FDA lifts hold on clinical trial testing gene-editing therapy for ATTR-CM
Enrollment back on for 2 global studies of Intellia's nex-z treatment
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The U.S. Food and Drug Administration (FDA) has lifted its hold on a large-scale clinical trial evaluating nexiguran ziclumeran, Intellia Therapeutics’ gene-editing therapy candidate, known as nex-z for short, in adults with transthyretin amyloid cardiomyopathy (ATTR-CM).
The regulatory agency had placed the clinical hold on the Phase 3 MAGNITUDE trial (NCT06128629) — which had then already enrolled more than 600 patients — late last year due to safety concerns. Specifically, an older man with ATTR-CM developed life-threatening liver damage and eventually died after receiving the therapy in the trial.
According to a company press release, Intellia and the FDA reached a consensus on “mitigation measures” for use in the study.
“We are very pleased to have aligned with the FDA on the path forward for our MAGNITUDE clinical trial, with measures designed to further enhance patient safety and allow us to continue to investigate nex-z in a broad ATTR-CM population,” said John Leonard, MD, Intellia’s president and CEO.
These measures include closer monitoring of liver function, guidance on short-term corticosteroid treatment if elevated liver enzymes (indicative of liver damage) are observed shortly after nex-z dosing, and exclusion of patients with certain liver or heart problems, the company noted.
The parallel Phase 3 MAGNITUDE-2 trial (NCT06672237), which is testing nex-z in adults with hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN), a related condition, had also been placed on hold for the same reasons. That clinical hold was lifted earlier this year.
“With the resolution in January of the clinical hold on our MAGNITUDE-2 Phase 3 trial for patients with [hATTR-PN], our attention now turns to completing enrollment in both ongoing trials,” Leonard said. “We appreciate the FDA’s responsiveness throughout this process and thank the many investigators and patients who are participating in these trials.”
ATTR amyloidosis comprises a group of diseases caused by the buildup of toxic clumps, called amyloid deposits, made of misfolded transthyretin (TTR) protein, in the body’s tissues. The accumulation of these clumps causes damage, leading to an array of symptoms.
Gene-editing therapy designed to treat ATTR-CM and hATTR-PN
In ATTR-CM, which can be caused or not by mutations in the TTR gene, amyloid deposits accumulate in the heart, causing progressive heart damage that ultimately leads to symptoms of heart failure.
hATTR-PN, also called familial amyloid polyneuropathy (FAP), is an inherited form of ATTR amyloidosis caused by TTR mutations. It is marked by the buildup of toxic clumps in the peripheral nerves, those outside the brain and spinal cord, causing neurological symptoms.
Nex-z, developed by Intellia along with Regeneron Pharmaceuticals, is a gene-editing therapy that uses the CRISPR/Cas9 technology to inactivate the TTR gene in liver cells, where most TTR protein is produced. The therapy, given as a one-time infusion into the bloodstream, aims to reduce TTR levels and the formation of amyloid deposits.
Formerly called NTLA-2001, nex-z has been granted orphan drug status in the U.S. and the European Union for the treatment of forms of ATTR amyloidosis. The treatment was also awarded regenerative medicine advanced therapy status in the U.S. for hATTR-PN. Both statuses are meant to accelerate the therapy’s clinical development and regulatory review.
Nex-z showed positive results in earlier clinical trial
In a previous Phase 1 clinical trial (NCT04601051), nex-z treatment resulted in sustained reductions of TTR levels in adults with hATTR-PN and those with ATTR-CM for as long as three years.
Most ATTR-CM patients experienced a reduction or stabilization in the severity of heart symptoms, as well as blood levels of heart damage markers, after two years. Treatment was also associated with improvements in patients’ quality of life.
Also, nex-z-treated ATTR-CM patients had a 73% lower risk of death when compared with an external group of matched ATTR-CM patients from the National Amyloidosis Center.
In the global MAGNITUDE trial, adults with ATTR-CM are randomly assigned to receive a single dose of either nex-z (55 mg) or a placebo. Before the clinical hold, the study had enrolled more than 650 participants of the planned goal of 1,200.
The study’s primary goal is to assess changes in the severity of heart damage, as indicated by a composite score of cardiovascular-related events, including death, after at least 1.5 years and up to four years.
Secondary assessments include changes in blood TTR levels and in the Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS), after 1.5 years. KCCQ-OS is a patient-completed questionnaire assessing the health status of heart failure patients, including symptoms, physical/social limitations, and quality of life.
