CRISPR gene-editing therapy shows promise as cardiac amyloidosis treatment in early study
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Key takeaways:
- In an early study, a gene-editing therapy drastically reduced levels of transthyretin, the protein that causes cardiac amyloidosis.
- Most patients had their disease progression halted at 1 year.
CHICAGO — A CRISPR-Cas9-based therapy targeting the gene encoding transthyretin reduced transthyretin levels in patients with cardiac amyloidosis, researchers reported at the American Heart Association Scientific Sessions.
Researchers administered the CRISPR-Cas9-based therapy, nexiguran ziclumeran (nex-z, Intellia/Regeneron) to 36 patients (median age, 78 years; 97% men; 22% Black) with transthyretin amyloidosis with cardiomyopathy (ATTR-CM; 69% with wild-type) and NYHA class I to III HF in a phase 1 open-label trial. The results were simultaneously published in The New England Journal of Medicine.
“These results represent the first link of evidence of in vivo CRISPR-designed gene-editing in cardiomyopathy showing that targeted inactivation of the TTR gene may reduce disease progression in ATTR cardiomyopathy,” Marianna Fontana, MD, PhD, professor of cardiology and honorary consultant cardiologist at the National Amyloidosis Centre, Division of Medicine, University College London, said during a presentation.
Nex-z inactivates the TTR gene with a one-time treatment, an IV infusion over 4 hours, Fontana said.
At 28 days, the mean percent change from baseline in serum transthyretin was –89% (95% CI, –92 to –87). At 1 year, the mean change was –90% (95% CI, –93 to –87), Fontana and colleagues found.
Adverse events occurred in 34 patients and serious adverse events in 14 patients, with most of the latter being consistent with adverse events typically seen with ATTR-CM, according to the researchers. The adverse events included transient infusion-related reactions in five patients and transient liver-enzyme elevations deemed by the researchers to be related to the treatment in two patients.
Only 8% of patients had worsening NYHA class over 1 year, with the rest improving in class or no change, Fontana said.
The geometric mean factor change from baseline to 1 year in N-terminal pro-B type natriuretic peptide was 1.02 (95% CI, 0.88-1.17), and in high-sensitivity cardiac troponin T it was 0.95 (95% CI, 0.89-1.01), according to the researchers.
Six-minute walk distance improved by 5 m from baseline to 1 year (interquartile range, –33 to 49), Fontana and colleagues found.
Taking into account the markers of disease progression represented by NT-pro BNP, troponin and 6-minute walk distance, nearly 80% patients stabilized or improved in terms of disease progression, Fontana said during the presentation, noting that 83% of patients with NYHA class I or II at baseline and 47% of patients with NYHA class III at baseline had no worsening in any of those markers at 1 year.
“These results also support the hypothesis that rapid, deep and durable reductions in serum TTR result in meaningful clinical changes,” Fontana said during the presentation. “The effects of nex-z on clinical outcomes are currently being evaluated in MAGNITUDE, an ongoing phase 3 randomized, placebo-controlled trial in patients with ATTR cardiomyopathy.”
During a discussant presentation, Sarah Cuddy, MBBCh BAO, MD, FACC, FASNC, cardiologist at Brigham and Women's Hospital Amyloidosis Program and assistant professor of medicine at Harvard Medical School, said “we know gene knockdown is safe and effective thanks to the gene silencer data, which has opened the door for a permanent treatment with gene editing.”
Cuddy said amyloidosis “was barely recognized as significant 50 years ago” and in large part due to work in the past decade has progressed “to having multiple effective therapies and possibly a cure in the coming decade.”
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Perspective
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This is a game-changer, depending on availability. The therapies we have now for ATTR-CM have to be taken forever. They do stop progression. But this is truly going upstream and attacking the gene itself. So depending on availability and cost, this could completely change the future of this disease state, as was stated in the excellent discussant presentation by Sarah Cuddy, MBBCh BAO, MD, FACC, FASNC.
Another important point is that you would not necessarily expect to see an increase in 6-minute walk distance or a change in symptoms, because what you are really looking for is stabilization. The fact that there was no change in some of those quality-of-life parameters is OK. The point is to stop the progression.
The phase 3 study that is ongoing will be very informative.
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Fontana M, et al. LBS.01. Presented at: American Heart Association Scientific Sessions; Nov. 16-18, 2024; Chicago.
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