‘Patients feel better’: New hope for obstructive hypertrophic cardiomyopathy
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Hypertrophic cardiomyopathy is the most common monogenic CV disorder, yet perhaps the most frequently misunderstood, and often goes undiagnosed in clinical practice.
Patients with hypertrophic cardiomyopathy (HCM) have a wide spectrum of symptom presentation. Many people are asymptomatic; others experience severe HF, syncope and risk for sudden cardiac death due to ventricular arrythmia. About two-thirds of patients with HCM have the obstructive phenotype, in which there is left ventricular outflow tract (LVOT) obstruction. About one-third have nonobstructive HCM, characterized by LV hypertrophy that does not cause outflow tract obstruction. For those with obstructive HCM, treatment is aimed predominantly at reducing the LV outflow tract obstruction to reduce what can be debilitating symptoms and perhaps modify the stimulus for hypertrophy.
“Patients can experience shortness of breath, dizziness, lightheadedness, pre-syncope, sudden cardiac death,” Milind Y. Desai, MD, MBA, director of the Hypertrophic Cardiomyopathy Center and director of clinical operations for the Cleveland Clinic Heart, Vascular and Thoracic Institute and professor of medicine at Cleveland Clinic Lerner College of Medicine, told Cardiology Today. “In patients with worsening disease, it is congestive HF. Another issue is many patients get put on restrictions because of risk for sudden cardiac death. So, they get deconditioned. They become depressed. They get deemed anxious or nervous. All these things continue to add to their symptoms, along with a poor quality of life.”
Until recently, none of the available medications for obstructive HCM worked predictably well; there were no disease-specific treatments available short of invasive surgery, according to Michelle M. Kittleson, MD, PhD, director of postgraduate medical education in heart failure and transplantation and professor of medicine at the Smidt Heart Institute at Cedars-Sinai.
“We know this overexuberant contraction of the left ventricle is the problem,” Kittleson told Cardiology Today. “The two currently used blunt instruments up until now have been, relaxing the muscle — with medical therapies like beta-blockers, calcium channel blockers or disopyramide — or making the muscle smaller through surgical reduction or catheter-based approaches.”
Patients now have a new therapeutic option. In April, the FDA approved mavacamten (Camzyos, Bristol Myers Squibb) for the treatment of symptomatic obstructive HCM. It is the first and only FDA-approved allosteric and reversible inhibitor selective for cardiac myosin that targets the underlying pathophysiology of obstructive HCM.
“This is an effort to provide an additional therapy to help improve the symptom burden and improve quality of life, not necessarily mortality,” Martin S. Maron, MD, director of the Hypertrophic Cardiomyopathy Center and Research Institute at Lahey Medical Center in Burlington, Massachusetts, told Cardiology Today. “Mavacamten, through a unique mechanism of action, can lower the pressure in the heart by decreasing the pressure gradient, the obstruction. By lowering the heart pressures, patients feel better. In addition to the other currently available therapies for HCM, mavacamten provides another opportunity to improve quality of life in patients with obstructive HCM.”
An unmet clinical need
Before the FDA approval of mavacamten, available drug treatments for obstructive HCM included beta-blockers, calcium channel blockers or, in advanced cases, addition of disopyramide. Yet, none of these drugs has ever been prospectively tested in randomized controlled trials, Desai said.
“In 2021, there was a small study of beta-blockers in less than 30 patients, which showed it improved the pressure gradient but not functional capacity in HCM,” Desai said. “Before that, the only other prospective randomized trial was conducted almost 50 years ago. Every other set of data is retrospective and observational.”
Medications have historically been used to reduce gradients, yet they come with adverse effects. Beta-blockers can be associated with fatigue and sexual dysfunction; disopyramide can be associated with dry mouth, urinary retention and long QT syndrome.
“What ends up happening is the treatment becomes worse than the disease,” Desai said. “In that situation, data show that surgical myectomy or, in select cases, alcohol septal ablation, would be a very good alternative to relieve outflow tract obstruction in obstructive HCM cases.”
Myectomy has been shown to be highly effective; however, despite guideline recommendations, not enough centers can provide a high-volume, high-quality procedure.
“There is clearly an unmet need for a precision drug developed specifically to treat the sarcomere, prospectively tested in a multicenter format in multiple trials and shown to improve not only biomarkers and quality of life, but also reduce the need for an invasive procedure,” Desai said.
Targeting the sarcomere
As a selective allosteric inhibitor of cardiac myosin ATPase, mavacamten reduces actin-myosin cross-bridge formation and contractility, improving myocardial energetics.
