Hello. My name is Iacopo Olivotto. I'm a clinical cardiologist working in Florence. I'm privileged to be part of this symposium. I will be speaking about the therapeutic landscape of patients with hypertrophic cardiomyopathy, and these are my disclosures.

We now know very well that hypertrophic cardiomyopathy is not as rare as we thought. It is a complex disease, and is far more complex than just a thick heart. We know that obstruction is an important determinant of symptoms. We know that the metabolic, energetic, and electrophysiological consequences of the disease are far-reaching and important. We also know that treatment of these patients is complex. It is not just giving drugs, it's not just sending patients to operations or interventions, it is a chronic, slowly, progressive disease, with low event rates. We need to comprehensively treat patients and take into account everything from the quality of life, to treatment of complications, to professional lifestyle decisions, and much more.

When we talk about comprehensive management, this is really what we mean. Of course, in terms of actual treating complications and treating the disease, I've been in this business for over two decades, and for a long time, the best landscape has been those of the interventional, the surgical, and interventional cardiologist. Simply because they were fantastic options, they still are fantastic options, which includes surgical myectomy for obstructive disease, alcohol septal ablation, the defibrillator that has really changed the outlook of high-risk patients for prevention of arrhythmia complications and treatment of atrial fibrillation. Of course, when you move to the landscape of pharmacological interventions, this is what the landscape looked like for a long time. We do have some palm trees, a little oasis here and there, but that's mostly because we have used with good effect drugs that have been developed for other diseases, such as beta-blockers or Verapamil. There's had been some joy, but not too much with drugs like ranolazine or paraxylene, trying to modify some of the substrates of disease, and of course, disopyramide which we use as a negative inotrope for control of arrhythmias, and particularly for control of obstruction. As you see, however, not much, and particularly, none of these drugs have ever been developed thinking about the real mechanism of disease. They have just been used because they were available and did some good things to our patients. Made our patients feel better to some extent.

Of course, if we move to the actual mechanism of disease, HCM is a disease caused by mutations in sarcomere gene proteins, which are the actual machinery of the heart. Of course, there's nothing as sensitive as the sarcomere in heart pathophysiology. We do know now that one of the determinants, particularly in the model of HCM caused by these myosin heavy chain mutation, is the fact that the conformation of the myosin dimers is altered, so that mutations in the dimers, as you see here, favor the on or the activated form of the molecule, as opposed to the super relaxed or inactive form of the molecule which is prevalent in nature. This is essential because the sarcomere needs time to recover, it needs to be sustainable. We cannot possibly use all our myosin heads in contraction at any given time. That in fact, in normal sarcomeres, 40-50% of the myosin heads are estimated to be in a super relaxed state. Therefore, not involving contraction. When you have mutations, in particular regions of the myosin molecules, this leads to a natural doping of the heart. Hyperactivation of these molecules, which tend to be much more commonly in inactivated state, which leads to a hypercontractile, but also high energy-consuming state. Which is, to some extent, what is really the main, the original thing behind the disease, leading to a number of downstream complications to anything to with regard to energy propagation, to an electrophysiological remodeling of the cardiomyocytes. Small defects leading to huge complications. In the clinical arena, this translates to the progressive build-up of complications of ventricular dysfunction, heart failure-related complications, and arrhythmias.

Although, the actual risk of arrhythmic events is definitely not as high as we thought. We can see from these data from the shared registry that the sooner you have a clinical-evident disease, the more likely you are to have some complication during your lifetime because of the pathophysiology I was referring to. Of course, in some unfortunate patients, about 7% to 10% of the patients, the progression of disease become so severe as to dominate the clinical picture and lead to dysfunction and heart failure subtended by severe diffuse fibrosis. In fact, we can make this a case of too much of a good thing, too much contractility leading to adverse consequences, which is really the essence according to the most brilliant minds that have thought about HCM is the actual essence of the disease.

