One-time nex-z gene-editing therapy eases FAP for two years
Treatment led to near-complete reduction of disease-causing TTR protein
A one-time gene-editing therapy from Intellia Therapeutics led to a sustained, near-complete reduction in blood levels of the disease-causing transthyretin (TTR) protein in adults with familial amyloid polyneuropathy (FAP), easing symptoms or preventing them from worsening for up to two years.
The data come from 36 FAP patients who received a single infusion into a vein, or intravenously, of nexiguran ziclumeran (nex-z) as part of an ongoing Phase 1 clinical trial (NCT04601051). The gene therapy was well tolerated by all the patients across all dose levels, with the most common side effects being mild or moderate infusion-related reactions.
“A single dose of nex-z leads to deep, durable and consistent reductions in [blood] TTRs, with evidence of disease stability or clinically meaningful improvements in neuropathic impairment measures through two years,” John Leonard, MD, Intellia’s president and CEO, said in a company press release.
Clinically meaningful improvements at two years were also observed in five of the six patients who continued progressing despite treatment with Onpattro (patisiran), which is approved to slow or prevent progression of FAP, also called hereditary ATTR amyloidosis with polyneuropathy.
“These data are also the first to show improvement in patients who had previously progressed on [Onpattro], further validating the hypothesis that increasingly deep reductions in TTR levels may lead to improved outcomes,” Leonard said.
Testing nex-z in FAP
The interim, two-year trial findings were shared in an oral presentation titled “CRISPR Gene Editing With Nexiguran Ziclumeran in Hereditary ATTR With Polyneuropathy: Phase 1 Interim Report” at the 2025 Peripheral Nerve Society annual meeting, May 17-20 in Edinburgh, in the U.K.
An ongoing Phase 3 trial called MAGNITUDE-2 (NCT06672237) is testing nex-z against a placebo in up to 50 adults with FAP at nine locations in Argentina, Australia, New Zealand, Singapore, and Taiwan, as well as in Brazil, where the first patient was dosed. If the results are positive, Intellia expects to submit an application to the U.S. Food and Drug Administration by 2028 for the therapy’s approval for FAP.
In FAP, mutations in the TTR gene produce an unstable form of TTR that tends to form toxic clumps, called amyloid deposits, that build up in peripheral nerves, which are outside the brain and spinal cord, resulting in nerve damage and symptoms of polyneuropathy.
Developed jointly by Intellia and Regeneron Pharmaceuticals, nex-z uses CRISPR/Cas9-based technology as molecular scissors to inactivate the TTR gene in liver cells, the main source of TTR. This should reduce the abnormal protein’s levels and prevent its toxic buildup, easing FAP symptoms.
Previously called NTLA-2001, the experimental medication received orphan drug status in the U.S. and European Union, a designation that’s meant to accelerate its clinical development and regulatory review.
The two-part Phase 1 trial is testing escalating doses in adults with FAP or ATTR amyloidosis with cardiomyopathy, a FAP-related condition where amyloid deposits build up in the heart.
Early data from the dose-escalating part showed a reduction in blood TTR after about a month in FAP patients, with larger reductions seen at higher doses. Based on this, the two highest doses — 55 mg and 80 mg — were chosen for testing for the dose-expanding part.
Newly presented results concerned 36 adults with FAP (median age, 61), most being men (72%), who’ve been followed up to at least a year after receiving a single dose.
All 33 patients who received a dose of at least 0.3 mg/kg — corresponding to about 24 mg — saw “deep, rapid, and durable reductions” in blood TTR, which remained at an average of 8% of the initial levels after two years.
Reduced impairment
Secondary goals included changes in the Neuropathy Impairment Score (NIS) and the Modified Neuropathy Impairment Score +7 (mNIS+7), two clinical tools of the level of impairment and functional impact of polyneuropathy, where lower scores indicate less severe impairment.
The 15 patients from the dose-escalating part saw their NIS scores decrease by a mean of 2 points after a year and by 4.5 points after two years. For the 21 patients from the dose-expanding part, the NIS score dropped by 2.1 points after a year and 5.2 points after two years.
Similar trends were seen in the dose-expanding part for mNIS+7 scores, which decreased by a mean of 0.6 points after a year and 8.5 points after two years.
Of the 18 FAP patients with two-year mNIS+7 data, 14 had a clinically meaningful improvement, defined as a reduction of at least 4 points. This included five of the six patients who’d progressed despite being on Onpattro for a mean of 5.5 years.
The participants also saw gains in quality of life and modified body mass index, a ratio of weight to height, along with reductions in blood levels of neurofilament light chain, a marker of nerve damage, indicating disease stability or lessening.
This is “the first clinical evidence of … CRISPR/Cas9 gene editing in polyneuropathy showing that targeted inactivation of the TTR gene with nex-z may favorably impact, and potentially improve, multiple disease-relevant measures in [FAP], including in patients previously progressing on [Onpattro],” the researchers wrote.
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