Marianna Fontana is Professor of Cardiology and Honorary Consultant Cardiologist at the National Amyloidosis Centre, Division of Medicine, University College London.

Marianna Fontana, MD, PhD

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 

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 

. “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.

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.

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.

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A novel CRISPR-based gene-editing therapy, nexiguran ziclumeran (nex-z), shows promise in treating transthyretin amyloidosis cardiomyopathy (ATTR-CM), a severe condition leading to heart failure. Interim results from a Phase 1 trial indicate a single infusion of nex-z reduces serum TTR levels by 90% over 12 months, stabilizing disease biomarkers and improving patient outcomes. The study, involving 36 patients, reported mild-to-moderate adverse events without major safety concerns. Larger trials are needed to confirm efficacy, potentially making nex-z the first successful CRISPR therapy for cardiovascular disease.

Marianna Fontana, MD, PhD discusses Phase 1 interim results on the CRISPR-based gene-editing therapy, nex-z, for ATTR-CM.

Marianna Fontana, MD, PhD: Declines in Kidney Function Frequent in ATTR-CM 

A decline in kidney function was common in patients with 

transthyretin amyloid cardiomyopathy (ATTR-CM)

 and linked to an elevated likelihood of mortality, even after adjustment for relevant biomarkers, according to new data presented at the 

This retrospective, observational, single-center cohort study assesed individuals with ATTR-CM at the National Amyloidosis Centre (NAC) in the United Kingdom, who underwent an assessment of baseline estimated glomerular filtration rate (eGFR) and 1-year follow-up between January 2000 and April 2024.

“We took a large population of patients, more than 2000 patients, with a ATTR-CM, and we did a landmark analysis at 12 months, where we measured the eGFR. We found, at 12 months, a change of 20% decline, an independently predictive prognosis,” Marianna Fontana, MD, PhD, a professor of cardiology and honorary consultant cardiologist at the National Amyloidosis Centre, division of medicine, University College London, told 

The study’s primary outcome was the risk of all-cause mortality associated with a decline in kidney function, considered a decrease in eGFR of >20%.

Upon analysis, the decline in kidney function was associated with a 1.7-fold higher risk of mortality (hazard ratio [HR], 1.71; 95% CI, 1.43-2.04; 

 < .001), with a similar risk across all 3 genotypes (wild type: HR, 1.64; 95% CI, 1.31-2.04; p.(V142I): HR, 1.70; 95% CI, 1.21-2.39; non-p.(V142I): HR, 1.51; 95% CI, 0.87-2.61) (

 for interaction = .93) and the 3 NAC disease stages (stage 1: HR, 1.69; 95% CI, 1.22-2.32; stage 2: HR, 1.69; 95% CI, 1.30-2.18; stage 3: HR, 1.61; 95% CI, 1.11-2.35) (

Importantly, the decline in kidney function was consistently, independently associated with mortality, after adjustment for increases in NT-proBNP and outpatient diuretic intensification (HR, 1.48; 95% CI, 1.23-2.76; 

“This is just the first step, one of the things that will need to be assessed is, for example, using this treatment to guide treatment response and [determine if] it improves management of the patients,” Fontana told 

Ioannou A, Razvi Y, Porcari A, et al. Kidney Outcomes in Transthyretin Amyloid Cardiomyopathy. JAMA Cardiol. Published online November 17, 2024. doi:10.1001/jamacardio.2024.4578

Decline in kidney function is prevalent in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) and correlates with increased mortality risk, even after adjusting for biomarkers. A study at the National Amyloidosis Centre in the UK analyzed over 2000 patients, revealing a 20% decline in eGFR at 12 months as a significant prognostic indicator. The decline was linked to a 1.7-fold higher mortality risk across genotypes and disease stages. This association remained significant after adjusting for NT-proBNP and diuretic use, suggesting potential implications for patient management.

Marianna Fontana, MD, PhD describes the prognostic importance of a decline in eGFR in a retrospective cohort of patients with ATTR-CM.

Marianna Fontana, MD, PhD

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