The Future of Gene Silencers for ATTR-CM After CARDIO-TTRansform, With Ronald Witteles, MD

Gene silencer therapies targeting transthyretin (TTR) remain among the most effective treatments developed for TTR amyloidosis, according to Ronald Witteles, MD, of Stanford Medicine, despite the recent failure of the CARDIO-TTRansform trial to meet its primary endpoint. Witteles discussed the result and its implications for the silencer drug class with HCPLive following the presentation at the European Society of Cardiology (ESC) Congress 2026 in Munich, Germany.

CARDIO-TTRansform's Miss in Context

CARDIO-TTRansform tested eplontersen, an RNA-targeted TTR silencer already approved for hereditary ATTR polyneuropathy, against placebo in 1432 patients with ATTR-CM. The trial did not meet its primary composite endpoint of cardiovascular mortality and recurrent cardiovascular events (rate ratio, 0.89; 95% CI, 0.73-1.09; P = .277), despite suppression of circulating serum TTR.¹

The result contrasts with HELIOS-B, the pivotal trial of the silencer vutrisiran, which met its primary endpoint and 4 key secondary endpoints in both the overall ATTR-CM population and the subgroup not on baseline stabiliser therapy, supporting its approval for ATTR-CM.²

Witteles offered several possible explanations for the divergent results. He pointed to greater baseline and on-trial stabiliser use in CARDIO-TTRansform compared with HELIOS-B, a difference in the primary endpoint's mortality component (cardiovascular versus all-cause), and what he described as apparently less TTR suppression in the liver with eplontersen. He noted eplontersen did show benefit in a prespecified but non-co-primary monotherapy subgroup, patients not on a baseline stabiliser, even though the overall trial result was negative.

Why One Negative Trial Doesn't Sink the Silencer Class

Witteles pushed back firmly on the notion CARDIO-TTRansform undermines the broader silencer class: "Those who have decided to throw the proverbial baby out with the bathwater and say that silencers have some just generic stain on them from this, I fully disagree with that," he said. "This result does not in any way, shape, or form invalidate the robust data from HELIOS-B, which was with another silencer, or all of the ATTR polyneuropathy trials, which showed remarkable efficacy."

Witteles said the trial does raise a genuine open question specific to combination therapy, stabiliser plus silencer, rather than to silencers broadly. "I would be more hesitant today to decide to start somebody on combination therapy than I was 2 months ago," Witteles said. "But in terms of silencers as a class, no. There should not be some... scarlet letter on them from this."

What Remains Open, and the Pipeline That Will Answer It

Witteles pointed to a pair of large phase 3 trials currently enrolling, which will help resolve the combination-versus-monotherapy question. TRITON-CM is testing nucresiran, a next-generation RNAi silencer dosed twice yearly, which has shown greater than 95% TTR knockdown in early-phase data, more than any TTR-lowering therapy tested to date. MAGNITUDE is testing nexiguran ziclumeran (nex-z), a one-time CRISPR gene-editing therapy designed to permanently reduce hepatic TTR production by about 90%; the trial resumed enrollment in 2026 after a temporary FDA clinical hold related to a liver-related adverse event was lifted.

"The good news is we will get answers to this, and anybody who thinks this is a settled question is wrong," Witteles said. "It remains a very open question, and we have two large trials that... we're a few years away from the data, but that I think will give us a much better idea."

Editors’ note: Witteles reports relevant disclosures with Alexion, Alnylam, AstraZeneca, Bridge Bio, Intellia, Medison, Novo Nordisk, and Pfizer.

References

1. European Society of Cardiology. Eplontersen trial did not meet its primary endpoint in transthyretin-mediated amyloid cardiomyopathy. Published August 28, 2026. Accessed August 30, 2026. https://www.escardio.org/news/press/press-releases/eplontersen-trial-did-not-meet-its-primary-endpoint-in-transthyretin-mediated-amyloid-cardiomyopathy/

2. Fontana M, Berk JL, Gillmore JD, Witteles RM, et al; HELIOS-B Trial Investigators. Vutrisiran in patients with transthyretin amyloidosis with cardiomyopathy. N Engl J Med. 2025;392(1):33-44. doi:10.1056/NEJMoa2409134

3. Intellia Therapeutics, Inc. Intellia Therapeutics announces FDA lift of clinical hold on MAGNITUDE phase 3 clinical trial in ATTR-CM. Published March 2, 2026. Accessed August 30, 2026. https://ir.intelliatx.com/news-releases/news-release-details/intellia-therapeutics-announces-fda-lift-clinical-hold-0