Intellia Therapeutics has announced positive clinical data from its Phase 1 trial of nexiguran ziclumeran (nex-z), a CRISPR-based gene editing therapy for transthyretin (ATTR) amyloidosis. The trial results indicate that a single dose of nex-z led to rapid, deep, and durable reduction in serum TTR, accompanied by evidence of disease stabilization or improvement. The data, presented at the 2024 American Heart Association (AHA) Scientific Sessions and published in the New England Journal of Medicine, offer compelling evidence for the potential of nex-z to modify the progression of ATTR amyloidosis.
Deep TTR Reduction and Cardiac Improvement in ATTR-CM
In the ATTR amyloidosis with cardiomyopathy (ATTR-CM) arm of the study, patients demonstrated a mean 90% reduction in serum TTR at 12 months. Notably, 81% of patients showed stability or improvement in NT-proBNP levels, a key marker of cardiac stress. Furthermore, 94% showed stability or improvement in high sensitivity Troponin T (hs-Troponin T), and 77% in the 6-minute walk test (6MWT). 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).
Positive Trends in ATTRv-PN Patients
The hereditary ATTR amyloidosis with polyneuropathy (ATTRv-PN) arm showed similar positive trends, with a 91% TTR reduction at month 12 in patients who received a dose of 0.3 mg/kg or higher. Clinical measures, including the Neuropathy Impairment Score (NIS) and modified BMI (mBMI), indicated stability or improvement in neuropathy.
Safety and Tolerability
Across both arms of the trial, 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.
RMAT Designation and Future Development
The FDA has granted Regenerative Medicine Advanced Therapy (RMAT) designation to nex-z for the treatment of ATTRv-PN. This designation will expedite the development and review of nex-z, offering benefits such as early interactions with the FDA and potential priority review of the Biologics License Application (BLA). Intellia is currently conducting Phase 3 trials (MAGNITUDE and MAGNITUDE-2) to further evaluate the efficacy and safety of nex-z in larger patient populations with ATTR-CM and ATTRv-PN, respectively.
Expert Commentary
"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," said Intellia President and Chief Executive Officer John Leonard, M.D.