“Beta-blockers and calcium channel blockers do not target the sarcomere. They work in other pathways, particularly oftentimes modulating intercellular calcium level, reducing contractility to a mild degree,” Andrew Wang, MD, professor of medicine and vice chief for clinical services at Duke University School of Medicine, told Cardiology Today. “Cardiac myosin inhibitors specifically target the interaction between myosin and actin in the sarcomere. They help reduce the number of activated myosin heads seen in HCM and thereby lead to reduction in hypercontractility.”
Previous phase 2 trials demonstrated improvements in HCM-related surrogate endpoints. In the 12-week, open-label PIONEER-HCM trial, mavacamten significantly reduced the postexercise LVOT gradient, improved exercise capacity, reduced brain natriuretic peptide level and was well tolerated. These data supported further evaluation of mavacamten on more clinically relevant outcomes in a larger, phase 3 study.
The landmark EXPLORER-HCM study, published in The Lancet in 2021, showed mavacamten improved functional capacity and symptom burden in patients with relatively advanced obstructive HCM at 30 weeks. Compared with placebo, mavacamten treatment led to improvement in all study endpoints: a 1.5 mL/kg/min or greater increase in peak oxygen consumption (VO2) and at least one NYHA class reduction, or a 3 mL/kg/min or greater peak VO2 increase without worsening of NYHA class. The primary endpoint was met in 36.6% of patients assigned mavacamten vs. 17.2% assigned placebo (difference, 19.4 percentage points; 95% CI, 8.7-30.1; P = .0005).
“[HCM treatment] has always been a bit unsatisfying,” Kittleson said. “You can put a man on the moon but you can’t fix these sarcomeric proteins? With mavacamten, you can relax the muscle on a molecular level. It is a targeted drug. You are not just putting a Band-Aid on what you see grossly looking at the heart. You are going down to a molecular level to figure out the problem and address it.”
Additionally, in the VALOR-HCM trial, presented at the American College of Cardiology Scientific Session in April, mavacamten reduced the need for septal reduction therapy and also improved symptoms, biomarker levels and quality of life metrics compared with placebo in patients with obstructive HCM. The primary endpoint of decision to proceed with septal reduction therapy or guideline-based eligibility for septal reduction therapy at 16 weeks occurred in 17.9% of the mavacamten group compared with 76.8% of the placebo group (treatment difference, 58.93 percentage points; 95% CI, 43.99-73.87; P < .0001). The primary endpoint was driven by guideline-based eligibility for septal reduction therapy, as only two patients from each group decided to have septal reduction therapy at the end of the study.
“VALOR-HCM took the most severe patients who were referred to get septal reduction therapy — patients who say, ‘I feel so bad that you can cut me open,’” Kittleson said. “When they put them on mavacamten for 16 weeks, 79% said they did not want surgery anymore. To me, that is where the excitement is.”
‘Challenging but necessary’ prescribing logistics
In EXPLORER-HCM, the mean decrease in LV ejection fraction was 4%, and 7% of treated participants experienced a transient reduction in LVEF to less than 50%. None of those reductions were associated with serious adverse events but, per protocol, all required temporary drug discontinuation for 4 weeks. At 4 weeks, all participants who discontinued mavacamten experienced recovery of their EF to greater than 50%.
Because of the observed risk, the drug was approved through the restricted Risk Evaluation and Mitigation Strategy (REMS) program of the FDA and includes a boxed warning about the potential risk for HF in treated patients. Clinicians prescribing the drug and patients taking it must register under the program; patients treated with mavacamten, which will only be dispensed through specialty pharmacies, must also be regularly monitored with echocardiograms to assess EF and LVOT obstruction.
“When I talk to my colleagues who deal with HCM a lot, we have all described [the REMS program] as challenging,” Maron said. “It is a challenging strategy put forward — but necessary. One, no one can just prescribe it; you must be certified. Two, when you do prescribe it to a patient with obstructive HCM, several echos are required over a short period of time, and then less frequently, but indefinitely, after that. For a patient, that presents several challenges. One is being able to get in and see your provider and take half a day to get an echocardiogram. Whether that will dampen some patient enthusiasm, we do not know yet, but that certainly could be a reality.”
Interpreting the required echocardiograms will provide its own challenges, Maron said.
