Marianna Fontana, MD, PhD: Nex-Z Shows Promise in ATTR-CM Phase 1 Trial

A groundbreaking CRISPR-based gene-editing therapy has demonstrated early success in treating transthyretin amyloidosis cardiomyopathy (ATTR-CM), a progressive and often fatal disease that can lead to heart failure, according to late-breaking at the American Heart Association (AHA) Scientific Sessions 2024.

Interim results from the Phase 1 trial of nexiguran ziclumeran (nex-z) revealed a single infusion of the therapy reduced serum TTR levels by approximately 90% over 12 months, offering a potential one-time treatment for this debilitating condition.

“After a single infusion of nex-z, there was a deep, rapid, and durable reduction in the circulating TTR levels and the reduction was similar across patients, with all patients achieiving a similar level, despite the genotype or the TTR at baseline,” primary investigator Marianna Fontana, MD, PhD, a professor of cardiology and honorary consultant cardiologist at the National Amyloidosis Centre, division of medicine, University College London, told HCPLive.

The study involved 36 patients with ATTR-CM, making it the largest gene-editing trial in cardiovascular disease. Participants, of which 50% had advanced heart failure (NYHA class III), experienced stabilization in biomarkers of disease progression, including NT-proBNP and hsTroponin-T, and a median increase of 5 meters in a 6-minute walk distance. Additionally, 92% of patients either maintained or improved their NYHA class over the 12 months of study.

Mild-to-moderate infusion-related reactions were the most common adverse events, with no major safety concerns reported. Overall, these results suggested that nex-z could alter the natural course of ATTR-CM by slowing or halting disease progression. With confirmation needed in larger trials, nex-z could become the first CRISPR-based therapy to successfully treat a cardiovascular condition, providing new hope for patients with few existing treatment options.

“The Phase 3 study, which is a randomized, multicenter, placebo-controlled trial, are sensing the efficacy and safety of nex-z in a large population of patients with ATTR-CM,” Fontana told HCPLive. “Hopefully, very soon, the enrollment will be completed and we’ll see the results of the Phase 3 trials.”

Disclosures: Relevant disclosures for Fontana include Alnylam Pharmaceuticals, Bayer, Intellia Therapuetics, Janssen Pharmaceuticals, Novo Nordisk, and others.

References

1. _{Fontana M, Taubel J, Gane E, Pilebro B, Adam D et al. Nexiguran ziclumeran (nex-z, also known as NTLA-2001), an investigational in vivo CRISPR-based therapy for patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM): interim report of the Phase 1 study. Presented at the American Heart Association (AHA) Scientific Sessions 2024. Chicago, Illinois. November 16-18, 2024.}
2. _{Intellia announces first clinical evidence from ongoing phase 1 study that nexiguran ziclumeran (nex-Z), an in vivo CRISPR/cas9-based gene editing therapy, may favorably impact disease progression in transthyretin (ATTR) amyloidosis. Intellia Therapeutics. November 16, 2024. Accessed November 16, 2024. https://ir.intelliatx.com/news-releases/news-release-details/intellia-announces-first-clinical-evidence-ongoing-phase-1-study.}