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RAPACAT trial: Rapamycin in cats with subclinical HCM

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Dr.  Joshua Stern author of "Delayed-release rapamycin halts progression of left ventricular hypertrophy in subclinical feline hypertrophic cardiomyopathy: results of the RAPACAT trial in: Journal of the American Veterinary Medical Association - Ahead of print (avma.org)" discusses how delayed-release rapamycin may prevent or delay progressive left ventricular hypertrophy in cats with subclinical HCM. Hosted by Associate Editor Dr. Sarah Wright and Editor-in-Chief Dr. Lisa Fortier.

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Sarah Wright:

You're listening to Veterinary Vertex. A podcast the AVMA Journals. In this episode, we chat about the effects of rapamycin in delaying progressive left ventricular hypertrophy in cats with subclinical hypertrophic cardiomyopathy with our guest, Joshua Stern.

Lisa Fortier:

Welcome to veterinary vertex, I'm Editor-in-Chief Lisa Fortier. And I'm joined by Associate Editor Sarah Wright. Today we have Joshua joining us from NC State as the newly appointed Associate Dean for Research. Joshua, thank you so much, you know, just landing in a new place and, and taking the time to be with us here today. We really appreciate it.

Joshua Stern:

Thank you so much, Lisa and Sarah.

Sarah Wright:

So Joshua, a diagnosis of hypertrophic cardiomyopathy or HCM in cats can be devastating. Your manuscripts in JAVMA make give feline practitioners and owners some hope. Your manuscript investigates the effects of rapamycin in cats with subclinical HCM, can you give our listeners some background on this topic?

Joshua Stern:

Absolutely. So hypertrophic cardiomyopathy is really a disease with a staggering prevalence in the cat population that afflicts about one in seven cats. And unfortunately, roughly half of those with this disease will go on to have significant disease outcomes, like congestive heart failure, sudden cardiac death, or even blood clot formation, what we call thromboembolism. And so really, anything we can do to try and prevent or slow the disease progression of hypertrophic cardiomyopathy is going to impact a really wild number of cats along the way. Unfortunately, this disease also happens in people, it happens in about one in 500 people. And there are very few therapies that have been shown to make any difference in the subclinical phase of this disease. And we're left typically just kind of managing the outcomes of this disease as they come along at us. And so really, the work that is published in this manuscript is looking at novel interventions to try and slow down the progression of hypertrophic cardiomyopathy with an ultimate aim to stop cats from progressing to a disease outcome. So to keep them in what we would call the subclinical phase would be the ultimate goal of a therapy like this. This manuscripts really the first look at giving a novel therapy a try and seeing how it's tolerated in cats, and whether it's doing what we expect it to do at the level of their heart muscle.

Sarah Wright:

As a cat owner, I especially appreciate your manuscripts. I have an eight year old and a six year old, the six year old has some kidney issues. And I'm like, Please don't be the kidney and the heart cat because those are never fun to manage clinically.

Joshua Stern:

Absolutely, though, that is certainly a rock and a hard place.

Sarah Wright:

Yes, most definitely. What are some important findings from this study?

Joshua Stern:

Thanks for that. I think probably the most important finding for this study is that this novel therapy rapamycin, it's a delayed release rapamycin treatment option was well tolerated in the cats in our study. And so we now feel confident that we can use a drug like rapamycin in patients with subclinical hypertrophic cardiomyopathy safely to get the data that we need to see how it will impact disease outcomes. And then the really exciting part of the work that we did was to see that it was having the targeted effects that we were looking for. So hypertrophic cardiomyopathy is a disease that causes thickening of the pumping chamber of the cat's heart, the left ventricle, and that thickening of the heart leads to all of the downstream bad outcomes that happen with hypertrophic cardiomyopathy. And so the idea of using rapamycin is that it modulates or alters the thickening of the heart muscle during what we call cardiac remodeling and kind of reversing that stage of disease. And so the most exciting takeaway for us was that kept that we're receiving one of the dose groups of this therapy in our trial, had reverse remodeling of their hypertrophic cardiomyopathy. And so compared to cats receiving placebo, their heart muscle stayed nice and thin or thinned out a little bit compared to what it started out as.

