Intellia Therapeutics has announced positive new clinical data from its ongoing Phase 1 trial of nexiguran ziclumeran (nex-z), an investigational in vivo CRISPR-based gene editing therapy for transthyretin (ATTR) amyloidosis. The data, presented at the 2024 American Heart Association (AHA) Scientific Sessions and published in the New England Journal of Medicine, suggest that nex-z may favorably impact disease progression in both ATTR cardiomyopathy (ATTR-CM) and hereditary ATTR amyloidosis with polyneuropathy (ATTRv-PN).
Deep and Durable TTR Reduction
Across all patients, a single dose of nex-z led to consistently rapid, deep, and sustained serum TTR reduction. At month 12, the mean serum TTR reduction was 90%, with a mean absolute residual serum TTR concentration of 17 μg/mL. Patients followed for 24 months continued to show a sustained response, with no evidence of waning effect over time.
Impact on Cardiac Disease Progression in ATTR-CM
In ATTR-CM patients (n=36), data showed evidence of disease stabilization or improvement at month 12 compared to baseline across multiple markers of cardiac disease progression. Specifically:
- 81% of patients showed stability or improvement in NT-proBNP.
- 94% of patients showed stability or improvement in high sensitivity Troponin T (hs-Troponin T).
- 77% of patients showed stability or improvement in the 6-minute walk test (6MWT).
- 66% showed stability or improvement across all three markers examined.
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).
Clinical Improvements in ATTRv-PN
In patients with ATTRv-PN who received a dose of 0.3 mg/kg or higher (n=33), the mean serum TTR reduction was 91% at month 12. Favorable trends indicating stability or improvement were observed in clinical measures, including Neuropathy Impairment Score (NIS) and modified BMI (mBMI).
Safety and Tolerability
Nex-z was generally well tolerated across all patients and at all dose levels tested. The most commonly reported treatment-related adverse events were infusion-related reactions (IRRs), which were predominantly mild and moderate in severity, and did not result in any discontinuations.
Ongoing Phase 3 Trials
Intellia is currently conducting the pivotal Phase 3 MAGNITUDE clinical trial, a randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of nex-z in approximately 765 patients with ATTR-CM. Additionally, the MAGNITUDE-2 study is evaluating nex-z in 50 adults with ATTRv-PN.
