Editor's note: According to results of the EXPLORER-HCM trial presented in a Hot Line session today at ESC Congress 2020, mavacamten improves heart function and symptoms in patients with obstructive hypertrophic cardiomyopathy(HCM). As the leader of this research, Dr. Iacopo Olivottohe gave an interview with International Circulation（China）to introduce the future research ideas of HCM.
Dr. Iacopo Olivotto
International Circulation: As an expert in the treatment of hypertrophic cardiomyopathy (HCM), what difficulties do you think the current HCM treatment is facing? Why is it possible for mavacamten to provide the ultimate solution to the HCM problem?
Dr Olivotto: We have been involved in the care of hypertrophic cardiomyopathy (HCM) patients for 25 years now, and we have followed many hundreds, even thousands, of patients. The frustration that we face every day in treating our patients is the fact that we have drugs available, and we can do a reasonable job with the drugs that we have, but they do not do a perfect job. We are using old drugs like the beta-blockers, calcium antagonists, amiodarone, and anticoagulants. So we have a number of drugs, and these are very useful. I am not suggesting what we are doing now is not useful. We can solve some of these problems for our patients. But these drugs are usually aimed at the very late consequences of disease, and they are not specific for the core physiological abnormality. There has never been a single drug registered specifically for HCM. There is no single drug with Class 1a evidence for HCM. So, I don’t think mavacamten demonstrates the ultimate response, but I think there will be progress and we will see other drugs developed for this condition and other genetic diseases. However, mavacamten is quite an exciting compound, because it is the first molecule that has been designed specifically for hypertrophic cardiomyopathy. It is an allosteric small-molecule, negative inotrope, which binds to myosin and reduces actin-myosin interactions. By doing so, it reduces hypercontractility, which is the basis of many manifestations of the disease, including obstruction. In the EXPLORER-HCM trial, we have used it successfully to reduce or even abolish obstruction in hypertrophic cardiomyopathy patients, as well in reducing circulating biomarkers such as NT-proBNP, which are long-term predictors of the outcomes of this disease. Also importantly, patients’ well-being, assessed by specifically developed scores improved very significantly. Patients actually felt better.
International Circulation: There are different definitions of HCM in European and American guidelines. Which one is your research focus on? Does this choice affect the evaluation of the efficacy of mavacamten ?
Dr Olivotto: So the definitions are not different. They are similar. Hypertrophy, not explained by abnormal loading conditions or overload of pressure and volume. This is characterized by a minimum hypertrophy of 15mm, or 13mm if the patient has a genotype or family history of the disease. This definition and the diagnostic criteria for HCM are really standard worldwide. What is different is the way that patients are managed and the way that arrhythmic risk stratification is performed. The American system is based on an individual evaluation of major risk factors, whereas the European system has proposed a score that combines several risk factors into a single scoring system that provides a percentage of risk over five years. Overall, the separate systems are not necessarily opposing or in competition. They can be used in conjunction, and to some extent are complimentary. The American system is more sensitive, and the European system is more specific. But both can be used and should be used, maybe in combination.
International Circulation: In your research or field of concern, are there any other new directions for HCM treatment?
Dr Olivotto: Firstly, mavacamten has proven successful in obstructive HCM, and has also shown promise in a pilot study in non-obstructive HCM. So I think mavacamten can be used on a wider scale if we gain enough information from new studies in larger populations. This will definitely be done. There is another drug being developed with a very similar concept. This is still being investigated in a phase II trial, and there is a little way to go before advancing to a phase III and possibly registration. And there definitely will be more drugs in the pipeline. We have personally worked on late sodium channel inhibitors, like ranolazine and eleclazine. The former showed limited efficacy, while the latter showed no success and the drug development was stopped. But I think this is a very promising area – the development of antiarrhythmics that are specific for individual genetic diseases. Mavacamten targets the mechanical effects of the disease. I think it would be nice to develop antiarrhythmics targeting specific channel abnormalities that occur as a direct consequence of the condition, or as a downstream effect. Gene therapy has been attempted in animal models, and there have been successful early experiences in patients with particular kinds of mutations. There has been a correction of a mutation in an embryo leading to a very promising application of this in the in vitro fertilization setting. However, gene therapy is unlikely to be a technique, at least in the short- to mid-term, to benefit the majority of HCM patients. The problem there is that the myocytes in the heart are terminally developed cells; they don’t duplicate, so you would have to target every single cell in the heart with gene therapy in order to be successful in achieving a cure. That will be a long time coming.
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