Lisa Fortier:

Pretty fascinating. Josh, as you as you might know, I'm an equine orthopedic surgeon. So HCM is a long way from my memory bank. How did you identify some clinical cats in this study?

Joshua Stern:

Yeah, so So the diagnosis of hypertrophic cardiomyopathy is really one that is largely made by echocardiography or cardiac ultrasound of the heart. So cats are either mildly sedated or not sedated and undergo a cardiac ultrasound where we can actually measure wall thickness on imaging, and that's the principal diagnostic method for hypertrophic cardiomyopathy. I think a lot of cats made their way to this study, because their family veterinarians heard a heart murmur in the cat, or identified an elevation and what's known as a cardiac biomarker, like NTproBNP on routine lab work. And that spurred them to recommend that the cat's heartbeat evaluated by a cardiologist who then subsequently could identify the thickening and diagnose hypertrophic cardiomyopathy. And so that's our principal way of of diagnosing the disease. Unfortunately, with hypertrophic cardiomyopathy, because, in the subclinical phase, it's a really silent disease. A lot of cats in the clinic actually get diagnosed at the end of their disease, when they're already in congestive heart failure and having difficulty breathing.

Lisa Fortier:

That's really that's so super cool. There's so few things that we can do other than like vaccines that are preventative. So this is, this is really ground breaking for all those cats. I love the title, RAPACAT trial. Who came up with RAPACAT?

Joshua Stern:

Yeah, that is that is actually a credit to my graduate students who were in the lab, and we were trying to get really creative, you know, cardiologists have a long history of thinking of amazing study titles for ongoing clinical trials. And we were coming up short when we put all of our words together to look at what we needed. And so we literally just shortened rapamycin and that we were targeting cats and to RAPACAT and it stuck.

Lisa Fortier:

That's awesome. I really like it. What personally sparked your research interest in HCM? Did you personally have a cat or did you see a couple cases as an intern or resident?

Joshua Stern:

Yeah, so I am really interested in cardiomyopathy is, in general, my labs research focus is really on INHERITED HEART DISEASE. And so as a geneticist, I'm really fascinated by hypertrophic cardiomyopathy, and the mutations that lead to hypertrophic cardiomyopathy. That really dovetails with my clinical interest in managing chronic heart disease. I'm a kind of medical cardiologist, by design, I really liked the medical cardiology, more so than interventional cardiology. And so hypertrophic cardiomyopathy is a disease that is incredibly frustrating, because we don't have a lot that we do before they're symptomatic. And so it's always been on my bucket list to be part of trials that might investigate novel therapies. So I really got my, my start because of my interest in genetics, and then that really piqued my clinical interest and led to all of this work with novel interventions.

Lisa Fortier:

What inspired you then to write this manuscript? It's highly collaborative, you've got a lot of the who's who on there, even I know them. What inspired you to gather up everybody and really try and do this clinical trial?

Joshua Stern:

Yeah, this was, you know, this is a industry sponsored clinical trial. So our partners at Trivium vet had the compound rapamycin, and worked really diligently to get a type of rapamycin together that would be delayed release, and could be used in an intermittent dosing schedule to really target the pathway that rapamycin hits in precisely the way that we wanted. And so they actually worked and reached out to us with their compound. And then we really started diving down the rabbit holes of what do we really expect this to do? What would a clinical trial with this product look like to be successful, and who are our partners that we can work with, to get this trial completed in the right number of cats at the right time, to really make a difference. And so that's when you call up your trusted colleagues and collaborators. And so Kate Meurs and team here at North Carolina State University, as well as our cardiology team at University of California Davis, have worked together on a number of trials in the past. And we just had great confidence that between those two clinical trials centers, that we could get this done even during COVID times in an effort to hopefully figure out whether it was safe and well tolerated, which it was, and whether it had the targeted effects that we predicted, which it did. So that, you know, we can move down the pathway of possible pivotal clinical trial.

