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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 ziclumeran^1,2. “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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