1st FAP patient dosed in Phase 3 trial of gene therapy nex-z
Intellia 'optimistic' about treatment's potential, CEO says
The first adult with familial amyloid polyneuropathy (FAP) has been dosed in a Phase 3 clinical trial testing nexiguran ziclumeran (nex-z), Intellia Therapeutics’ one-time gene therapy.
The trial, called MAGNITUDE-2 (NCT06672237), is recruiting up to 50 adults diagnosed with FAP, also known as hereditary transthyretin (ATTR) amyloidosis with polyneuropathy, at six locations in Australia, New Zealand, and Taiwan, as well as in Brazil, where the first patient was dosed.
“This milestone marks important progress toward our goal of completing the MAGNITUDE-2 clinical program and we are optimistic the study will enable us to demonstrate nex-z’s potential to be the first to halt or reverse disease progression with a single dose in hereditary ATTR with polyneuropathy,” John Leonard, MD, Intellia’s president and CEO, said in a company press release.
This step in nex-z’s clinical development follows up to two years of data from an ongoing Phase 1 trial (NCT04601051), in which the experimental gene therapy, formerly known as NTLA-2001, safely led to a rapid and near-complete reduction in blood levels of the disease-causing TTR protein in adults with FAP.
The company said it expects to share more Phase 1 clinical data on nex-z later this year, and, if MAGNITUDE-2 data readouts are positive, to file by 2028 an application with the U.S. Food and Drug Administration requesting the therapy’s approval for FAP.
Therapy could ‘redefine treatment paradigm’
“We are pleased to have dosed the first patient with a treatment that has such strong potential to redefine the treatment paradigm for those living with ATTR with polyneuropathy,” said Paulo Sgobbi, MD, PhD, medical director of the PSEG Clinical Research Center in São Paulo, Brazil. “This is a debilitating, progressive disease that leaves people feeling increasingly helpless.”
In FAP, mutations in the TTR gene result in an unstable TTR protein prone to forming toxic clumps, known as amyloid deposits, that build in peripheral nerves, the ones outside the brain and spinal cord. This causes polyneuropathy, or damage to multiple nerves, resulting in FAP symptoms.
Developed by Intellia in collaboration with Regeneron Pharmaceuticals, nex-z uses CRISPR-based technology as molecular scissors to inactivate the TTR gene in liver cells, the main source of TTR in the body. This is expected to reduce levels of the abnormal protein and prevent its aggregation and toxic buildup, easing symptoms of FAP.
The therapy received orphan drug designation in the U.S. and Europe, as well as regenerative medicine advanced therapy designation in the U.S. for FAP and other forms of ATTR amyloidosis. These statuses are meant to accelerate nex-z’s clinical development and regulatory review.
“Through nex-z’s potential to favorably impact disease progression, patients living with ATTR polyneuropathy could experience life-changing benefit while being freed from the existing chronic treatment regimen of pills, injections and infusions,” Sgobbi said.
MAGNITUDE-2 is evaluating how well nex-z works compared with a placebo in up to 50 FAP patients who have never been treated with TTR silencers like Onpattro (patisiran) and Tegsedi (inotersen), which interfere with the protein’s production.
Participants are being randomly assigned to receive a single, into-the-vein infusion of either nex-z, at a dose of 55 mg, or a placebo. One to 1.5 years after the one-time treatment, participants assigned a placebo will have the option to receive nex-z.
As main outcome measures, researchers will look for changes in blood TTR levels about one month after treatment and in the Modified Neuropathy Impairment Score +7, which assesses polyneuropathy severity, after about 1.5 years.
Secondary goals include changes in life quality, through the Norfolk Quality of Life-Diabetic Neuropathy Questionnaire; the modified body mass index, a measure of clinical frailty and nutritional status; and blood TTR levels from the trial’s start to 1.5 years after the infusion.
Intellia is also developing nex-z as a potential treatment of ATTR amyloidosis with cardiomyopathy, a FAP-related disease in which damage from toxic TTR clumps mainly occurs in the heart. A global Phase 3 trial, called MAGNITUDE (NCT06128629), is testing the therapy in up to 765 adults with the condition.
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