Lisa Fortier:

You know, again, just a great collaborative event and super great example of how important collaboration with industry is.

Joshua Stern:

Yeah, I think so too. It was a really, this was a really lovely study for us to do and to work with the Trivium team and to really leverage their scientists and what they know about the pathway of rapamycin and our clinical teams and what they know about cardiology, and then our research minds and unanswered questions that we want to know So it really was a lovely collaboration. And we're looking forward to many more of those, as we answer more questions about the same compound and other disease processes, as well as the future of caps with this compound and hypertrophic cardiomyopathy.

Sarah Wright:

That's excellent. Your manuscript has received a lot of attention and has been mentioned by the news and 51 people on Twitter. So people are talking about this and it has been noticed, I think the catchy title really does help as well as having that really great clinically applicable information.

Joshua Stern:

Thank you. I think, you know, there's a lot of cat owners out there that are just as frustrated with this disease as we are. Nobody likes being told that we don't have a lot that we do that makes a big difference. And so it's always great to be part of something that that can change the way we practice.

Sarah Wright:

Agreed, very well said. So back to you for a minute. How did your advanced training prepare you to write this manuscripts?

Unknown:

Oh, that's a great question. I mean, I, I did my cardiology, residency and PhD in cardiac genetics kind of, concurrently. And I was really fortunate to be introduced to teams of clinician scientists. And that's what I consider myself, we're always thinking about unanswered questions, and where we could make a difference in the way that we practice veterinary cardiology, as well as trying to take what we know from humans take what we know from other animals, and crossed the aisle with it. And so I think I principally had really great role models in that area, both in the more benchtop science and the clinical science along the way. And so I think my training prepared me for that and it fit pretty nicely. And then, I think, my work at University of California Davis, and intersection with our Veterinary Center for Clinical Trials, really showed me how important getting clinical trials on the books and getting answers to whether novel therapies were going to make a difference was. And so I really felt like when this came along, it was just the right time for us to dive in and go the route of a novel therapy and see what we could find.

Sarah Wright:

It's certainly an area of interest to make a difference. So nicely done. This is an important question for our listeners. What is one piece of information the veterinarian should know before discussing this topic with the clients?

Unknown:

That is a great question. I think veterinarians should be prepared to understand that not every cat that has hypertrophic cardiomyopathy is going to be suitable for a novel therapy like this. And we're really in our infancy in figuring out what this drug is going to do long term for hypertrophic cardiomyopathy, we are incredibly hopeful, but it has limited the scope of animals that we have experienced using this drug in, for example, we are not yet using this compound in cats that are symptomatic with hypertrophic cardiomyopathy. So veterinarians are no doubt going to get a lot of desperate owners where their cat has an advanced stage of disease and want to try this compound. What I would say there is that it's probably not the right time for that yet. We really investigated this in subclinical hypertrophic cardiomyopathy. And that's very likely where a future pivotal trial is going to go. And so I hope that our veterinarians that are listening can bear with us, and know that there's nobody that wants to advance the science any faster than we do. And keep an eye on the social media spaces and clinical trials pages, to see when those pivotal trials come up, because we're going to be looking for enrollment centers around the country and internationally. And we're going to be adding new cats to the rapamycin trials just as soon as we can to answer that next level of questioning. So I think that's probably what I would share with them first. And then secondly, I think it's important to have a optimistic outlook. You know, this is one compound that we were very fortunate to get to investigate, and it made a difference. And no doubt, we're excited to see where it goes, but there could even be others. So keep an eye on this space. I think research is moving at a really rapid pace in this area.

Sarah Wright:

And then on the flip side, what is one thing the client should know about this topic?

