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CRISPR-Cas9 gene editing with nexiguran ziclumeran was associated with large and sustainable reductions in circulating transthyretin in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). The safety profile in this phase 1 study was also favorable, supporting further investigation of this agent in larger studies.
Nexiguran ziclumeran is an investigational CRISPR-Cas9 therapy that aims to inactivate the transthyretin gene with a single treatment. The gene-editing therapy is delivered intravenously over 4 hours. The current phase 1 study (NCT04601051) enrolled 36 patients with either hereditary or wild-type ATTR-CM who received a single dose of nexiguran ziclumeran1,2. “The population was representative of ATTR-CM, including patients with advanced disease,” said Prof. Marianna Fontana, MD, PhD from the University College of London, in the UK1.
Treatment with nexiguran ziclumeran resulted in swift, deep, and durable reductions in circulating transthyretin. The reduction in serum transthyretin was -89% on day 28, maintained through month 24. “The mean absolute serum level at day 28 was 18.9 µg/mL,” added Prof. Fontana. Furthermore, markers of disease progression, such as NT-proBNP, high-sensitive troponin T, and the 6-minute walk test remained stable over 12 months. “For patients with NYHA class I/II, 83% of the patients remained stable or improved on these markers, and 47% of the patients with NYHA class III had no worsening markers,” reported Prof. Fontana. Infusion-related reactions (14%) and increased aspartate aminotransferase (6%) and were the most common treatment-related AEs. “These events were mild and self-limiting,” emphasized Prof. Fontana. No patients discontinued the treatment due to AEs.
“These findings represent the first clinical evidence of in vivo CRISPR/Cas9 gene editing in patients with ATTR-CM,” decided Prof. Fontana. “The positive effects of nexiguran ziclumeran must be confirmed in randomized-controlled trials, such as the phase 3 MAGNITUDE study.”
Medical writing support was provided by Robert van den Heuvel.
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