FDA lifts clinical hold on Phase 3 trial of nex-z for hATTR-PN
Intellia agrees to modifications, including closer liver-function monitoring
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The U.S. Food and Drug Administration (FDA) has lifted a clinical hold on a Phase 3 clinical trial testing the investigational gene-editing therapy, nexiguran ziclumeran (nex-z), in adults with hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN), allowing the study to resume.
The FDA placed the hold on the trial, dubbed MAGNITUDE-2 (NCT06672237), last fall alongside a parallel Phase 3 trial, MAGNITUDE (NCT06128629), designed to evaluate the therapy in adults with a related condition called ATTR amyloidosis with cardiomyopathy (ATTR-CM).
The FDA action followed safety concerns raised after Intellia Therapeutics, the drug’s lead developer, reported life-threatening liver damage in an older man with ATTR-CM after receiving nex-z in MAGNITUDE. The man eventually died.
The decision to lift the hold on MAGNITUDE-2 followed an alignment between Intellia and the FDA on study modifications and preventive measures, including closer monitoring of liver function. Intellia said it will provide an update on the MAGNITUDE trial once discussions with the agency on how to proceed are finalized.
“We appreciate the FDA’s expeditious review of our submission and ongoing engagement and thank our study investigators and patients for their continued participation,” John Leonard, MD, Intellia’s president and CEO, said in a company press release. “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 [hATTR-PN].”
Suppressing protein by gene editing
hATTR-PN and ATTR-CM are forms of ATTR amyloidosis, a disease caused by the buildup of toxic clumps of an abnormal transthyretin (TTR) protein in the body, which can worsen over time and affect organ function.
ATTR amyloidosis can be hereditary, caused by inherited mutations in the TTR gene (hATTR-PN), or wild-type, which spontaneously develops later in life in the absence of genetic mutations.
In hATTR-PN, also called familial amyloid polyneuropathy (FAP), amyloid buildup primarily damages the peripheral nerves, those outside the brain and spinal cord, driving various neurological symptoms. ATTR-CM is marked by amyloid buildup in the heart muscle, which makes it harder for the heart to pump blood effectively.
Nex-z, developed by Intellia in collaboration with Regeneron Pharmaceuticals, uses the CRISPR/Cas9 gene-editing tool as molecular scissors to inactivate the TTR gene in liver cells, where most transthyretin is made.
Given as a one-time infusion into the bloodstream, the therapy, previously known as NTLA-2001, aims to suppress the production of transthyretin and its toxic clumps, which drive tissue damage.
Regulators in the U.S. and Europe have granted the therapy orphan drug designation and, in the U.S., regenerative medicine advanced therapy status for ATTR amyloidosis. Together, these designations are intended to speed development and regulatory review for nex-z.
In a Phase 1 clinical trial (NCT04601051) involving adults with hATTR-PN and ATTR-CM, the gene-editing therapy demonstrated durable suppression of transthyretin levels, lasting as long as 3 years in people with hATTR-PN. As a result, most evaluable hATTR-PN patients experienced meaningful reductions in the severity of neurological symptoms.
MAGNITUDE-2 dosed its first patient last April. Adults with ATTRv-PN are randomly assigned to receive a single dose of either nex-z (55 mg) or a placebo. As part of the company’s agreement with the FDA, the target enrollment was increased from about 50 to about 60 participants.
The study’s primary goals are changes in TTR levels in the bloodstream about one month after treatment and in the severity of nerve damage, as indicated by a Modified Neuropathy Impairment Score of +7, after 1.5 years.
Secondary assessments include changes in quality of life, as measured by the Norfolk Quality of Life-Diabetic Neuropathy Questionnaire — a modified body mass index that accounts for both body size and nutritional status — and TTR levels at 1.5 years.
The larger MAGNITUDE study had enrolled more than 650 adults with hereditary or wild-type ATTR-CM before its pause.
