Ahmad Masri, MD, MS, is the director of the Hypertrophic Cardiomyopathy Center at Oregon Health and Science University. 

Ahmad Masri, MD, MS

Beta-blockers have served as initial treatment for symptomatic obstructive 

 (HCM) despite limited evidence of their efficacy.

The phase 3 MAPLE-HCM trial randomized 175 adults with symptomatic obstructive HCM to aficamten or metoprolol monotherapy, with results published in 

 At 24 weeks, peak oxygen uptake increased by 1.1 mL/kg/min with aficamten and declined by 1.2 mL/kg/min with metoprolol (difference, 2.3 mL/kg/min; 95% CI, 1.5-3.1; 

Patients receiving aficamten also showed greater improvements in New York Heart Association functional class, Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), left ventricular outflow tract gradient, and N-terminal pro-B-type natriuretic peptide level.

 Late-stage development in HCM now extends beyond cardiac myosin inhibition. Lexicon Pharmaceuticals completed enrollment in SONATA-HCM, a phase 3 trial of the dual SGLT1 and SGLT2 inhibitor sotagliflozin in nonobstructive and obstructive HCM, with topline results expected in the first quarter of 2027.

The trial exceeded its target of 500 patients across more than 130 sites in 20 countries, and its primary end point is change in KCCQ-CSS at week 26.

 Edgewise Therapeutics plans to start phase 3 development of EDG-7500, a cardiac sarcomere modulator designed to address impaired relaxation, in the fourth quarter of 2026.

 In the 12-week phase 2 CIRRUS-HCM trial, no patients receiving EDG-7500 had reductions in left ventricular ejection fraction to below 50%.

Ahmad Masri, MD, MS, director of the Hypertrophic Cardiomyopathy Center and Cardiac Amyloidosis Program at Oregon Health & Science University, is a coauthor of MAPLE-HCM and principal investigator of ACACIA-HCM. Masri sat down with HCPLive at the American Heart Association Scientific Sessions 2026 in Chicago to discuss the HCM agents to watch in 2027 and how MAPLE-HCM reshaped the evidence base.

Q&A: Sotagliflozin, EDG-7500, and the HCM pipeline for 2027

HCPLive: Looking ahead to 2027, which studies, trials, or new agents should the field keep an eye on?

 It's such an exciting time to think about this, because again, everybody is realizing that there's severe unmet need and HCM is actually a sizable population that you can work with. The sites, the PIs, and the clinicians are now very sophisticated in how they find the patients and how they select them for studies, so part of the work has already been done there, which is really setting up for success. In terms of ongoing trials, we have a few. You have 2 new phase 3 trials that should come next year. One is with a sarcomere modulator called EDG-7500 that has a different mechanism of action than the CMIs, so that's going to be in a phase 3 trial. We have a phase 3 trial of a third CMI in class. I don't really like lumping these drugs together. Mavacamten, aficamten, and the third one, BHB-1893 or HRS-1893, all bind to different sites. They have different implications, so I like to treat them as individual drugs, if possible. That's another phase 3 that is also coming to sites.

Outside of this, there are actually a few other things that are quite novel in our thinking. One of them is very close to the finish line, which is a combined SGLT1 and SGLT2 inhibitor called sotagliflozin. The study is SONATA-HCM, and it should be reporting out next year. Keep your eye on that, because it's a completely different mechanism from what we usually do in HCM.

We have a new antifibrotic, and it's not just that it's a new antifibrotic that makes it very exciting. It is actually the first-in-human approach to addressing what's called a long noncoding RNA. It's an RNA medicine by HAYA Therapeutics called HTX-001 that is meant to reduce a certain long noncoding RNA called WISPER. If you downregulate it, you have less fibrosis. So it's hitting 2 things at the same time. One is characterizing this biology for all of medicine when you're addressing a long noncoding RNA, and the other is doing something in HCM that could extend to other disease spaces and hasn't been done, which is: How can you address the big problem of progression of fibrosis in diseases of the heart? We don't have solutions for that at this stage, so that's another mechanism we're very excited about.

There are a lot of things happening in the early clinical space. We also have a different mechanism of action on energy modulation. Ninerafaxstat is a drug that shifts how the heart uses energy, maybe allowing it to be smarter in how it works with a disease condition like HCM. We have a study called FORTITUDE-HCM that is in phase 2b and ongoing as well. So, lots of things happening.

HCPLive: How does your optimism about where the cardiomyopathy field is going now compare to where is was 5 years ago?

