Journal Article

CRISPR-Cas9 Gene Editing with Nexiguran Ziclumeran for ATTR Cardiomyopathy

Walsh, Liron, Olbertz, Joy, Täubel, Jörg, Razvi, Yousuf, Rocha, Ricardo, Zhu, Peijuan, Lebwohl, David, Smith, Derek, Gane, Edward J., Solomon, Scott D., Haagensen, Alexandra, Xu, Yuanxin, Sonderfan, Alison, Gutstein, David E., Adams, David, Kachadourian, Jessica, Fontana, Marianna, Leung, Adia, Pilebro, Björn, Gillmore, Julian D.

2024

Overview

Transthyretin amyloidosis with cardiomyopathy (ATTR-CM) is a progressive, often fatal disease. Nexiguran ziclumeran (nex-z) is an investigational therapy based on CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease) targeting the gene encoding transthyretin ( ). In this phase 1, open-label trial, we administered a single intravenous infusion of nex-z to patients with ATTR-CM. Primary objectives included assessment of the effect of nex-z on safety and pharmacodynamics, including the serum TTR level. Secondary end points included changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, high-sensitivity cardiac troponin T levels, the 6-minute walk distance, and the New York Heart Association (NYHA) class. A total of 36 patients received nex-z and completed at least 12 months of follow-up. Of these patients, 50% were in NYHA class III and 31% had variant ATTR-CM. The mean percent change from baseline in the serum TTR level was -89% (95% confidence interval [CI], -92 to -87) at 28 days and -90% (95% CI, -93 to -87) at 12 months. Adverse events were reported in 34 patients. Five had transient infusion-related reactions, and two had transient liver-enzyme elevations that were assessed as treatment-related. Serious adverse events, most of which were consistent with ATTR-CM, were reported in 14 patients. The geometric mean factor change from baseline to month 12 was 1.02 (95% CI, 0.88 to 1.17) in the NT-proBNP level and 0.95 (95% CI, 0.89 to 1.01) in the high-sensitivity cardiac troponin T level. The median change from baseline to month 12 in the 6-minute walk distance was 5 m (interquartile range, -33 to 49). A total of 92% of the patients had either improvement or no change in their NYHA class. In this phase 1 study involving patients with ATTR-CM, treatment with a single dose of nex-z was associated with transient infusion-related reactions and consistent, rapid, and durable reductions in serum TTR levels. (Funded by Intellia Therapeutics and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT04601051.).

• Publisher: Massachusetts Medical Society
• Subject: Adverse events / Aged / Aged, 80 and over / Amyloid Neuropathies, Familial - blood / Amyloid Neuropathies, Familial - complications / Amyloid Neuropathies, Familial - genetics / Amyloid Neuropathies, Familial - therapy / Amyloidosis / Brain natriuretic peptide / Cardiology / Cardiology General / Cardiomyopathies - blood / Cardiomyopathies - genetics / Cardiomyopathies - therapy / Cardiomyopathy / CRISPR / CRISPR-Cas Systems / Endonuclease / Female / Gene Editing - methods / Gene therapy / Genetic Therapy - adverse effects / Genetic Therapy - methods / Genetics / Genetics General / Genome editing / Heart / Heart failure / Histamine / Hospitalization / Humans / Hypothesis testing / Infusions, Intravenous - adverse effects / Lipids / Liposomes - administration & dosage / Liposomes - adverse effects / Male / Middle Aged / Myocarditis / Nanoparticles / Nanoparticles - administration & dosage / Nanoparticles - adverse effects / Natriuretic Peptide, Brain - blood / Neurology / Neurosurgery / Neurosurgery General / Peptide Fragments - blood / Pericarditis / Pharmacodynamics / Prealbumin - genetics / Proteins / Quality of life / RNA, Guide, Kinetoplastida - administration & dosage / RNA, Guide, Kinetoplastida - adverse effects / RNA, Guide, Kinetoplastida - genetics / Transthyretin / Troponin / Troponin T / Troponin T - blood