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ESC HF 25: CRISPR-Cas9 Gene Editing in ATTR Cardiomyopathy: Treatment Effect in Hereditary Vs Wild-Type Disease
Published: 17 May 2025
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ESC HF 25 - A study investigating CRISPR gene editing with nexiguran ziclumeran in ATTR cardiomyopathy demonstrated favourable safety and tolerability, with consistent reductions in serum TTR in both wild-type and variant disease.
Prof Marianna Fontana (University College London, UK) joins us to discuss the key findings from a two-part, open-label, phase 1 study investigating the treatment effect, safety and tolerability of CRISPR gene editing in patients with hereditary compared to wild-type ATTR cardiomyopathy.
Findings showed that after a single infusion of nexifuran ziclumeran, there was evidence of a rapid reduction in serum TTR, irrespective of TTR levels at baseline in both wild-type and variant disease. The drug appeared to be safe and tolerable, with similar adverse event rates in both groups. Functional capacity and clinical biomarkers indicative of disease progression were favourably impacted in both groups.
Interview Questions:
- What research question does this study aim to address?
- What was the study design and patient population?
- What were the key findings?
- Were there any notable safety concerns or adverse events associated with the intervention?
- What are your take-home messages?
- What are the next steps in this programme, and are there any ongoing or planned trials that will further evaluate durability or long-term safety?
Recorded on-site at ESC HF in Belgrade, 2025.
Editors: Jordan Rance, Yazmin Sadik
Videographers: Tom Green, Mike Knight
Support: This is an independent interview produced by Radcliffe Cardiology.
“Mariana Fontana, professor of Cardiology at the University College London. I work at the National Disease Centre and today I'm going to focus on the analysis of wild type patients versus hereditary patients with ATTR cardiomyopathy treated with nexiguran ziclumeran in the phase 1 trial.
This study aims to address assessing if there are any differences in the efficacy and safety of nexiguran ziclumeran known as known as Nex-Z in patients with variant ATTR cardiomyopathy vs wild type ATTR cardiomyopathy.
This study is an ongoing phase 1 study which recruited 36 patients with hereditary or wild type ATTR cardiomyopathy and In the study. The phase one study consists of two different parts. Part one which was the dose finding portion of the study and part two which was the dose expansion of the study where every patient received a fixed dose of 55 milligrammes which was the fixed equivalent dose of 0.7 milligrammes per kilo.
25 patients had wild type disease, 11 patients had hereditary disease and of these 64% of the patients had a V142Y mutation.
The key findings of the study is that in terms of the primary endpoint there was a deep rapid and sustained reduction in the TTR levels irrespective of the TTR values at baseline and irrespective of the genotype in wild type or hereditary. So the absolute TTR levels reached at 12 months was exactly the same in wild type and hereditary patients in keeping with a consistent treatment effect in both genotypes. And also the Reduction was durable over time. So over the 24 months of observation the values remained low and practically unchanged and this reduction, the TTR levels was associated with evidence of stability on three known markers of disease progression like the NTproBNP hs-Troponin and 6 Minute Walking Test. And there was also evidence of stability or improvement on the quality of life and NYHA class.
There were no safety concerns and the most common AES was cardiac failure and this is extremely normal for patients with this condition and it was similar in wild type patients and hereditary patients. So there was a favourable safety and tolerability profile.
The key take home message from this is that one single infusion is associated with a deep durable and sustained reduction in the TTR levels in both the wild type patients and the hereditary patients and this associated with stability on key markers of disease progression with no safety concerns.
The Phase three trial called MAGNITUDE is actually ongoing and recruiting. So we are really keen to finish the recruitment as soon as possible and then we will wait for the follow up dedications because we are really all excited to see the results of the MAGNITUDE trial.”
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