Heart pill eases symptoms in thickened hearts without a blockage

People with a thickened heart muscle but no blockage to blood flow have had no treatment aimed at the cause of their condition. A phase 3 trial presented at ESC Congress 2026 suggests that may be about to change.

In ACACIA-HCM, aficamten, a daily tablet that relaxes overactive heart muscle, improved symptoms and exercise capacity in adults with symptomatic nonobstructive hypertrophic cardiomyopathy, compared with placebo. Both of the trial's main goals were met. The gains were modest, and some patients needed dose cuts because their heart pumping weakened, but it is the first phase 3 success in this form of the disease.

Dr Ahmad Masri, director of the Hypertrophic Cardiomyopathy Center at Oregon Health & Science University in Portland, presented the results in the Hot Line 1 session in Munich on 28 August 2026, at 11:45 local time (11:45 in Madrid). They were published simultaneously in the New England Journal of Medicine.

What hypertrophic cardiomyopathy is

Hypertrophic cardiomyopathy (HCM) is the most common inherited heart condition. It affects around 1 in 500 people. The walls of the heart, particularly the main pumping chamber (the left ventricle), become abnormally thick. It is often caused by changes in genes for the proteins that make heart muscle contract.

At the centre of the problem is a protein called cardiac myosin. Myosin acts like a tiny motor, pulling on other proteins to make the muscle contract. In HCM, too many of these motors are active at once. The heart squeezes too hard and struggles to relax, and over time the muscle thickens and stiffens.

Doctors split HCM into two types:

• Obstructive HCM, where the thickened muscle partly blocks blood leaving the heart. This creates a pressure difference, or gradient, that can be measured on an ultrasound scan.
• Nonobstructive HCM, where there is no significant blockage. The heart is still thick and stiff, and people can still have breathlessness, chest pain, tiredness and palpitations.

Roughly a third of people with HCM have the nonobstructive form, according to commonly cited estimates. For them, treatment has been limited to medicines that ease symptoms, such as beta blockers, with no therapy shown to change the underlying problem.

A new class of medicine

Cardiac myosin inhibitors reduce the number of active myosin motors, calming the overactive muscle. Mavacamten was the first, and aficamten, developed by Cytokinetics, is the second. Both have shown benefits in obstructive HCM, where reducing contraction force also eases the blockage.

Whether the same approach helps without a blockage has been uncertain. There is no gradient to relieve, so any benefit would have to come from improving how the heart relaxes and fills. A trial of mavacamten in nonobstructive HCM, ODYSSEY-HCM, did not meet its main goals in 2025.

"Building on our experience in obstructive HCM, we conducted the ACACIA-HCM trial to investigate the effects of aficamten on symptom burden and exercise capacity in patients with non-obstructive HCM," Masri said.

The ACACIA-HCM trial

ACACIA-HCM (NCT06081894) was a double-blind phase 3 trial run at 182 sites internationally and funded by Cytokinetics. It enrolled 517 adults with symptomatic nonobstructive HCM. Their average age was 55, 54% were women, and their average left ventricular ejection fraction, a measure of how well the heart pumps, was 68%, which is normal to high.

Participants were randomly assigned to:

• Aficamten, starting at 5 mg a day and adjusted up to a maximum of 20 mg based on heart scans (258 people)
• Placebo (259 people)

Treatment lasted up to 72 weeks. The trial had two main goals, both measured at week 36:

• Symptoms and daily life, using the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS). It runs from 0 to 100, with higher scores meaning fewer symptoms and limitations.
• Exercise capacity, using peak oxygen uptake (peak VO2) on a cardiopulmonary exercise test. This measures the most oxygen the body can use during maximal exercise, in millilitres per kilogram of body weight per minute.

What the trial found

Both main goals were met.

On the questionnaire, scores rose by 11.4 points with aficamten and 8.4 points with placebo. The difference of 3.0 points (95% confidence interval 0.5 to 5.5) was statistically significant.

Exercise capacity improved by 0.64 ml/kg/min with aficamten and was virtually unchanged with placebo, a difference of 0.67 ml/kg/min (95% confidence interval 0.22 to 1.11).

According to the ESC, aficamten also significantly improved several secondary measures: heart failure symptom class (NYHA class), submaximal exercise performance, and NT-proBNP, a blood marker of strain on the heart. Cytokinetics said results were consistent across the prespecified subgroups studied.

Masri noted that improvements were seen "as early as 12 weeks and there was a pronounced return of symptoms after aficamten treatment was stopped." That pattern suggests the effect comes from the drug.

Side effects

Because myosin inhibitors reduce how hard the heart squeezes, they can push pumping strength too low. In ACACIA-HCM, ejection fraction fell below 50% in 27 people (10.5%) on aficamten, compared with 2 people (0.8%) on placebo. These falls were reversible and managed by adjusting the dose. This is why patients taking these drugs need regular heart scans.

Serious adverse events were reported in 52 people (20.2%) on aficamten and 38 (14.7%) on placebo.

How experts reacted

"Results from the ACACIA-HCM trial provide really positive news for patients with symptomatic non-obstructive HCM," Masri said. "For the first time, we have shown clinically meaningful improvements in symptoms and exercise capacity with a treatment that targets the cause of the disease."

Most clinicians welcomed the result as the first positive phase 3 trial in nonobstructive HCM, according to a tally of expert comments by Synapse. Some were more cautious. The questionnaire difference of 3 points falls below the 5-point change often used as a benchmark for a noticeable difference to patients. The placebo group also improved substantially, by 8.4 points, which shows how much expectations and closer care can influence symptom scores.

The limits of the evidence

• Symptom endpoints. Both main goals measured how people feel and how much they can exercise. The trial wasn't designed to show fewer deaths, heart failure admissions or dangerous rhythm problems.
• Modest effect. The differences were statistically significant, but small on both measures. Individual patients may respond more or less than the average.
• Short main assessment. Week 36 is short for a lifelong condition. Longer-term data will come from the FOREST-HCM extension study.
• Safety monitoring. The ejection fraction falls mean treatment requires regular scans and dose adjustments, adding to the burden of care.
• Who benefits most. It is not yet clear which types of nonobstructive HCM respond best.

What happens next

Cytokinetics plans to submit a supplemental new drug application to the US Food and Drug Administration in the fourth quarter of 2026, seeking approval of aficamten for adults with symptomatic nonobstructive HCM. Further analyses from the trial, including effects on heart structure and function, were presented later at the same congress.

For now, people with nonobstructive HCM should continue their current treatment and discuss with their cardiologist whether a myosin inhibitor might be an option in the future.

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