Editor’s note: You have probably noticed a distinct uptick in clinical trials of potential treatments for hypertrophic cardiomyopathy. HCMBeat has been following this trend and has previously published a host of stories about such trials, including this story about the positive results from the REDWOOD-HCM Phase 2 clinical trial, as well as past stories discussing the biopharmaceutical company Cytokinetics, its drug aficamten (previously known as CK-274), and the REDWOOD-HCM trial.
Some of these earlier stories are as follows:
Recently, Cynthia Waldman of HCMBeat had the opportunity to speak over Zoom with Dr. Martin Maron, who recently served as the principal investigator of Cytokinetics’ REDWOOD trial. The conversation focused both on Cytokinetic’s drug aficamten (previously known as CK-274), and the new class of drugs known as “myosin inhibitors.” What follows is a transcript of their conversation (which has been edited for readability).
HCMBeat: How does aficamten work?
MM: Aficamten is a second generation oral myosin inhibitor. Its mechanism of action is similar to a first-generation myosin inhibitor like mavacamten. It binds to the myosin head to decrease the number of active myosin interactions that are going on at the sarcomere level; the structural apparatus of the heart. There are excess interactions in a disease like HCM, so by decreasing the interactions using a drug like aficamten, it decreases the force of the heart’s contractility and by doing that, you can decrease the left ventricular outflow tract gradient which will improve how patients feel.
HCMBeat: When you say it is a “second generation” drug, what exactly does that mean? Does that just mean that it is the second drug in the class to be tested?
MM: At this point in time neither mavacamten nor aficamten are FDA approved. Aficamten is the second drug in the class of myosin inhibitors to be investigated and go through the FDA approval process. It differs from the first generation myosin inhibitor based on a number of pharmacodynamic properties; how the drug is metabolized is different between the two and there are some differentiating features to the two drugs in terms of the pharmacodynamic profile. Things such as the half-life of the two drugs are different, the time that it takes to reach steady state in a person would be different, and other aspects of the metabolism of the drug that are focused on therapeutic window and so forth. That is what differentiates it, at least at this point. We don’t know how they differ clinically yet. It is too early in the clinical experience to understand that.
HCMBeat: Do you think there is a way to compare mavacamten and aficamten head to head in terms of their efficacy at this point in time? Since the endpoints in the EXPLORER trial for mavacamten were different than the endpoints in the REDWOOD trial, it is hard to compare the data.
MM: No, not yet. I don’t think that we are ready to make those kind of comparisons between the drugs. It is still like comparing apples to oranges. Aficamten is much earlier in development than mavacamten so you can’t yet draw comparisons of EXPLORER which was a Phase 3 study to REDWOOD which was a Phase 2 study. Those answers and clarity will come over time,
HCMBeat: Did you see any side effects of aficamten during the REDWOOD study?
MM: The safety profile of aficamten was excellent. There were only 2 serious adverse events during the trial. One was in a patient that was not on aficamten but was taking the placebo. The other had an exacerbation of pre-existing musculoskeletal pain which ultimately resolved. Otherwise, it was really well tolerated. There were no patients that discontinued aficamten. Everyone that started the trial on the drug finished on it, so in that sense, the safety profile looked really good.
HCMBeat: Would you expect to see any remodeling changes from the drug, and would they reverse after discontinuing the drug? Or is it just too early to tell?
MM: When the drug was stopped, all of the factors which were being looked at in the trial returned to pre-treatment levels, so there was fairly rapid reversibility. At the end of the two week “washout period,” ejection fraction, resting gradient and provocable gradient all returned to baseline. What you are asking is if there were any changes to the heart’s structure. This study was not designed to do that. It was about safety and tolerability. We didn’t have the number of patients to do that and the treatment period was too short to see any structural changes.
HCMBeat: Is there any basis to conclude that any particular class of patient might benefit from taking aficamten over mavacamten?
MM: It’s just too early to speculate about whether one of these drugs is going to prove to be better than the other. There are some attractive pharmacodynamic properties of aficamten that are different than mavacamten. Whether those can be leveraged to differentiate it in a clear, clinical way is not yet known. That is what we are going to investigate in the Phase 3 study. We did learn that it is possible to adjust the dose of aficamten fairly quickly based on echocardiographic parameters which could prove to be useful. While this was a nice aspect to aficamten, we are not yet in a position to compare it to the first generation drug.
HCMBeat: Do you see any potential for this class of drugs for non-obstructive HCM patients?
