Liver damage pauses nex-z gene therapy trials
Intellia says 2 studies on hold for safety review after participant falls ill
Two trials testing nexiguran ziclumeran (nex-z), a gene-editing therapy for familial amyloid polyneuropathy (FAP) and the related condition ATTR amyloidosis with cardiomyopathy (ATTR-CM), are on hold after a participant developed potentially life-threatening liver damage.
The participant received the therapy on Sept. 30 as part of the Phase 3 MAGNITUDE clinical trial (NCT06128629), which is testing nex-z against a placebo in adults with ATTR-CM. In response, Intellia Therapeutics, which is developing the therapy alongside Regeneron Pharmaceuticals, paused screening and dosing in MAGNITUDE and its parallel Phase 3 MAGNITUDE-2 trial (NCT06672237) in adults with FAP, while a safety review is conducted.
“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,” John Leonard, MD, president and CEO for Intellia, said in a company press release.
Shortly after Intellia announced the trials’ temporary pause, the U.S. Food and Drug Administration placed the studies under clinical hold.
The patient, a man in his early 80s, was hospitalized after experiencing abdominal pain. He “is being closely monitored and is receiving medical intervention,” Leonard said on a conference call. His blood levels of certain liver enzymes and bilirubin — all markers of liver damage — exceeded the upper limit of normal by two to three times. This adverse event was classified as Grade 4, a level denoting a life-threatening or disabling medical event that requires urgent attention.
Company works to detect problems sooner, form plan to resume trials
Intellia has been “consulting with clinical investigators and external experts to ensure optimal care for the patient and further assess the event itself,” said Lenoard. The company has also “mandated clinical sites to collect additional labs from patients in the initial weeks following dosing to detect potential [liver damage] sooner,” and is “working with the trials’ independent safety monitoring committees as we consider other potential monitoring and risk mitigation strategies,” he said. “And of course, we are engaging with regulatory authorities and other stakeholders to finalize a plan that allows us to resume enrollment as soon as appropriate.”
FAP, also known as hereditary ATTR amyloidosis with polyneuropathy (hATTR-PN), is caused by mutations in the TTR gene, which encodes the protein transthyretin. These mutations result in the production of an abnormal transthyretin protein that is prone to forms toxic clumps in the body’s tissues.
In people with FAP, these toxic clumps accumulate mainly on peripheral nerves, or those outside the brain and spinal cord, ultimately causing neurological symptoms.
ATTR-CM is a FAP-related condition in which toxic transthyretin aggregates build up mainly in the heart, causing heart damage. ATTR-CM can be caused by TTR mutations or be associated with aging.
Nex-z is designed to inactivate the TTR gene in the liver, where transthyretin protein is produced. The one-time treatment is expected to reduce transthyretin production and the number of toxic protein clumps driving tissue damage.
Long-term data from an ongoing Phase 1 clinical trial (NCT04601051) testing nex-z FAP and ATTR-CM patients showed that the gene-editing therapy reduced transthyretin levels as designed, and for up to three years in people with FAP. Also, most evaluable FAP patients reported clinically meaningful reductions in the severity of neurological symptoms.
The global MAGNITUDE-2 trial was designed to include up to 50 adults, ages 18 to 85, with FAP, who would be randomly assigned to receive a one-time dose of either nex-z or a placebo and be followed for about 1.5 years. MAGNITUDE was similarly designed, and expected to include up to 765 adults with ATTR-CM.
According to Intellia, 47 people with FAP and 650 people with ATTR-CM have been enrolled across the two Phase 3 trials so far, and more than 450 of them have been dosed with nex-z.
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