 In terms of optimism, we finally are at a stage where everyone understands the unmet need and understands the why. If you look back 6 or 7 years ago, there was actually hesitancy and suspicion: Why are you developing therapies in HCM? It's a solved problem. [UNCLEAR — please review: "and now you're inching it to"] I think we've already done that, which is convincing the majority that you need to step away from the traditional thinking and really become more evidence-based, and think about it like how we think in heart failure with reduced ejection fraction, for example. Show me the data and show me the evidence. I think MAPLE-HCM delivered big on this, where it challenged decades of beta blocker use in hypertrophic cardiomyopathy. It's a courageous trial. You could argue, why would you risk running such a trial? But it delivered for HCM what none of the other trials delivered, not because of efficacy, but because of showing that metoprolol, the primary drug used in all of the United States (outside, they use other beta blockers), is actually harmful to these patients. This is what I see changing: Finally, it is sticking that there is a problem here and that we have to move away from expert opinions and expert consensus. We have to actually think about the data and the evidence. Where do we have areas where we don't have data and evidence that we can actually work on and solve as well? I think there is no going back. The last 5 years have been amazing, and I think it's the start of something really great in hypertrophic cardiomyopathy and beyond, because this space now allowed us to think about cardiomyopathies as individual diseases, not as a group that is a subset of heart failure, which I think is really important.

Editor's Note: This transcript has been edited for grammar and clarity using artificial intelligence tools.

Garcia-Pavia P, Maron MS, Masri A, et al. Aficamten or metoprolol monotherapy for obstructive hypertrophic cardiomyopathy. 

Lexicon Pharmaceuticals. Lexicon Pharmaceuticals completes enrollment of pivotal phase 3 SONATA-HCM study of sotagliflozin in symptomatic non-obstructive and obstructive hypertrophic cardiomyopathy (HCM). Published July 27, 2026. Accessed November 7, 2026. 

https://www.biospace.com/press-releases/lexicon-pharmaceuticals-completes-enrollment-of-pivotal-phase-3-sonata-hcm-study-of-sotagliflozin-in-symptomatic-non-obstructive-and-obstructive-hypertrophic-cardiomyopathy-hcm

Edgewise Therapeutics. Edgewise Therapeutics announces positive top-line data from 12-week phase 2 CIRRUS-HCM trial with EDG-7500 in obstructive and nonobstructive hypertrophic cardiomyopathy (HCM). Published June 16, 2026. Accessed November 7, 2026. 

https://www.prnewswire.com/news-releases/edgewise-therapeutics-announces-positive-top-line-data-from-12-week-phase-2-cirrus-hcm-trial-with-edg-7500-in-obstructive-and-nonobstructive-hypertrophic-cardiomyopathy-hcm-302801108.html

Articles

Ahmad Masri, MD, MS, highlights HCM agents to watch in 2027, including sotagliflozin and EDG-7500, and how MAPLE-HCM challenged beta-blocker use.

The HCM pipeline and Moving Past Beta-Blockers, with Ahmad Masri, MD, MS

 (HCM) has moved steadily away from invasive procedures and toward targeted medical therapy, led by the cardiac myosin inhibitor class.

Patients with nonobstructive disease have long faced the widest gap, with no proven medical therapy and little randomized evidence behind the beta-blockers and calcium channel blockers often used in practice.

Journal of the American College of Cardiology

 found bisoprolol reduced exercise capacity in this population, while verapamil had no significant effect.

The phase 3 ACACIA-HCM trial, published in 

, became the first positive trial of a targeted therapy in nonobstructive HCM.

 Aficamten improved both patient-reported health status and exercise capacity vs placebo at 36 weeks.

Cytokinetics announced plans to submit a supplemental New Drug Application for this indication in the fourth quarter of 2026.

Beyond new drugs, the field has also leaned more heavily on imaging and circulating biomarkers to confirm the diagnosis and track patients over time. Ahmad Masri, MD, MS, director of the Hypertrophic Cardiomyopathy Center and Cardiac Amyloidosis Program at Oregon Health & Science University, served as principal investigator of ACACIA-HCM. 

In the following interview, Masri spoke with 

 at the American Heart Association Scientific Sessions 2026 in Chicago about the evolution of HCM care, the nonobstructive treatment gap, and imaging.

Q&A: Nonobstructive HCM Treatment Gap and Imaging in Follow-Up

HCPLive: What has been the biggest shift in how hypertrophic cardiomyopathy is treated over the past 5 years?

