Promising results for CRISPR-based therapy in ATTR-CM

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 favourable, supporting further investigation of the 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 wildtype 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 (University College London, UK) [1].

Treatment with nexiguran ziclumeran resulted in swift, deep, and durable reductions in circulating transthyretin. Serum transthyretin was reduced by 89% at day 28, which was maintained through month 24 (see Figure). “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 participants remained stable or improved on these markers, and 47% of the participants with NYHA class III had no worsening in these markers,” reported Prof. Fontana.

Figure: Nexiguran ziclumeran associated with large reductions in serum TTR [1]



CI, confidence interval; TTR, transthyretin.

Infusion-related reactions (14%) and increased aspartate aminotransferase (6%) were the most common treatment-related adverse events. “These events were mild and self-limiting,” emphasised Prof. Fontana. No patients discontinued the treatment due to adverse events.

“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 need to be confirmed in randomised-controlled trials, such as the phase 3 MAGNITUDE study.”

1. 
   
   1. Fontana M, et al. Nexiguran ziclumeran, an investigational in vivo CRISPR-based therapy for patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM): interim report of the phase 1 study. LBS.01, AHA Scientific Sessions 2024, 16–18 November, Chicago, USA.
   2. Fontana M, et al. N Engl J Med 2024;391:2231-2241.

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Posted on 3 February 2025