- Deep, durable and consistent reductions in TTR were sustained at two years, following a one-time dose of nex-z
- Clinically meaningful improvements in ATTRv-PN related outcomes observed at 24 months compared to baseline, including in patients who were previously progressing on patisiran
- Continue to observe generally favorable safety and tolerability data in the full Phase 1 cohort with no new drug-related adverse events within the follow-up period
- Enrollment continues to progress well in MAGNITUDE-2, which is designed to measure clinical outcomes (including mNIS+7) and evaluate how a single dose of nex-z can lead to reduction in serum TTR, to potentially support a BLA submission by 2028
CAMBRIDGE, MA, USA I May 18, 2025 I Intellia Therapeutics, Inc. (NASDAQ:NTLA), a leading clinical-stage gene editing company focused on revolutionizing medicine with CRISPR-based therapies, today announced positive two-year follow-up data from the ongoing Phase 1 trial of investigational nexiguran ziclumeran (nex-z) for the treatment of hereditary ATTR amyloidosis with polyneuropathy (ATTRv-PN). Results were shared in an oral presentation on Sunday, May 18 at the 2025 Peripheral Nerve Society (PNS) Annual Meeting in Edinburgh, United Kingdom. The Phase 3 MAGNITUDE-2 trial design of nex-z in ATTRv-PN was also exhibited in a poster presentation.
“We are pleased to share new findings at PNS, which continue to support our growing body of evidence that a single dose of nex-z leads to deep, durable and consistent reductions in serum TTRs, with evidence of disease stability or clinically meaningful improvements in neuropathic impairment measures through two years,” said Intellia President and Chief Executive Officer John Leonard, M.D. “These data are also the first to show improvement in patients who had previously progressed on patisiran, further validating the hypothesis that increasingly deep reductions in TTR levels may lead to improved outcomes in ATTR amyloidosis.”
ATTRv-PN Results
- Rapid, Deep and Durable Serum TTR Reduction: Across patients who received a one-time dose of 0.3 mg/kg or higher (n=33), the mean serum TTR reduction by Day 28 was 90% (corresponding mean absolute serum TTR level of 23.8 µg/mL), with levels remaining virtually unchanged for at least 24 months.
- Evidence of Disease Modification on Clinical and Biomarker Measures: Favorable trends indicating stability or improvement were observed in patients with ATTRv-PN, including six patients previously on patisiran for a mean(sd) of 5.5(1.7) years, who had evidence of disease progression prior to entering the study. Stability or improvement was based on evaluation of multiple clinical and biomarker measures, including Neuropathy Impairment Score (NIS), modified Neuropathy Impairment Score +7 (mNIS+7), modified BMI (mBMI), Norfolk Quality of Life-Diabetic Neuropathy (QoL-DN) questionnaire and neurofilament light chain (NfL). Among the 18 patients in whom a mNIS+7 assessment was completed at 24 months, 14 out of 18 demonstrated a clinically meaningful improvement of ≥4 points as of the April 11, 2025 data cutoff, including 5 of the 6 patients who were previously progressing on patisiran. The clinical and biomarker measure results are detailed in the table below.
| Clinical and Biomarker Measures | Change from Baseline at Month 12 | Change from Baseline at Month 24 |
| Part 1: Dose-escalation portion N=15* | ||
| NIS, mean (SD) | -2.0 (5.3) | -4.5 (7.4) |
| Part 2: Dose expansion portion N=21* | ||
| NIS, mean (SD) | -2.1 (10.2) | -5.2 (10.7) |
| mNIS+7, mean (SD) (overall) | -0.6 (11.1) | -8.5 (9.6) |
| mNIS+7, mean (SD) (patients previously on patisiran) † | -6.3 (11.6) | -6.5 (9.8) |
| Full cohort N=36‡ | ||
| Norfolk QoL-DN, mean (SD)** | -3.5 (21.0) | -8.5 (19.3) |
| NfL (% change from baseline)*** | -8.6 (41.7) | N/A |
| mBMI, mean (SD)** | 13.4 (93.2) | 39.0 (87.1) |
* Data cutoff April 11, 2025; ** Data cutoff August 21, 2024; *** Data cutoff April 12, 2024; † N=6; ‡ 24-month data in 19 patients; N/A: Data not available at Month 24
Negative change reflects improvement in the following results: NIS, mNIS+7, Norfolk QoL-DN and NfL
Positive change reflects improvement in mBMI
Study is ongoing and reported results reflect the available data as of the data cutoff
- Safety: Nex-z has been generally well tolerated as of the data cutoff date across all patients and at all dose levels tested. The most commonly reported treatment-related adverse events were infusion-related reactions, which were mild or moderate, and did not result in any discontinuations. Observed liver enzyme abnormalities were not considered serious, were asymptomatic and resolved spontaneously without medical intervention or sequela.
