• Marianna Fontana, Scott D Solomon, Jessica Kachadourian, Liron Walsh, Ricardo Rocha, David Lebwohl, Derek Smith, Jörg Täubel, Edward J Gane, Björn Pilebro, David Adams, Yousuf Razvi, Joy Olbertz, Alexandra Haagensen, Peijuan Zhu, Yuanxin Xu, Adia Leung, Alison Sonderfan, David E Gutstein, and Julian D Gillmore.
• From the National Amyloidosis Centre, University College London, Royal Free Hospital (M.F., Y.R., J.D.G.), and Richmond Pharmacology (J.T.) - both in London; Brigham and Women's Hospital, Boston (S.D.S.), and Intellia Therapeutics, Cambridge (J.K., L.W., R.R., D.L., D.S., J.O., A.H., P.Z., Y.X., A.L., A.S.) - both in Massachusetts; the University of Auckland, Auckland, New Zealand (E.J.G.); Umea University, Umea, Sweden (B.P.); Centre Hospitalo-Universitaire de Bicêtre, Assistance Publique-Hôpitaux de Paris, University Paris-Saclay, Le Kremlin-Bicêtre, France (D.A.); and Regeneron Pharmaceuticals, Tarrytown, NY (D.E.G.).
• N. Engl. J. Med. 2024 Nov 16.

BackgroundTransthyretin 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 (TTR).MethodsIn 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.ResultsA 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.ConclusionsIn 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.).Copyright © 2024 Massachusetts Medical Society.

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