MM: It is possible, and I think that there is a lot of enthusiasm and hope for that. There are a lot of patients who are non-obstructed who are very frustrated by their symptoms and there are just no good therapies for them at all. The non-obstructed HCM patients represent a greater unmet treatment need than the obstructed patients. If there is a way to use this class of drugs to improve the symptom burden in non-obstructive patients beyond what we currently have, that would be really important. We know that there was a Phase 2 study of mavacamten in non-obstructive HCM called MAVERICK where there were some clearly positive signals in terms of levels of BNP levels which reflect the pressures in the heart and other blood and imaging markers which improved. It was less clear whether these improvements translated into the patients feeling and functioning better and it was a small study. So right now, the answer to that is unknown. There will likely be future investigations looking into whether this class of drugs will help non-obstructed patients, Hopefully, the results will be positive.
HCMBeat: At the HCM Summit in 2018, you expressed concern that mavacamten might reduce the ejection fraction too much, thereby causing systolic heart failure. Can you elaborate on your concern and describe whether the properties of aficamten might lessen this concern?
MM: There is a concern about this class of drugs and their suppression of systolic function and ejection fraction. In certain patients, systolic function can change quite dramatically. Because we are so early in terms of experience with these drugs, we don’t really know how these concerns will manifest. If there were certain aspects to a version of the drug that might lessen that risk, such as a shorter half-life, that would be attractive. We will just have to wait and see if these qualities may translate into a better safety profile in terms of ejection fraction stability.
HCMBeat: Since Cytokinetics has seen positive results from the Phase 2 REDWOOD trial and is planning on moving forward with a Phase 3 trial, can you tell us when that trial will that begin? Is the study design complete?
MM: There are plans to begin that trial by the end of the year. The study design is not yet complete so we don’t yet know the details.
HCMBeat: How long would you expect a Phase 3 trial of this type to last?
MM: MyoKardia’s EXPLORER trial involved a similar patient population and that trial enrolled pretty rapidly. It’s hard to say when we will know the results of the Phase 3 trial, but these types of trials usually take about 2 years to complete from beginning to end.
HCMBeat: How can patients interested in participating in the Phase 3 trial of aficamten get involved?
MM: The listing for the trial will be listed on Clinicaltrials.gov, as are all clinical trials. Patients can also reach out to their cardiologist or HCM Center to see if they are participating in the trial. If not, these providers could probably steer them to a nearby center that is enrolling. As the trial gets closer, there will be more specific information available about the trial and how to enroll for interested patients.
HCMBeat: Do you have anything else that you would like to add?
MM: It is a very exciting time for the disease. Going back twenty years, there were no clinical trials because there were no drugs being investigated, so the fact that there are now several companies heavily invested in finding new treatments for HCM is to me a very exciting sign for the patients. These treatments will hopefully relieve the symptom burden in this disease, and maybe even more than that. So in that sense, we have entered into a new era. I think that there is a lot of hope that soon, even more treatment options will be available for patients with this disease. There is real reason for optimism here.
HCMBeat: Thank you Dr. Maron for taking the time to share your knowledge and experience with HCMBeat’s readers. These are indeed exciting times for HCM patients!
DON’T FORGET THE UPCOMING HCM SUMMIT!
Dr. Maron would like to remind the readers about the upcoming International HCM Summit which will take place October 15 – 17, 2021. This year the Summit will be fully virtual and will not only allow viewers the opportunity to watch presentations and ask questions in real time, participants will have access to the archived videos for 6 months following the event.
The cost is $100 for patients, $350 for physicians with CME credit, $150 for physicians without CME credit and $100 for health professionals (with and without CME credit).
For more details and to sign up visit: hcmsummit.org
Click here to register.
About Dr. Maron: Martin Maron, MD serves as the Director of the Hypertrophic Cardiomyopathy Center and the Co-Director of the Cardiac CT and MRI program at Tufts Medical Center and Associate Professor at Tufts University School of Medicine. He recently was the Principal Investigator of Cytokinetics recent Phase 2 Trial, REDWOOD-HCM. He completed his medical training at Tulane University School of Medicine, Washington University School of Medicine – Barnes-Jewish Hospital and Tufts Medical Center. Dr. Maron’s specialties include cardiac imaging, hypertrophic cardiomyopathy, and cardiac magnetic resonance imaging. He was the Hypertrophic Cardiomyopathy Association’s 2011 Clinician of the Year, and currently serves on the association’s Board of Directors. He is board certified in Cardiovascular Disease and Internal Medicine.
You can follow him on Twitter @MartinMaronMD