The presentation will be available on the Scientific Publications & Presentations section of intelliatx.com.
About the Nexiguran Ziclumeran (nex-z, also known as NTLA-2001) Clinical Program
The global Phase 1 trial is an ongoing open-label, multi-center, two-part study of NTLA-2001 in adults with hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) or transthyretin amyloidosis with cardiomyopathy (ATTR-CM). Part 1 of the ATTRv-PN arm of the study is an open-label, single-ascending dose escalation cohort and Part 2 is an open-label, single-dose expansion cohort. Visit clinicaltrials.gov (NCT04601051) for more details.
About the MAGNITUDE-2 Study
The pivotal Phase 3 MAGNITUDE-2 clinical trial is a randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of nexiguran ziclumeran (nex-z) in approximately 50 patients with hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN). The primary endpoints of the study are a change in modified neuropathy impairment score and a change in serum TTR levels. Adult patients with ATTRv-PN will be randomized 1:1 to receive a single 55 mg infusion of nex-z or placebo. For more information on MAGNITUDE-2 (NCT06672237), please visit clinicaltrials.gov.
About Nex-z
Based on Nobel Prize-winning CRISPR/Cas9 gene editing technology, nex-z has the potential to become the first one-time treatment for transthyretin (ATTR) amyloidosis. Nex-z is designed to inactivate the TTR gene that encodes for the transthyretin (TTR) protein. Interim Phase 1 clinical data showed the administration of nex-z led to consistent, deep and long-lasting TTR reduction. Intellia leads development and commercialization of nex-z as part of a multi-target discovery, development and commercialization collaboration with Regeneron Pharmaceuticals, Inc.
About Transthyretin (ATTR) Amyloidosis
Transthyretin amyloidosis, or ATTR amyloidosis, is a rare, progressive and fatal disease. Hereditary ATTR (ATTRv) amyloidosis occurs when a person is born with mutations in the TTR gene, which causes the liver to produce structurally abnormal transthyretin (TTR) protein with a propensity to misfold. These damaged proteins build up as amyloid in the body, causing serious complications in multiple tissues, including the heart, nerves and digestive system. ATTRv amyloidosis predominantly manifests as polyneuropathy (ATTRv-PN), which can lead to nerve damage, or cardiomyopathy (ATTRv-CM), which can lead to heart failure. Some individuals without the genetic mutation produce non-mutated, or wild-type TTR proteins that become unstable over time, misfolding and aggregating in disease-causing amyloid deposits. This condition, called wild-type ATTR (ATTRwt) amyloidosis, primarily affects the heart. There are an estimated 50,000 people worldwide living with ATTRv amyloidosis and between 200,000 and 500,000 people with ATTRwt amyloidosis. There is no known cure for ATTR amyloidosis and currently available medications are limited to slowing accumulation of misfolded TTR protein.
About Intellia Therapeutics
Intellia Therapeutics, Inc. (NASDAQ: NTLA) is a leading clinical-stage gene editing company focused on revolutionizing medicine with CRISPR-based therapies. Since its inception, Intellia has focused on leveraging gene editing technology to develop novel, first-in-class medicines that address important unmet medical needs and advance the treatment paradigm for patients. Intellia’s deep scientific, technical and clinical development experience, along with its people, is helping set the standard for a new class of medicine. To harness the full potential of gene editing, Intellia continues to expand the capabilities of its CRISPR-based platform with novel editing and delivery technologies. Learn more at intelliatx.com and follow us @intelliatx.
SOURCE: Intellia Therapeutics