 I think the first thing is the excitement we have in this space. People recognize that this is a common problem with significant unmet need, and seeing that you have medications that can actually improve how patients feel and function has been really transformative. I think the biggest shift is that you're transforming a disease with very few treatments, where the definitive treatments used to be more invasive, into one with more medical approaches. You see this excitement from the patients, from the physicians, from the clinicians, and so I think this has been really transformational, because it also showed everybody the potential of focusing on specific forms of heart disease. It always used to be that you'd hear people say, "I'm going to do HFpEF and HFrEF and this and that." HCM, and to a similar degree amyloid, for example, have shown that, no, you can ask more specific questions, and as long as you have the science, as long as you have a good drug to try, you actually can have really good answers as well.

HCPLive: Where do patients with nonobstructive HCM stand today relative to those with obstructive HCM in terms of available treatments?

 It's very frustrating, because everything is stacked against these patients. One, their identification is much harder than in obstructive HCM. Two, a historical lack of therapies, even invasive therapies. They are usually chronically limited, but because they're not dying with contemporary management of sudden cardiac death, people usually dismiss some of their chronic limitations and exercise limitations. And finally, there are no evidence-based therapies available that are known to improve how these patients can live their lives and their quality of life. Even the beta blockers and calcium channel blockers that are recommended by the guidelines actually have no role in these patients. If anything, there was a small triple-crossover study from Europe showing that the best thing you can do for your nonobstructive patient, compared with beta blockers and calcium channel blockers, is do nothing, because placebo performed the best, verapamil was slightly worse, and bisoprolol was really worse than placebo on [how they] feel and function. That's exactly where the frustration comes from. You're seeing patients day in, day out in the clinic, and you actually start by saying, "I am so sorry. You don't have obstruction on your exercise test or any of the echoes we've done for you, which limits your treatment options. So you either consider doing nothing, or you consider addressing just the risk factors that you have, or doing a clinical trial." That's why, with ACACIA-HCM, we were very excited to finally have a medical therapy that can get us to a point where, potentially with an approval from the regulators, this can change.

HCPLive: How has imaging changed the way you diagnose and follow patients with HCM?

 The truth of the matter is that HCM is an image-based diagnosis. It is a clinical phenotype, but the clinical phenotype then has to be accompanied by a good-quality image to be able to make that diagnosis. You cannot run an HCM program, you cannot serve your patients well, without having a well-characterized, sophisticated set of images. Usually, it's a combination of echo and MRI, if possible. During follow-up, you also need some of those modalities to allow you to understand in a precise way what is happening with your patients. There's a lot of conversation about what you need to learn about your patients with HCM when you follow them over time, and at the individual patient level, we're afforded the tools, between circulating biomarkers and imaging tools on echo, that allow us to be precise and to understand what's happening with our patients. So in HCM, most of the people I know in this space are big fans of imaging and circulating biomarkers to allow us to study the disease. This obviously doesn't translate to all other diseases. Think about transthyretin amyloidosis. You don't need echocardiography beyond the first run unless something happens to the patient. That's very different in HCM.

Cytokinetics. Cytokinetics announces positive results from ACACIA-HCM presented in Hot Line session at the European Society of Cardiology (ESC) Congress 2026 and published in The New England Journal of Medicine. Published August 28, 2026. Accessed November 7, 2026. 

https://ir.cytokinetics.com/press-releases/press-release-details/2026/Cytokinetics-Announces-Positive-Results-from-ACACIA-HCM-Presented-in-Hot-Line-Session-at-the-European-Society-of-Cardiology-ESC-Congress-2026-and-Published-in-The-New-England-Journal-of-Medicine/default.aspx

Masri A, Maron MS, Bhatia A, et al. Aficamten for symptomatic nonobstructive hypertrophic cardiomyopathy. 

Bjerregaard L, Dybro AM, Saaby L, et al. Beta-blocker (bisoprolol) vs calcium-channel blocker (verapamil) in nonobstructive hypertrophic cardiomyopathy: a randomized triple-crossover physiologic trial. 

Ahmad Masri, MD, MS, discusses the move toward medical therapy in HCM, the nonobstructive treatment gap, and imaging's role in diagnosis and follow-up.

Understanding the Treatment Gap in Nonobstructive HCM, with Ahmad Masri, MD, MS

non-obstructive hypertrophic cardiomyopathy (nHCM

) who were treated with aficamten saw significant improvements in symptom burden and exercise capacity, according to full results from ACACIA-HCM.