It was about time that we had a molecule that could actually counter this mechanism. This is exactly what Mavacamten is. Mavacamten is a first-in-class allosteric ionotropic negative myosin modulator which binds to the myosin head, reduces its affinity for actin, and therefore, tries to restore, to normalize the state of things with less has involving contraction in a given time. Really normalizing the core mechanism of disease in HCM, at least as far as we know on patients that have a secondary gene mutation-associated disease. Does Mavacamten work? We know it does work because there's been extensive experimental work particularly in animal models, transgenic, HCM animal models. In the mouse model, of course, in which we can have a lot of information, a lot of tissue available, and also prognosis because of the short lifespan of these animals, we know that the drug treatment with Mavacamten, so normalization of sarcomere status, is to reduce hypercontractility, improves diastolic function, stops the development or even sometimes reverses development of hypertrophy, and to some extent normalizes fibrosis and disarray. It is really a disease-modifying agent in the animal model. What about humans? Of course, it's much harder to study a drug like this in humans, but we do have a lot of information now and information is building up the studies we do. We know that in patients with obstructive disease, which has been the original target simply because obstructive disease is easier to study because symptoms are so correlated to obstruction and relieve LVOT gradient really translates into clinical improvement. In patients with obstructive HCM, we know that the drug is capable by its negative inotropic action to relieve the gradient, improve performance, improve quality of life, and to some extent, positive cardiac remodeling as well as improved the biomarker profile of these patients.

This is data from the EXPLORER-HCM trial which is the first and the largest phase three study performed in HCM so far with Mavacamten looking at obstructive symptomatic HCM patients. You can see here how, on the left, the gradient in patients who are treated with Mavacamten is very clearly very nicely reduced by Mavacamten as opposed to virtually no change in placebo. This is exercise-related gradient. On the right, how this effect is obtained with only a very small reduction in ejection fraction, only 4% drop in ejection fraction. In a safe and well-tolerated manner, very huge effect on the gradient. This is one patient from my center. You can see at baseline, the typical gradient, and you can see here after 30 weeks of treatment, the gradient on Valsalva has disappeared.

Quality of life increases very extensively. There was a nine-point improvement with KCCQ which is a massive improvement in patients simply because they're not obstructive anymore. Even more interestingly in terms of thinking ahead, and for long-term prognosis, the biomarkers, as I was referring to, NT-proBNP and troponin I, which are very heavily impacted in a beneficial way by the drug. In terms of cardiac function, we know that diastolic function improves in patients treated with Mavacamten. There are other evidence of positive remodeling from CMR; sub-studies of Explorer and other studies. What we were not expecting to see is this. This is an ECG from one patient with my center participating in EXPLORER. You can see the typical and huge evident ECG abnormalities, repolarization abnormalities typical of HCM. This is the same patient same heart rate at the end of the study. This is something we have not really seen, this kind of normalization of repolarization abnormalities with other drugs. Even though you may drop the gradient, you never see this happen with disopyramide for example. We don't really know what this is due to, but it's quite intriguing to think that some of the disease-modifying effect we have seen in animal model may actually translate in clinical practice into this sort of effect. We're definitely looking more into this because this is a consistent effect. If you use artificial intelligence algorithm to detect HCM, you can see that at the beginning of the trial with mavacamten, most of the patients are picked up by artificial intelligence. At the end of the study, the same patients are not diagnosed anymore by the same algorithm because their ECGs have improved so much.

We hope to show more and more with time, but this is only the tip of the iceberg in terms of what the drug can do for disease modification. This is the most recent trial, the VALOR-HCM trial, which aimed to understand whether patients who were candidates for surgery, so obstructive patients, candidates for surgery, surgical myomectomy, could actually benefit from mavacamten. You can see randomized with placebo. You can see that, in green, the patients that were candidates for surgery at the beginning of the study were basically, became non-eligible at the end of the study, and therefore dropped from the waiting list as opposed to very little effect into that respect in the placebo arm.

While we are waiting to know more about long-term effect of the drugs, we definitely know that in a shorter term, this is a very effective drug in controlling obstruction symptoms and even may postpone or delay or even eliminate, who knows, the need for surgery.

In conclusion, we are now at the beginning of a new era for treatment of hypertrophic cardiomyopathy. Simply because the first drug that has been designed specifically for the disease, has been developed successfully and is now entering clinical use in the US. It is already approved by the FDA. In Europe, we're still awaiting EMA approval. We think that the drug will initially be positioned in patients with symptomatic obstructive disease as a sort of intermediate step, will probably be used in patients who have failed to respond to the standard pharmacological options, and before moving on to surgery, and hopefully, will stop the need for these patients to go on into invasive, and sometimes potentially dangerous interventions. Of course, we hope that the era that has just begun with the advent of myosin modulators, there are other molecules along this pipeline that have been developed, will change the treatments landscape of HCM forever, bringing more and more opportunities to our patients, and hopefully, demonstrating that treating patients with this kind of approach not only improves symptoms in the short term, but really modifies the disease and is capable of interfering with the natural history of the disease. Thank you very much.

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