New drugs. Interview with Iacopo Olivotto, Full Professor of Cardiology, University of Florence
di Francesca Conti
Mavacamten and Aficamten are the two new drugs for the treatment of hypertrophic cardiomyopathy. Mavacamten has entered the “compassionate” use phase. This means that the drug is already available and can be supplied by the manufacturer for patients with hypertrophic obstructive cardiomyopathy, upon request by expert cardiologists. Aficamten is a little further behind in the experimentation process.
At what stage are the clinical studies with the drugs Mavacamten and Aficamten?
Prof. Iacopo Olivotto
Clinical trials with Mavacamten are completed regarding the registration of the drug for obstructive cardiomyopathies. In many countries the drug is already available and reimbursable for patients with obstruction, in Italy it will probably still take a year to be reimbursed. In the meantime we can proceed with compassionate use for patients with precise indications. Instead, for non-obstructive forms there is an ongoing study called Odyssey which will end in a couple of years. We have now finished enrolling patients, and as soon as the last patient has finished treatment we will have to wait a couple of years to see the results obtained. As regards Aficamten, the study on the obstructive forms is finished and will be presented in the spring, for the non-obstructive the study is underway and enrollment has yet to be completed.
Can we explain what is meant by compassionate use? How many patients are or will be involved?
Compassionate use is no longer experimentation, it means that the drug is already available and the manufacturer is asked to supply it to patients with an indication while waiting for the drug to become reimbursable.
At the moment there are no patients in Italy because this phase started in January, we are sending the sheets with the anonymized data of the patients we deem suitable to the manufacturing company. The manufacturer must give his approval. At that point the drug will be sent to us for each of the various patients. It is a big commitment, requires many controls and a lot of bureaucracy. We expect over a hundred patients at an Italian level, but in Italy there is no cap on the entry of patients for compassionate use. It is important at this stage that the drug is used by expert hands because a new drug if given to the wrong patient could create problems, it would be a shame to risk ruining the reputation of a drug that actually has great potential.
There will be an Italian registry that will collect patient data and which will be coordinated by the University of Florence and a board that includes around ten Italian centers where pathology experts work. There are already around twenty centers that have asked to participate, and perhaps we could reach around forty.
What is the difference in action of the two drugs? Will there be more new ones in the future?
The most important difference is that Mavacamten has a very long half-life, about nine days. This means that to have a full effect you have to wait at least a month and therefore it also has a slow titration, the process to arrive at the optimal dose for the patient can last up to six months. It may also have some interactions with some medications such as antifungal and antiretroviral drugs.
The Aficamten is quicker, the titration can be done in less than two months and should not have the same interactions. The fact that it has a shorter life can be seen in two ways: on the one hand the titration is done first, on the other hand with a patient who responds abnormally a problem arises more quickly. With Mavacamten everything happens more slowly but the "washout", i.e. the end of the effect, is also slower. We can conclude by saying that the profile is very similar in both safety and effectiveness. Patients have a very comparable response, the choice of which drug to use will mainly depend on interactions with other drugs and costs.
Then there are other molecules being tested: one similar to Aficamten or a faster Mavacamten. Other American companies are developing other small molecules, such as small precision bullets, with action similar to Mavacamten but which act on different phases of the cardiac cycle.
Not only that, there are drugs with different actions, which work by improving the action of the mitochondria, which control energy production in cells. These are drugs that were developed primarily for diabetic heart disease but it seems that they also work for cardiomyopathy, particularly the hypertrophic forms. They are less revolutionary but very interesting.
Furthermore, for the first time a gene therapy was administered to a patient with Hypertrophic Cardiomyopathy, a truly ambitious project whose outcome is still very difficult to predict.
What does the possibility of being treated with these drugs mean for patients suffering from cardiomyopathy? How much can the quality of life of these patients improve thanks to the use of these drugs?
If patients have obstructive forms, the quality of life changes radically, some realize for the first time in their lives what it means to feel good. Others have more recent symptoms so they go back to how they were many years ago. The result is comparable to those obtained with surgery (“myectomy”). In some patients the results have been amazing, it really is something that changes the quality of life.
The problem is always that of security, because events can happen that create alarms. However, after 5 years of experience, it is unlikely that they will have any, but it is too early to be able to claim victory. The company can always stop production in the event of serious adverse events.
One problematic aspect is the price. In the United States these drugs started with a price of 80/90 thousand euros a year, in our country it will perhaps reach a third of this figure, that is, around 20/30 thousand euros, because in the first phase the pharmaceutical companies have to recover the costs of studies which are very high. But after this phase it is possible that prices will drop further because these drugs are not expensive to synthesize and the raw material is cheap. If several of these drugs come out, there will be competition and if there are many patients, this is expected to happen. If the same drug had been developed for heart failure and not for hypertrophic cardiomyopathy, the same drug today would cost less than one hundred euros per month. Certainly if the indications are confirmed this drug could become a standard drug for patients with hypertrophic cardiomyopathy. At that point, with millions of patients who could use it, the price could approach that of common heart failure drugs.
Is there anything else to add to give patients correct information about these drugs?
Giving correct information is very important. The first thing to understand is that receiving the diagnosis of cardiomyopathy does not automatically mean having access to the drug because the drug has very precise indications for patients who have the same characteristics as the patients in the clinical study, i.e. patients with obstructive HCM. It is important not to create false expectations. The second point is that access to the drug consists of a very complex protocol and an important organization that not all facilities are able to guarantee, especially at this time when healthcare facilities are overloaded with work and demands. But what we have seen so far with the experiments gives us great hope.