Aficamten Safe, Efficacious in nHCM, Improves Symptoms and Exercise Capacity

European Society of Cardiology (ESC) Congress 2026

 in Munich, Germany, by Ahmad Masri, MD, MS, cardiomyopathy section head at Oregon Health & Science University, director of the OHSU hypertrophic cardiomyopathy center and the OHSU Knight Cardiovascular Institute Cardiac Amyloidosis Program, and co-author of the study.

“Non-obstructive HCM represents a substantial proportion of patients with HCM who arguably have the highest unmet need right now, since they don’t have any therapies available or approved that can actually improve their symptoms and exercise capacity,” Masri told 

ACACIA-HCM was a double-blind phase 3 trial, conducted across 182 sites internationally. Patients were eligible for inclusion if they were between 18 and 85 years of age with a body mass index <40 kg/m2. Additionally, patients were required to have a respiratory exchange ratio ≥1 at screening by cardiopulmonary exercise testing and predicted peak oxygen uptake ≤90% for age and sex. Patients with significant valvular heart disease, infiltrative, genetic, or storage disorder causing cardiac hypertrophy, or unrevascularized coronary artery stenosis of ≥70%, among other criteria, were excluded.

A total of 517 patients were enrolled in the trial and randomly assigned in a 1:1 ratio to aficamten or placebo. Treatment continued for ≤72 weeks. Aficamten doses were adjusted based on LV ejection fraction (LVEF). The trial featured a dual primary endpoint of change in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) and in maximal exercise performance (pVO2) from baseline to week 36.

At 36 weeks, Masri and colleagues found that KCCQ-CSS had improved by 11.4 in the aficamten group compared to 8.4 in the placebo group (

 = .02). These benefits were noted as early as 12 weeks, according to the team. pVO2 also improved by 0.64 mL/kg/min in the aficamten group while remaining almost fully unchanged in the placebo group (-.03 mL/kg/min) (

Secondary endpoints, such as New York Heart Association functional class, submaximal exercise performance, and NT-proBNP, also saw improvements with aficamten treatment. The trial did display an increased incidence of patients with LVEF <50% with aficamten (10%) compared to placebo (1%), but this was managed through dose adjustment and no patients discontinued treatment.

Ultimately, Masri and colleagues concluded the definitive improvements provided by aficamten in this population, highlighting its clear efficacy in reducing symptoms for nHCM. In the interview, Masri expressed anticipation of results from the trial’s long-term extension, FOREST-HCM, which includes >80% of the patients from ACACIA-HCM following trial completion.

“What we are looking forward to is the long-term extension, FOREST-HCM, which will provide more data on the longer-term exposure to aficamten and what the results could look like for those patients,” Masri said. “We will also at some point report results from the echocardiographic outcomes as well as the cardiac MRI substudy related to that change in structure and function. So, stay tuned.”

Editors’ Note: Masri reports disclosures with Pfizer, Attralus, Lexicon, Ionis, Cytokinetics, BioMarin, and others.

Masri A. ACACIA-HCM: Aficamten for symptomatic nonobstructive hypertrophic cardiomyopathy. Presented at the European Society of Cardiology Congress 2026, Munich, Germany. August 28-31, 2026.

Cytokinetics. A Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy (nHCM) (ACACIA-HCM). ClinicalTrials.gov Identifier: NCT06081894. Updated August 5, 2026. Accessed August 28, 2026. 

https://clinicaltrials.gov/study/NCT06081894

Videos

Ahmad Masri, MD, MS, discusses his presentation of the full results of the ACACIA-HCM trial at the ESC Congress 2026.

ACACIA-HCM: Aficamten Beats Placebo in Non-Obstructive Hypertrophic Cardiomyopathy

Aficamten has outperformed placebo among patients with 

symptomatic non-obstructive hypertrophic cardiomyopathy (nHCM)

, according to topline data from ACACIA-HCM.

These data were announced by parent company Cytokinetics on May 5, 2026, highlighting improvements in both Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) and maximal exercise performance (pVO2). These results highlight aficamten’s potential as a treatment for the underlying hypercontractility associated with nHCM.

