RARE Daily

How One Drug Developer Is Addressing Health Inequities

December 14, 2023

Hypertrophic cardiomyopathy is a rare, genetic heart condition that has a disproportionate impact on people in the Black community because of socio-economic and access issues. Cytonkinetics’ experimental therapy aficamten is in late-stage development to treat the condition, but it also reflects a long-term focus of the company to address health inequities. We spoke to Robert Blum, CEO of Cytokinetics, about hypertrophic cardiomyopathy, how the company has worked to build relationships in the black community to expand participation in clinical trials, and how it is thinking ahead to issues of access and affordability as it advances the drug towards the market.

Daniel Levine: Robert, thanks for joining us.

Robert Blum: Thank you very much. Thanks for having me.

Daniel Levine: We’re going to talk about heart failure, hypertrophic cardiomyopathy, and Cytokinetics’ efforts to develop a treatment for this genetic heart disease. Let’s start with hypertrophic cardiomyopathy. For listeners not familiar with the condition, what is it?

Robert Blum: Sure. So hypertrophic cardiomyopathy refers to a disease rooted in genetics and dysfunction of cardiac muscle contractility. It affects a couple of hundred thousand patients in the United States alone, slightly more in Europe, and it comes in two forms, obstructive and non-obstructive hypertrophic cardiomyopathy. And in both cases you’ve got a situation where the cardiac wall that is intrinsic to the muscle mechanics becomes thickened. And there’s an impairment in the cardiac biomachinery such that in the case of obstructive disease, you’ve got a much thicker ventricle that has effect to cardiac performance. In the case of non-obstructive, it’s not necessarily as thick, but in both cases you have high pressure gradients and this contributes to breathlessness and morbidity and mortality and sudden death. Patients live with these symptoms where it affects cardiac function, cardiac performance. In effect, you have a hyperactive heart that one wants to ideally suppress in order to relieve the pressure and produce a more normal quality of life. So it’s a genetic disease and it’s quite a serious one for which there have not been recent treatments until one just approved and we’re developing what will be potentially a next in class treatment.

Daniel Levine: You talked about a certain breathlessness, but how does the condition manifest itself and progress?

Robert Blum: So most pronounced amongst the symptomology for this disease are patients who have an inability to exercise the kinds of things that we would consider activities of daily living. So walking up a flight of stairs, walking a long distance. This is fraught with shortness of breath and other impairments. There’s a very heavy burden of depression, mental symptoms, cognitive symptoms, and ultimately patients have fear, anxiety, angst. These patients live with the constant threat that they may go into a serious cardiac episode that could contribute to sudden death, and that happens more typically later in life, or it’s not as much a high incidence of sudden death, it’s the threat or the fear of it that causes these patients to live with their disease burden in a way that compromises their quality of life.

Daniel Levine: You mentioned there was recently an approval for a therapy to treat the condition. What’s the prognosis for patients diagnosed with the disease today and how have treatment options evolved?

Robert Blum: So, the prognosis, again, high morbidity with modest mortality risk, but it’s the morbidity that can be so debilitating. And until recently, there were no drugs indicated for this disease. Although physicians were using beta blockers and calcium channel blockers much for the reason that they lower heart rate. And it was thought that lowering heart rate would be beneficial to these patients. And there’s some evidence to suggest that there’s some symptom relief that comes with lowering heart rate, but also those drugs carry certain liabilities, including ones that, in limiting heart rate, limit ability to function and exercise. So you get less shortness of breath, but also at the cost of less exercise endurance, and I’m using the word exercise differently than the way you might think of it. It’s not going working out on a treadmill, it’s activities of daily living. Now there’s also a surgical procedure that’s used in younger patients more primarily. It’s a quite invasive surgical procedure called a myectomy, and that’s done by a few centers around the country, and where that can produce an effect that can be beneficial for these patients [is] by removing the wall thickening that contributes to the high pressure gradients inside the heart. Unfortunately, that can only offer transient relief because it doesn’t address the underlying disease, and disease progression can still occur despite the surgical intervention. So the world has been looking for a pharmacotherapy that could be inhibiting the hyperactive cardiac contractility. And one was recently approved—a drug with a generic name mavacamten that’s now commercialized by Bristol Myers Squibb under the trade name Camzyos. That was approved about a year ago based on a clinical trials program that showed a very meaningful effect to reduce pressure gradients and to improve exercise endurance and lower biomarkers associated with cardiac risk, and improve quality of life and functional life for these patients, reducing symptom burden. Our scientists played an instrumental role in the discovery of that compound mavacamten as it was a collaboration between Cytokinetics and a company that we formed as a spin out of our research called Myocardia, where mavacamten was discovered in our laboratories during the time that new company that we formed was incubating and before it began to hire its own employees and developed that compound ultimately to an approval and the acquisition by Bristol Myers Squibb. Now we are our same scientists advancing a next generation compound called aficamten.