Unknown:

For clients, I think it's important to recognize that hypertrophic cardiomyopathy is a disease that comes in many flavors and has many different degrees of severity. And that your veterinarian is really your partner in helping you identify the best treatment path for your cat. And not all cats are going to be in the right phase to go ahead and use rapamycin at this point and so I would say for clients, ask the question, is there anything new that we can try? Understand that your veterinarian is is learning about these things just as the research teams are as we go, and so that might change. And so always check in those reevaluation appointments and just see whether something new is hit that they could work with.

Sarah Wright:

And what would you say is the most surprising finding from this manuscript? This doesn't have to be the most important one. But what was the thing that surprised you by your study?

Unknown:

I would say I've learned in research that many times, you go into a project with a hypothesis, and you learn something entirely new or different. And so for me, the most surprising thing in this study was, we really did hypothesize that the lowest dose group was going to be the most successful treatment group. And we really did hypothesize that it was going to alter wall thickening. And it was surprising that we were correct. It almost never happens that all of your our priori, or first first go hypotheses come out to be correct. And so it was both surprising and delightful to see that we were headed in the right direction.

Lisa Fortier:

It's awesome. The flip side of that Josh was not like, hey, we were wrong. So now we have more studies to do, but you obviously have plenty of studies to do. That's right. It's been you can feel your passion for veterinary medicine. And congratulations on your new role as Associate Dean of Research at NC State. You clearly have what we talk about in veterinary medicine is resilience and determination. Where do you think yours came from?

Unknown:

Oh, thank you for that. That is a that's a great question. I mean, I think I think I have always been a person that doesn't really settle for the no answer and goes back to the drawing board to try and figure out where I'm going to go. And that started when I was trying to get into vet school, which wasn't an easy road, back when I applied, and certainly it's an even harder road for students applying right now. You know, as a geneticist, we often look in many, many, many haystacks before we find the answer to a question. And so I feel like my research has really set me up for that pretty nicely. And I've had some pretty amazing mentors along the way, including Kate Meurs, who's one of my lead co authors on this study, and now the Dean of our School here at NCSU.

Lisa Fortier:

Yeah, she's fabulous. I know what you mean. And I think people would, I'm sure some of your friends and colleagues and family members when you said I always ask the question are like listening to like, oh, yeah, he's that one. Sometimes you're like, I'm so tortured by that sometimes you wish you could just like, blank out. Why do you always like why? Why is that? How come? Why?

Joshua Stern:

Exactly.

Lisa Fortier:

Yeah. And we know you haven't been at your desk for very long but we love asking this question or this desk anyway, what is the oldest or the most interesting item on your desk or in your desk drawer?

Unknown:

Oh, it's actually on my desk. I have a really lovely heart model that was made by one of my mentors in my clinical training. It has a silicone base through the venous and arterial system and you can take it apart and exactly explain where everything goes and heads and I just love that thing. I get it out and use it as my stress reliever when I'm trying to solve a problem.

Sarah Wright:

I love everyone's answers that question. We recently had a podcast about another cat topic as well. And there's someone had like an old foreign body from a cat. I feel do that really does align with a person's academic interests as well, which is quite funny.

Unknown:

I would have happily shown it to you except for it's in one of the boxes behind me because it hasn't been unpacked yet with my move.

Sarah Wright:

I think it's understandable. You said it's been like eight days. No worries. But just thank you again, Joshua. We really appreciate your time today and for joining us and sharing your manuscript with JAVMA. And also now with all of our Veterinary Vertex listeners. Thank you so much. And to our listeners, you can read Joshua's manuscript on our journals' website and in print JAVMA. I am Sarah Wright with Lisa Fortier. We want to thank each of you for joining us on this episode of the Veterinary Vertex podcast. We love sharing cutting edge veterinary research with you and we want to hear from you. Be sure to leave us a rating review on Apple podcasts or whatever platform you listen to

People on this episode

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Lisa Fortier, DVM, PhD, DACVS

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Sarah Wright, DVM

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