“Because the drug dosing is predicated on the findings of the echo, there is concern that could represent an area of complexity,” Maron said. “This is the first time that we have had a cardiac drug approved by the FDA in which the drug administration and dose changes are predicated on the results of an imaging test. Not a lab test, but an imaging test.”
Desai said the echocardiogram requirements were part of a “brave new world” in prescribing a drug like mavacamten.
“We are not monitoring blood levels. We are doing what we do clinically,” Desai said. “How do I handle a patient with HCM? I see them, I listen to the heart and lungs, listen to their story and look at the imaging, specifically the echo. Then, we make clinical decisions. Now, this is not just an understanding of what I am going to do. It is an expectation.”
Kittleson, who said she was delighted by the “hoops” clinicians must navigate to prescribe mavacamten, said the REMS program for the drug will help ensure safety.
“Will that mean fewer patients receive the drug initially?” Kittleson said. “Perhaps, but that is OK. What I worry about most is not that not enough people will get it, but rather too many people will get it. Until we have more clinical experience in a real-world population, it is fine that the uptake may be slow and tentative, and limited to clinicians who are most comfortable with management of HCM.”
More to learn
Research shows cardiac myosin inhibitors reduce contractility and outflow tract obstructions, improving symptoms and quality of life.
What remains unknown, according to experts, is the effect of the drug class on other HCM clinical complications, particularly atrial fibrillation and ventricular arrythmias.
“That is an important question for those who are prone to both,” Wang said. “The longer-term safety and efficacy of these drugs are also unknown. Mavacamten was studied for 30 weeks. What will happen to the person after taking this drug for years? There is a long-term extension study for mavacamten that is ongoing now that shows a durable benefit, but again, that is a small group of patients.”
“In echocardiography and cardiac MRI analyses of the EXPLORER-HCM cohort, there has been some evidence that [treatment] leads to mild degree of LV hypertrophy regression, as well as smaller left atrial volume,” Wang said.
Another open question is whether myosin inhibitors will be beneficial for patients with nonobstructive HCM, who do not have as many options. A phase 3 study of mavacamten in adults with symptomatic, nonobstructive HCM could reveal that answer soon, Kittleson said.
“Nonobstructive HCM is in many ways is more challenging, because patients still have symptoms like shortness of breath, but there is no outflow tract gradient to target with therapies,” Kittleson said.
A second cardiac myosin inhibitor, aficamten (Cytokinetics), is in development, and enrollment has begun for SEQUOIA-HCM, a phase 3 study of its safety and effectiveness in patients with symptomatic obstructive HCM. The FDA granted it a breakthrough therapy designation in December.
Desai said that, beyond exciting new treatments, it is important to make sure every person with HCM is properly diagnosed and has access to safe and effective options. There is marked heterogeneity, for example, in septal myectomy-related in-hospital mortality in the United States, which reaches 16% in low-volume centers.
“The excitement of new drugs aside, the bigger calling is to expand the tent of the number of people appropriately diagnosed with HCM and offerings available to all of these people,” Desai said. “Let’s up our game in terms of accurate diagnoses of obstructive vs. nonobstructive. Let’s up our game in terms of outcomes with invasive therapies. We simply cannot have a program with half a percent mortality and a program with 16% mortality, both in North America, and pretend everything is OK. That is not acceptable.
“Science is not going to stop here,” Desai said. “I am sure we will have additional molecules. But HCM is inherently a genetic disease. One thing I am excited about is the potential of gene therapy. How is that going to impact these patients? There are things in the pipeline that make for an exciting future.”
- For more information:
- Milind Y. Desai, MD, MBA, can be reached at desaim2@ccf.org; Twitter: @desaimilindy.
- Michelle M. Kittleson, MD, PhD, can be reached at michelle.kittleson@cshs.org; Twitter: @mkittlesonmd.
- Martin S. Maron, MD, can be reached at martin.maron@lahey.org; Twitter: @martinmaronmd.
- Andrew Wang, MD, can be reached at a.wang@duke.edu; Twitter: @awangdukeu.
- References:
- Desai MY, et al. Joint American College of Cardiology/Journal of the American College of Cardiology Late-Breaking Clinical Trials. Presented at: American College of Cardiology Scientific Session; April 2-4, 2022; Washington, D.C. (hybrid meeting).
- Olivotto I, et al. Lancet. 2020;doi:10.1016/S0140-6736(20)31792-x.
- Maron BJ. N Engl J Med. 2018;doi:10.1056/NEJMra1710575.
- Saberi S, et al. Circulation. 2020;doi:10.1161/CIRCULATIONAHA.120.052359.
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