Daniel Levine: This is a condition that disproportionately affects people in the black community because of socioeconomic and access issues. Cytokinetics has embarked on efforts to build relationships in this community and better reach patients who have been traditionally underserved and underrepresented in clinical trials. How does the impact vary in the black community?

Robert Blum: So, I appreciate you asking about that. As you know, you followed us for a long time. We’ve been in business for 25 years and during that time we’ve not only been pioneering in this research as it relates to muscle biology, but we’re also thinking about our role in our communities in ways that I think are unconventional as it relates to delivery and access to our medicines. And in that way, we think about Cytokinetics as an exemplar punching above our weight class for the benefit of a larger population. There are a lot of inequities in cardiovascular care and they primarily affect black and brown patients who are deserving of much better access to medical care and cardiovascular medicine. To answer your question, in the case of hypertrophic cardiomyopathy, there’s a higher burden of functionality, a limited heart failure, and they experience inequities in the care, for instance, a lower use of that invasive septal reduction therapy that I mentioned as well as genetic testing. Moreover, and this is all published in peer reviewed journals, black patients with HCM more often present with heart failure and less often are referred for management of their symptoms for risk stratification as it relates to sudden cardiac death for surgical myectomy or implantation of defibrillators. And in fact, when these patients do have a need for cardiopulmonary resuscitation, it’s less often provided to black patients by bystanders. They have lower survival rates after hospital discharge, and I think there’s a more urgent need for biomedical and social interventions to reduce the disparities in these health outcomes. I do believe that black patients are underrepresented in the way that they get specialty care for hypertrophic cardiomyopathy. And as we think about advancing a potential new medicine, we want to be part of a solution to address the inequities in care, not just by providing a new medicine, but also by leveling the playing field by which all patients can benefit from the care that they deserve.

Daniel Levine: You alluded to your experimental therapy in development, aficamten. This is to treat HCM. What is aficamten?

Robert Blum: So aficamten is a drug that we’ve been developing in clinical trials. It’s still investigational, so it’s not yet approved by the FDA, but its mechanism of action is as an oral therapy that would be an inhibitor of an enzyme called cardiac myosin. That’s the leading catalyst for cardiac muscle contractility. This enzyme is in effect driving cardiac muscle force and power. It’s powering the contractility in which with every beat of your heart, blood is pumped out of the heart. Unfortunately, patients with hypertrophic cardiomyopathy have a mutation, one of many, in cardiac myosin that limits its ability and by inhibiting cardiac myosin, we’re trying to, in many ways, restore normal cardiac contractility. We’re trying to suppress with this drug what is a hyperactive cardiac contractility to reduce that syndrome and to restore normal functionality or at least move back towards normal. So aficamten has been studied in preclinical and clinical studies, and it’s the subject of a pivotal clinical trial called SequoiaHCM that builds off of evidence already presented and published from phase 2 studies. Sequoia is a study that is due to readout in late December. It’s completed enrollment. We’re now collecting the final data before we lock the database and unblind the results. But we’re very hopeful that aficamten in this study will demonstrate, relative to standard of care or placebo, an improvement in exercise stamina, an improvement in quality of life, and symptom relief and other biomarkers that will be sufficient for FDA review and approval.

Daniel Levine: What did earlier studies show about its safety and efficacy?

Robert Blum: So those earlier studies looked primarily at the pressure gradients, both at rest and using a maneuver called Valsalva that induces more pressure, and demonstrated rapid decreases in those pressure gradients that were sustained over the course of treatment. And they returned back to those high pressure gradients upon removal of the drug. So these were placebo controlled studies that looked at pressure gradients that was very favorable in line with a potential treatment benefit. Moreover, those clinical studies demonstrated decreases in BNP, which is a biomarker of cardiac wall stress as well as improvements in the KCCQ, which is a measure of quality of life, an improvement in NYHA class where reducing NYHA class is reflective of lower symptom burden. So, all these things line up as we’re supportive of proceeding into phase 3 and now we’re awaiting the phase 3 data. We’ve also studied aficamten in an ongoing open label extension where some patients have received it for out to two years. And what’s encouraging is that these effects remain durable and endure even as we go out to these later time points. So we think that’s underscoring of continued patient effect and benefit and safety and tolerability.

