretin protein in the body’s tissues and organs, causing damage.
ATTR amyloidosis can be hereditary — passed down through families due to a mutation in the TTR gene — or it can develop later in life, typically in older adults (classified as wild-type).
In FAP, also called hereditary ATTR with polyneuropathy, toxic transthyretin clumps accumulate mainly in the peripheral nerves — those outside the brain and spinal cord — causing widespread nerve damage and neurological symptoms. In ATTR-CM, accumulation of these toxic aggregates occurs mostly in the heart muscle, causing heart damage, or cardiomyopathy.
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.
Given as a single infusion into the bloodstream, nex-z uses CRISPR/Cas9-based technology as molecular scissors to inactivate the TTR gene in liver cells, the main source of transthyretin.
In a Phase 1 clinical trial (NCT04601051) in adults with FAP, the therapy was shown to reduce transthyretin protein levels for up to three years. Lowering these levels is expected to limit further protein aggregation and accumulation in tissues, helping to ease symptoms or even slow disease progression.
So far, the MAGNITUDE-2 trial has enrolled 47 adults with FAP, while the larger MAGNITUDE study has enrolled more than 650 adults with hereditary or wild-type ATTR-CM.
Life-threatening liver transaminase elevations have occurred in fewer than 1% of participants in MAGNITUDE and none in MAGNITUDE-2. The fatal liver event occurred in a man in his early 80s, who was hospitalized about a month after receiving his single dose of nex-z.
After learning about the case of severe liver damage, Intellia asked all clinical sites to conduct additional blood tests in the weeks after dosing to better monitor for potential liver problems. With clinical testing on hold, the company suspended its milestone guidance for nex-z and said it will provide an update once next steps are agreed upon with regulators.
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