Monthly gene-silencing jab fails to cut events in stiff hearts

A monthly injection that switches off production of a rogue protein has failed its biggest test in a stiffening heart disease. In CARDIO-TTRansform, the largest trial ever run in transthyretin amyloid cardiomyopathy, eplontersen did not significantly reduce cardiovascular deaths and heart-related emergencies compared with placebo over almost three years.

There was a twist. The drug appeared to help people who were not already taking one of the existing treatments, called stabilisers, while offering no extra benefit to those who were. Because that finding comes from a subgroup, it can only suggest an answer, not prove one.

The results were presented by Dr Mathew Maurer of Columbia University Irving Medical Center in New York at the opening Hot Line 1 session of ESC Congress 2026 in Munich, at 11:00 on 28 August 2026 (11:00 in Madrid). They were published the same day in the New England Journal of Medicine, with Professor Marianna Fontana of University College London as first author.

What ATTR cardiomyopathy is

Transthyretin (TTR) is a protein, made mainly by the liver, that carries thyroid hormone and vitamin A around the blood. Normally, four TTR molecules lock together in a stable unit. In transthyretin amyloidosis, that unit falls apart, and the single pieces misfold and clump into stiff fibres called amyloid.

When amyloid builds up in the heart muscle, the walls thicken and stiffen. The heart can't relax and fill properly, which leads to heart failure, rhythm problems and, eventually, death. This is transthyretin amyloid cardiomyopathy, or ATTR-CM.

There are two forms:

• Wild-type ATTR-CM, the more common form, happens with age as the normal protein becomes less stable. It mostly affects men over 70.
• Hereditary (variant) ATTR-CM is caused by a mutation in the TTR gene. Some variants also damage nerves, causing a condition called polyneuropathy.

ATTR-CM was once considered rare. Better heart scans, including the bone-tracer scan shown above, now find it far more often, and it is increasingly recognised as a cause of heart failure in older men.

Two ways to treat it

Current treatments work in one of two ways.

Stabilisers, such as tafamidis and acoramidis, are tablets that hold the four-part TTR unit together so it doesn't fall apart. Both are approved for ATTR-CM and have been shown to reduce deaths and hospital admissions.

Silencers reduce how much TTR the liver makes in the first place. Eplontersen is one of these. It is an antisense oligonucleotide, a short strand of genetic material that binds the messenger RNA carrying instructions for TTR and marks it for destruction. It is injected under the skin once a month. Eplontersen, developed by Ionis and AstraZeneca, is already approved for hereditary ATTR polyneuropathy. Another silencer, vutrisiran, is approved for ATTR-CM in the US after its HELIOS-B trial.

The idea behind CARDIO-TTRansform was that cutting TTR production would slow amyloid build-up and reduce heart events, either on its own or on top of a stabiliser.

The CARDIO-TTRansform trial

CARDIO-TTRansform (NCT04136171) was a double-blind phase 3 trial run at 130 centres in 20 countries and funded by Ionis Pharmaceuticals and AstraZeneca. It enrolled people with either wild-type or hereditary ATTR-CM who were receiving available standard care.

In total, 1,438 people were randomised and 1,432 received at least one dose. They were assigned 1:1 to:

• Eplontersen 45 mg by injection under the skin every four weeks (715 people)
• A matching placebo injection (717 people)

Treatment continued for 140 weeks, about two years and eight months. The average age, as reported in the journal paper, was 76.4 years, and 90.6% of participants were men. Most (57%) were already taking a stabiliser when they joined.

The main goal was a combined count of cardiovascular deaths and recurrent cardiovascular events, such as hospital admissions or urgent visits for heart failure, through week 140. Because it counted repeat events, someone admitted to hospital three times contributed three events.

What the trial found

The trial missed its main goal.

The rate ratio for the main goal was 0.89 (95% confidence interval 0.73 to 1.09, p=0.28). That points to about 11% fewer events with eplontersen, but the confidence interval runs from roughly 27% fewer to 9% more, so chance can't be ruled out.

Cardiovascular deaths were numerically slightly higher with eplontersen (74 against 70), while other cardiovascular events were slightly lower (307 against 322). A broader measure that counted deaths from any cause plus cardiovascular events gave a rate ratio of 0.86 (95% confidence interval 0.71 to 1.04), also short of significance.

The drug did what it was designed to do biologically. TTR levels in the blood fell quickly and deeply, and stayed down throughout the trial. According to the presentation slides, eplontersen also preserved walking ability and quality of life compared with placebo.

Eplontersen was well tolerated, with no new safety concerns. Serious adverse events were similar in both groups.

The stabiliser question

Before the trial started, the researchers planned to look separately at people who were or weren't taking a stabiliser.

Among the 43% not taking a stabiliser at the start, fewer primary events occurred with eplontersen than with placebo. The ESC described the result as nominally significant, meaning it passed the usual statistical threshold on its own but can't be treated as a confirmed finding because the overall result was negative.

Among the 57% already on a stabiliser, eplontersen offered no added benefit.

"Baseline stabiliser use appeared to influence the primary results," Maurer said. "No additional benefit was observed in patients receiving background stabiliser therapy, while fewer primary endpoint events were observed with eplontersen in patients not receiving a stabiliser. These findings will inform clinical practice and the evaluation of TTR-lowering treatment strategies in ATTR-CM."

One explanation is that stabilisers already do much of the work. If the TTR unit is held together, there may be little left for a silencer to add, at least over three years. Another is that people on stabilisers were a different group, perhaps diagnosed earlier or treated more intensively. Subgroup results can also arise by chance, which is why they need confirming in a separate trial.

Why the result matters to patients

For people with ATTR-CM, the result is a disappointment. Many hoped that adding a silencer to a stabiliser would give a bigger effect than either alone. CARDIO-TTRansform doesn't support that approach, at least for eplontersen.

It also adds to an open debate. HELIOS-B, which tested vutrisiran, reported benefits on deaths and heart events, including in people taking tafamidis. CARDIO-TTRansform was larger, but recruited at a time when stabilisers were more widely used, which may have made any extra benefit harder to detect. Comparing the trials directly is difficult, because they differed in design, endpoints and patient groups.

The ESC concluded that an unmet need remains for treatments that improve the outlook for people with ATTR-CM.

The limits of the evidence

• Mostly older men. Fewer than one in ten participants were women, so the results say little about women with ATTR-CM.
• Background treatment. With more than half on a stabiliser, the trial was largely a test of adding eplontersen to existing therapy.
• Subgroup signal. The apparent benefit without a stabiliser is hypothesis-generating. It may influence how regulators and doctors view the drug, but it isn't proof.
• Fixed duration. The trial ran for 140 weeks. A slow-acting effect on amyloid might take longer to show.

What happens next

Eplontersen remains approved for hereditary ATTR polyneuropathy, and the trial raised no new safety concerns that would affect that use.

People with ATTR-CM should continue their current treatment and discuss any questions with their heart specialist. The trial was reviewed at the session by Professor Gianfranco Sinagra of Trieste, and more detailed analyses of the stabiliser subgroups will be needed before the signal can be judged.

This article explains published research and isn't medical advice. Talk to your own doctor or specialist team before changing any treatment.