Daniel Levine: There’s long been recognized the problem of underrepresentation of people of color in clinical trials. Did Cytokinetics do anything to address this with regard to enrollment of its study for aficamten?

Robert Blum: Yes. So, I think Cytokinetics is amongst the leaders in cardiovascular drug development in terms of recruiting patients of color into clinical trials. And even with that said, I think we can do better and we’ve entered into partnerships, like for instance recently with the National Black Church Initiative, the goal being from the pulpit, communicating to congregants the importance of diagnosis, participating in clinical trials, and reaching out to cardiologists if you have any of these particular types of symptoms so that you may be deemed a candidate for clinical research. So, we’re trying to get in front of all of this by engaging these communities into the clinical research process as it could also benefit them so as to ensure they’re well represented, from their ethnic diversity, in the outcomes of these clinical trials.

Daniel Levine: What goes hand in hand with this is a mistrust of the medical establishment that many people in these communities have, sometimes with good reason. What are you doing to build trust in the community beyond just the work you’re doing with the churches?

Robert Blum: Yeah, so I think it comes with meeting them where they are and appealing to hearts and minds. I think Cytokinetics, perhaps uniquely, but certainly uncommon, is participating very actively in ways that are serving their interests, apart from our own in terms of education and awareness, transparency. I mentioned clinical trials and other things that we think can be enabling of trust, credibility, and integrity as it relates to a company like ours for which there is a prevailing mistrust. And that’s where we listen and learn. And it’s more than just rhetoric. I think we’re very actively engaging these partners in ways that provide support and funding, as well as where there could be public policy and reimbursement, and ultimately pricing and access to the benefit of more diversity in cardiovascular medicine.

Daniel Levine: Access to care and the cost of medications are an obvious impediment to getting access to medicines like this. Are you thinking about strategies in terms of once you have an approval, how you’ll work with the community to gain access to a drug that they may not have insurance for, reimbursement for?

Robert Blum: Yeah, we’re thinking about ways that we can address some of those gaps in coverage, whether that’s private, commercial, or Medicare, and as would be enabling of programs that ultimately can serve these patients where it’s not enough that they have a copay card if they can’t afford what is the non-covered portion. So I think the pharma industry is doing some of the basics as it relates to some of these matters, addressing inequities in access, especially amongst a more disadvantaged population if impoverished. But it’s those people who don’t necessarily qualify for those programs who are still representative of a prevailing need. And I think we need to do much more. If you look at the quality of care in some of our urban centers and our rural populations, they don’t have access to cardiologists, they don’t have access to, therefore, the same standards of care. So maybe there are telemedicine approaches, maybe there are other ways that we can address the shortage of cardiologists and the access to good cardiovascular care. And in that way, we’re looking to partner with the physician community as well as show up in these communities with our programs. So I hope that if we do go to market, we’ll be demonstrating that we’ve listened and learned and that our hearts and minds are aligned with theirs.

Daniel Levine: There is growing awareness within the biopharmaceutical industry about the need to address issues of health equity. Are there lessons you could share from Cytokinetics’ experience that might help others looking to do the same?

Robert Blum: Yeah, I would say there’s a great deal of rhetoric amongst biopharma and pharma companies, and if you talk to them, everyone refers to “patients are our north star” and everyone refers to “a need to address inequities.” But very few of them are showing up in ways that I think, to your earlier question, are reinforcing of trust, credibility, and integrity. And I hope that Cytokinetics will be counted among some of those pioneers in these programs, much like I think we’ve already demonstrated that we are enrolling more patients of color in our clinical trials or involving more patients of color and other patients who are disadvantaged in our patient advisory groups and listening to them in terms of what matters to them in the course of design and conduct of clinical trials. And ultimately, as we think about a patient hub and how we assist patients, I hope that we’ll have reimbursement programs, education programs, and other things reflective of a company that’s sincere and authentic about its “want to do this” more than is rhetoric.

Daniel Levine: Robert Blum, president and CEO of Cytokinetics. Robert, thanks so much for your time today.

Robert Blum: Thank you. I appreciate the time.

This transcript has been edited for clarity and readability.


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