Intellia Therapeutics has announced positive clinical data from its Phase 1 trial of nexiguran ziclumeran (nex-z), an investigational CRISPR-based gene editing therapy for transthyretin (ATTR) amyloidosis. The data, presented at the 2024 AHA Scientific Sessions and published in the New England Journal of Medicine, demonstrate rapid, deep, and durable reduction in serum TTR levels, accompanied by evidence of disease stabilization or improvement following a one-time treatment.
ATTR-CM Arm Results
In the ATTR amyloidosis with cardiomyopathy (ATTR-CM) arm of the study, a single dose of nex-z led to a 90% mean reduction in serum TTR at month 12, with a mean absolute residual serum TTR concentration of 17 µg/mL. Notably, 11 patients followed for 24 months maintained sustained TTR reduction without any waning effect. Improvements were observed across multiple markers of cardiac disease progression, including NT-proBNP, hs-Troponin T, and the 6-minute walk test (6MWT). Specifically, 81%, 94%, and 77% of patients showed stability or improvement in NT-proBNP, hs-Troponin T and 6MWT, respectively. Furthermore, 92% of patients were stable or improved in their New York Heart Association (NYHA) functional classification.
The hospitalization rate for cardiovascular events among the 36 patients with ATTR-CM was 0.16/patient/year (95% CI: 0.08 to 0.36).
ATTRv-PN Arm Results
In the hereditary ATTR amyloidosis with polyneuropathy (ATTRv-PN) arm, patients receiving a dose of 0.3 mg/kg or higher (n=33) experienced a 91% mean serum TTR reduction at month 12, with a mean absolute residual serum TTR concentration of 20 µg/mL. Sixteen patients followed for 24 months continued to exhibit sustained TTR reduction. Favorable trends indicating stability or improvement were observed in clinical measures such as Neuropathy Impairment Score (NIS) and modified BMI (mBMI).
Safety and Tolerability
Across both arms of the study, nex-z was generally well tolerated. The most commonly reported treatment-related adverse events were infusion-related reactions (IRRs), which were predominantly mild to moderate in severity and did not lead to any discontinuations.
Ongoing Phase 3 Trials
Intellia is currently conducting two pivotal Phase 3 trials: MAGNITUDE (NCT06128629) in ATTR-CM and MAGNITUDE-2 (NCT06672237) in ATTRv-PN. These randomized, double-blind, placebo-controlled studies are designed to evaluate the efficacy and safety of nex-z in larger patient populations. The MAGNITUDE study will enroll approximately 765 patients with ATTR-CM, while MAGNITUDE-2 will enroll 50 patients with ATTRv-PN.
About Nexiguran Ziclumeran
Nexiguran ziclumeran (nex-z, also known as NTLA-2001) is an in vivo CRISPR-based gene editing therapy designed to inactivate the TTR gene, which encodes for the transthyretin (TTR) protein. It is being developed as a one-time treatment for ATTR amyloidosis. Intellia leads the development and commercialization of nex-z as part of a collaboration with Regeneron.
