Consistent results for nexiguran ziclumeran across wildtype and variant ATTR-CM

The CRISPR gene editing therapy nexiguran ziclumeran was associated with swift, deep, and durable reductions in serum transthyretin in patients with wild-type and variant transthyretin amyloid cardiomyopathy (ATTR-CM).

Nexiguran ziclumeran was designed to inactivate the transthyretin (TTR) gene and has been associated with deep and quick reductions in serum transthyretin in patients with ATTR-CM [1]. Prof. Marianna Fontana (University College London, UK) looked at the safety and efficacy of this treatment in patients with wild-type and variant disease [2]. The phase 1 study (NCT04601051) included 25 patients with wild-type disease and 11 with variant disease, all treated with a single dose of nexiguran ziclumeran administered by intravenous infusion.

After 12 months of follow-up, the percentage change from baseline in serum TTR was -92.5% in participants with wild-type disease and -85.4% in those with variant disease. Furthermore, markers of disease progression, such as NT-proBNP, hs-troponin T, and functional measures like 6-minute walking distance, remained stable or improved in participants from both groups (see Figure). “This is remarkable, since we usually see a rapid decline and severe disease progression in patients with variant disease,” added Prof. Fontana. The safety profile of the study drug was similar in both groups, with cardiac failure being the most common adverse event in the wildtype group (32%) and the variant group (45%). “This is what you expect to see in this patient population,” commented Prof. Fontana.

Figure: Markers of disease progression [2]



6MWT, 6-minute walking distance; ATTR, transthyretin amyloid cardiomyopathy; ATTRv, variant ATTR; ATTRwt, wildtype ATTR.

In conclusion, a single dose of nexiguran ziclumeran appeared safe and was associated with an improvement in serum TTR levels in patients with wild-type and variant ATTR-CM. Furthermore, various disease markers displayed stability or improvement in the included patients, which is considered a good result in this aggressively progressing disease. These findings support further evaluation of this innovative therapy in a clinical trial programme.

1. Fontana M, et al. N Engl J Med 2024;391:2231-2241.
2. Fontana M, et al. CRISPR gene editing with nexiguran ziclumeran in ATTR cardiomyopathy: treatment effect in hereditary vs wild-type disease. Hottest trials and trial updates (1), Heart Failure 2025, 17–20 May, Belgrade, Serbia.

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Posted on 17 July 202521 July 2025