Category: Clinical Trials

Based on presentations at the European Society of Cardiology Congress (ESC) Congress 2026, Munich (Aug 28 & 30), and simultaneous publications

CARDIO-TTRansform clinical trial

CARDIO-TTRansform is the largest clinical trial ever run in transthyretin amyloid cardiomyopathy (ATTR-CM), a disease in which a misfolded protein called transthyretin builds up in the heart muscle and causes progressive heart failure. The trial tested eplontersen, a drug that lowers the liver’s production of TTR (an antisense oligonucleotide (ASO) sometimes called a “gene silencer”), against placebo in over 1,400 people. Everyone in the trial was also allowed to stay on their standard treatment, and at the start of the trial, about 57% of all patients were already on a TTR “stabilizer” drug, a different type of ATTR-CM medicine that works by keeping TTR from misfolding in the first place. Over the course of the trial, more patients started TTR stabilizing therapy.

Two presentations at the ESC Congress 2026 covered this trial. One walked through the main results (Prof. Mathew Maurer, MD) and which are published in New England Journal of Medicine. The other presentation took a closer look at how already being on a stabilizer changed the results (Prof. Pablo García-Pavía, MD PhD), and that second analysis has also now been published in Nature Medicine.

Headline result: the main goal was narrowly missed

The CARDIO-TTRansform trial set out to see whether eplontersen could lower the combined risk of dying from heart problems or having repeat heart-related hospital visits and events, compared with placebo, over about two and a half years. Looking at everyone in the trial together, eplontersen did not clearly beat placebo on this measure. The difference between the two groups was small enough that treatment effects could plausibly have happened by chance. That’s despite the drug doing exactly what it’s designed to do in the body: it lowered TTR levels in the blood by about 79%, quickly and consistently, in everyone who took it.

Taking a closer look: it depended on stabilizer use

When the researchers split the results by whether someone was already taking a stabilizer drug when they joined the trial, a more detailed picture showed up.

This split was large enough that it’s unlikely to be a coincidence. In plain terms, people who took eplontersen on its own, without a background stabilizer, saw a real benefit. In that first group, patients who took eplontersen alone also walked farther, reported better quality of life, and had lower levels of a blood marker that reflects how hard the heart is working, all compared with placebo.  People who added eplontersen to a stabilizer they were already taking did not see an extra benefit. Eplontersen was well tolerated across the board, with no new safety concerns, whether or not someone was also on a stabilizer.

One more detail worth knowing: blood TTR levels dropped by a similar amount, just as quickly, in both groups. So the lack of extra benefit in the stabilizer group doesn’t seem to be because the drug worked less well in their bodies. It worked just as well biologically. It simply didn’t translate into a measurable added benefit in that group.

A caveat worth knowing

Because the trial’s main goal wasn’t clearly met when looking at everyone together, these more detailed findings, including the split by background stabilizer use, are considered supportive for clinical benefit of eplontersen and consistent with other similar silencing treatments, rather than formally proving the trial goal. This is a normal, expected situation when a trial’s main result is a near miss. It means these findings deserve to be taken seriously as a strong signal for eplontersen working as expected, but they aren’t the final word yet on whether it improves patient outcomes on top of other stabilizer treatment.

What’s still an open question

Does combining a silencer and a stabilizer help more than either drug alone? This trial doesn’t answer that question for gene silencers and stabilizers as a whole, it only tested one specific silencer, eplontersen, added on top of whichever stabilizer a patient happened to already be taking. No extra benefit showed up in that combination, but that wasn’t the main question the trial was built to answer, and it’s not yet clear whether there’s a natural limit to how much these two types of drugs can add on top of each other, whether more time would reveal a difference, or whether something about how these particular drugs interact is blunting the added effect.  While both silencers and stabilizers can play an important role in treatment, the CARDIO-TTRansform data suggest that adding both types of treatment may not always provide extra benefit. Future research is needed to help determine which treatment approach works best for different patients and whether using these therapies together or at different times during the course of the disease leads to the best outcomes.

What you should not conclude

It would be a mistake to read this trial as proof that TTR silencers don’t work. In patients who weren’t already on a stabilizer, eplontersen showed a real, meaningful benefit across several different measures of health. The overall result looked weaker mainly because roughly half of everyone in the trial was already on a stabilizer which improved patient outcomes, and that particular group didn’t show an added benefit from adding a silencer. That’s a very different finding from “the drug doesn’t work.” Silencer drugs remain a well-established, biologically active treatment approach for this disease, including in other settings where they’re already approved.

Bottom line

CARDIO-TTRansform is a large, carefully run trial that didn’t clearly meet its main goal when looking at everyone together, but it did show a meaningful benefit for patients who took eplontersen as their only ATTR-CM treatment. Just as important, the data confirm that eplontersen is a safe treatment, with no new safety concerns showing up regardless of whether patients were also on a stabilizer. The open question for the field now is whether and how combining silencers and stabilizers adds benefit beyond either drug alone. Two ongoing trials, TRITON-CM (NCT07052903) and MAGNITUDE (NCT06128629), are currently recruiting patients and should generate data to help move that question forward. Sign-up or log-in to My Amyloidosis Pathfinder (MAP) to learn more about each study.

Source:

• Maurer MS, et al. “Eplontersen in transthyretin amyloid cardiomyopathy: results from the randomised, double-blind, placebo-controlled CARDIO-TTRansform trial.” ESC Congress 2026, Hot Line, August 28, 2026.
• Fontana M, Masri A, Solomon SD, et al. “Eplontersen for transthyretin amyloid cardiomyopathy.” New England Journal of Medicine (2026). https://doi.org/10.1056/NEJMoa2608510
• García-Pavía P, et al. “Efficacy and safety of transthyretin gene silencer eplontersen in patients with transthyretin amyloid cardiomyopathy receiving stabiliser therapy in the CARDIO-TTRansform trial.” ESC Congress 2026, Late-Breaking Science, August 30, 2026.
• García-Pavía P, Cappelli F, Davis MK, et al. “Eplontersen with and without background transthyretin stabilizers in transthyretin amyloid cardiomyopathy: secondary analysis of a phase 3, randomized controlled trial.” Nature Medicine (2026). https://doi.org/10.1038/s41591-026-04670-6