Intellia Therapeutics has announced positive clinical data from its 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, indicate that nex-z may favorably impact disease progression following a one-time treatment.
The Phase 1 trial is an open-label study evaluating the safety and activity of nex-z in patients with ATTR amyloidosis with cardiomyopathy (ATTR-CM) or hereditary ATTR amyloidosis with polyneuropathy (ATTRv-PN). The data cutoff date for the new results was August 21, 2024.
Consistent TTR Reduction
Across all ATTR-CM patients (n=36), a single dose of nex-z led to rapid, deep, and sustained serum TTR reduction, irrespective of baseline levels. At month 12, the mean serum TTR reduction was 90%, with a mean absolute residual serum TTR concentration of 17 µg/mL. Among 11 patients followed for 24 months, all continued to exhibit a sustained response without any waning effect. Intellia anticipates that these consistently low TTR levels will reduce ongoing amyloid formation and potentially allow for amyloid clearance and improved cardiac function.
Impact on Cardiac Disease Progression
New data revealed that patients treated with nex-z showed disease stabilization or improvement at month 12 compared to baseline across multiple markers of cardiac disease progression. This was observed despite a high proportion of patients with advanced disease. Specifically, 81%, 94%, and 77% of patients showed stability or improvement in NT-proBNP, high sensitivity Troponin T (hs-Troponin T), and the 6-minute walk test (6MWT), respectively. Furthermore, 66% of patients were stable or improved across all three markers. Quality of life, measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ), also showed evidence of benefit. 92% of patients were stable or improved in their New York Heart Association (NYHA) functional classification.
ATTRv-PN Clinical Measures
In patients who received a dose of 0.3 mg/kg or higher (n=33), the mean serum TTR reduction was 91% at month 12, with a mean absolute residual serum TTR concentration of 20 µg/mL. Sixteen patients followed for 24 months continued to show a sustained response. Favorable trends indicating stability or improvement were observed based on evaluation of multiple clinical measures, including Neuropathy Impairment Score (NIS), modified Neuropathy Impairment Score (mNIS+7) and modified BMI (mBMI).
Safety Profile
Across all patients and dose levels tested, nex-z was generally well tolerated. The most commonly reported treatment-related adverse events were infusion-related reactions (IRRs), predominantly mild to moderate in severity, and did not result in any discontinuations.
Ongoing Phase 3 Trials
Intellia is currently conducting two pivotal Phase 3 trials: MAGNITUDE (NCT06128629) for ATTR-CM and MAGNITUDE-2 (NCT06672237) for ATTRv-PN. These randomized, double-blind, placebo-controlled studies aim to further evaluate the efficacy and safety of nex-z.
John Leonard, M.D., President and Chief Executive Officer of Intellia, stated, "The Phase 1 data presented today offer compelling evidence that deep and persistently low levels of TTR reduction achieved with nex-z, an investigational in vivo CRISPR-based gene editing therapy, may favorably impact disease progression for people living with ATTR amyloidosis."
