Gene therapy nex-z lowers FAP protein levels for 3 years
Single dose leads to deep TTR reductions in Phase 1 clinical trial
A single dose of gene-editing therapy nexiguran ziclumeran (nex-z) leads to deep reductions in blood levels of the disease-causing transthyretin (TTR) protein in adults with familial amyloid polyneuropathy for up to three years.
That’s according to longer-term data from a Phase 1 clinical trial (NCT04601051). The trial also showed sustained reductions or stabilizations in symptoms of nerve damage and related disability two years after treatment.
The results were presented at the 5th International ATTR Amyloidosis Annual Meeting for Patients and Doctors, held Sept. 25-26 in Baveno, Italy, and simultaneously published in The New England Journal of Medicine.
The study, “Nexiguran Ziclumeran Gene Editing in Hereditary ATTR with Polyneuropathy,” was funded by Intellia Therapeutics and Regeneron Pharmaceuticals, the therapy’s co-developers. Several study authors are affiliated with the companies.
“After receiving a one-time treatment of nex-z, patients continue to experience durable TTR reductions, including those who have reached three years of follow-up,” John Leonard, MD, president and CEO for Intellia, said in a company press release. “The results from our ongoing Phase 1 study of nex-z support our belief that deeper and more consistent reductions in TTR translate to better outcomes for patients.”
Study ‘progressing swiftly’
The gene-editing therapy is now being tested against a placebo in the Phase 3 MAGNITUDE-2 trial (NCT06672237), which is still recruiting up to 50 FAP patients, ages 18-85, at sites in Argentina, Australia, Brazil, New Zealand, Singapore, Taiwan, and Thailand. Enrollment is expected to finish in the first half of 2026.
The results could support regulatory applications seeking the treatment’s approval for FAP, which Intellia plans to submit to U.S. regulators by 2028.
“Our Phase 3 MAGNITUDE-2 study is progressing swiftly, and we are eagerly anticipating the results, which we believe will demonstrate nex-z’s potential to halt or reverse disease progression in people living with [FAP],” Leonard said.
FAP, also known as hereditary ATTR amyloidosis with polyneuropathy (ATTRv-PN), is a rare hereditary disease in which TTR gene mutations lead to the production of an abnormal form of the TTR protein.
This faulty protein accumulates to toxic levels in the nerves outside the brain and spinal cord, causing damage to multiple nerves, or polyneuropathy, that drive the most common FAP symptoms.
Formerly known as NTLA-2001, nex-z uses the CRISPR/Cas9 gene-editing technology to inactivate the TTR gene in liver cells, where TTR is mainly made. When given as a one-time, into-the-vein infusion, nex-z is expected to reduce TTR production and prevent the harmful accumulation that drives FAP symptoms.
Nex-z’s developers are also investigating it as a possible treatment for ATTR amyloidosis with cardiomyopathy (ATTR-CM), where faulty TTR mainly accumulates in the heart.
The ongoing Phase 1 trial was designed to evaluate the safety and efficacy of increasing doses of nex-z in adults with FAP or ATTR-CM.
A total of 36 FAP patients were enrolled across two trial parts, all of whom received nex-z at various doses. Participants were followed for two years, after which 31 enrolled in a 15-year long-term follow-up study (NCT05697861).
Previously reported results from FAP patients showed that the treatment led to rapid drops in blood TTR levels that were sustained for up to two years.
The newly published results concern the 36 participants with FAP who were followed for a mean of 27 months (a little over two years) and the 12 whose follow-up reached three years.
Efficacy data covered the 33 participants who received a nex-z dose of 0.3 mg/kg or higher. These patients experienced a 92% drop in blood TTR levels after two years. For the 12 patients with three years of follow-up, TTR levels were down 90% from the study’s start.
Of the 18 people with two-year data from the modified Neuropathy Impairment Score +7 (mNIS+7) — a standard assessment of polyneuropathy severity — 72% exhibited a clinically meaningful improvement of at least four points. That included most of the six trial participants who had previously experienced disease progression on the FAP-approved therapy Onpattro (patisiran).
Eighty-nine percent of participants showed stability or improvement in polyneuropathy disability scores, which evaluate how substantially polyneuropathy is impeding physical function. The FAP stage was also stable or improved in 81% of the patients.
Modified body mass index (a ratio of weight to height), polyneuropathy-related life quality, and blood levels of neurofilament light chain (a biomarker of nerve damage) all similarly trended toward improvement.
Nex-z was generally well tolerated at all dose levels. The most common treatment-related side effects were mild or moderate infusion reactions.
“Our results showed a profound and sustained lowering of the [blood] TTR level after nex-z therapy … that appeared to be safe and was accompanied by evidence of limited disease progression,” the researchers wrote. “The results support further clinical investigation in a phase 3 trial.”
In MAGNITUDE-2, which started dosing earlier this year, participants are randomly assigned to receive a one-time dose of nex-2 (55 mg) or a placebo, and followed for about 1.5 years. Its primary goals are to assess changes in blood TTR levels and mNIS+7 scores.
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