“Traditionally, we have placed more weight on peak oxygen consumption – it is a very hard endpoint to move,” Ahmad Masri, MD, cardiomyopathy section head at Oregon Health & Science University, director of the OHSU hypertrophic cardiomyopathy center and OHSU Knight Cardiovascular Institute Cardiac Amyloidosis Program, and co-author of the study, told 

 in an exclusive interview. “We’ve shown that the minimal change in peak VO2 that patients perceive as clinically significant is 0.5. Most of the heart failure therapies we use don’t even hit on pVO2, even when they improve mortality and heart failure hospitalizations.”

ACACIA-HCM is a multicenter, randomized, double-blind phase 3 trial comparing aficamten to placebo in adults with symptomatic nHCM. The trial itself was conducted across 180 locations worldwide and included patients with a body mass index (BMI) <40 kg/m2 who had been diagnosed with nHCM and had a screening echocardiogram with end-diastolic left ventricular wall thickness ≥15 mm in ≥1 myocardial segment. Additionally, patients were required to have NYHA class II or III, a respiratory exchange rate of ≥1 at screening, and a KCCQ-CSS score of ≤85, among other criteria.

Patients were excluded from ACACIA-HCM if they presented with significant valvular heart disease, known or suspected infiltrative, genetic, or storage disorders causing cardiac hypertrophy, or a history of LV systolic dysfunction, syncope, symptomatic ventricular arrhythmia, resistant hypertension, or sustained ventricular tachyarrhythmia with exercise, among other criteria.

The study consisted of 2 primary endpoints – change in KCCQ-CSS and change in pVO2 from baseline to week 36. Secondary endpoints included the proportion of patients with ≥1 class improvement in NYHA functional class and changes in the composite z-score of 2 cardiopulmonary exercise testing parameters of sub-maximal exercise performance, NT-proBNP, and left atrial volume index.

A total of 516 patients were enrolled in the trial and randomly assigned in a 1:1 ratio to either aficamten or placebo. Each patient was administered ≤4 escalating doses of aficamten or placebo based on echocardiographic guidance – those in the treatment arm began with 5 mg daily. Echocardiograms were performed at weeks 2, 4, and 6 to determine the safety of up-titrating to doses of 10, 15, or 20 mg. Escalation only occurred in the presence of LVEF ≥60%.

By week 36, patients in the aficamten arm saw improvements in KCCQ-CSS of 11.4 points (95% CI, 9.6 to 13.2) and of 0.64 mL/kg/min in pVO2 (95% CI, 0.32 to 0.95), compared to 8.4 points (95% CI, 6.6 to 10.2) and -0.03 mL/kg/min (95% CI, 0.22 to 1.1), respectively, in the placebo arm (

 = .021 and .003, respectively). The improvement in KCCQ was robust and consistent throughout treatment; however, following washout, it decreased among the aficamten arm to match placebo. pVO2 remained unchanged for patients on placebo despite increasing for those on aficamten, consistent with previous research.

Investigators also reported statistically significant improvements in NYHA functional class, the composite z-score of ventilatory efficiency and pVO2, and NT-proBNP. No new safety signals were identified, and only 2 participants receiving aficamten experienced serious adverse events of heart failure associated with LVEF <50%.

“What we are looking at here is symptom improvement as a continuous variable. You’re looking at the mean average population change,” Masri said. “We all know that there are some patients who might report feeling better, some who report feeling worse, and so you will have to understand, who are the patients who felt better? What is the categorical change of having 5 or more points of improvement in KCCQ? That’s where we don’t have the data yet, and I think that data will help us understand the symptom perspective.”

Editors’ Note: Masri reports disclosures with Pfizer, Attralus, Eidos, Ionis, Cytokinetics, BioMarin, and others.

Cytokinetics. Cytokinetics Announces Positive Topline Results from ACACIA-HCM, the Pivotal Phase 3 Clinical Trial of Aficamten in Patients with Non-Obstructive Hypertrophic Cardiomyopathy. May 5, 2026. Accessed May 8, 2026. 

https://ir.cytokinetics.com/press-releases/press-release-details/2026/Cytokinetics-Announces-Positive-Topline-Results-from-ACACIA-HCM-the-Pivotal-Phase-3-Clinical-Trial-of-Aficamten-in-Patients-with-Non-Obstructive-Hypertrophic-Cardiomyopathy/default.aspx

Cytokinetics. Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic nHCM (ACACIA-HCM). ClinicalTrials.gov Identifier: NCT06081894. Updated February 2, 2026. Accessed May 8, 2026. 

Ahmad Masri, MD, from OHSU, discusses the positive topline results from this phase 3 trial, highlighting a new path forward for nHCM.