Roham Zamanian, MD, FCCP - phaware® interview 527

Dr. Roham Zamanian, discusses the concept of "disease modification" in the treatment of pulmonary hypertension. He describes how this idea emerged from discussions with colleagues about the future of pulmonary hypertension therapies, and the potential for treatments to impact the underlying disease process beyond just reducing pulmonary artery pressures.

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My name is Roham Zamanian, and I'm the Medical Director of the Adult Pulmonary Hypertension Program at Stanford. Today, I want to talk about disease modification, something that historically, probably is not on the radar of the work that we were doing, but now, because of advents of new therapies, is a concept that we should be discussing. It's a concept that people have talked about in the last couple of years. It became a paper that we ended up writing with a PH patient involved, that received some traction during the World Symposium on Pulmonary Hypertension.

Like a lot of concepts in research and pulmonary vascular disease, concepts come up in discussion with colleagues. I remember sitting in Barcelona with Vinicio de Jesus Perez, MD and Harm Bogaard, MD. This was probably 2019. We were talking about the next phase of what's coming up in pulmonary hypertension research. The two concepts that sort of came together was this idea of doing a large sort of efficient clinical trial using something called the master protocol. Then, the conversation led to, well, what's the future of therapies in pulmonary hypertension and what are the hopes that we have for these therapies?

A lot of us are not naive enough to say, "Well, we want a cure." We certainly do, but are we there yet? We're not sure. But we were talking about therapies that are on the horizon, being tested in animal models and being spoken about in clinical trials that have the potential for changing the vasculature or really impacting the disease in a way that is significant.

When you look into medicine around therapies that have that kind of capacity, you get conversations around anti-immune therapies that what were called DMARD, disease modifying anti-rheumatic drugs. Then, it was like a light bulb sitting at this cafe in Barcelona. Before we knew it, we were talking about, "Well, what does the concept of disease modification look like in pulmonary hypertension?" Are we there yet? Do the drugs that we have now modify the disease?

We realized very quickly we didn't have consensus around that definition. To all of us, disease modification or changing the disease in a way that was substantial, but short of a cure meant different things to all of us. To some people it was like, "Hey, let's take the blood vessels of the lungs and reduce occlusion and the new intimal changes from a pathology perspective."

To others, it was like, "Yeah, I care about that, but I also care about what's happening to the right heart." To others it was like, "Well, how does the patient feel about this?" So that conversation began. I don't think we're the only ones in the community having these kind of conversations, because we're realizing now that these therapies that are coming out have the potential to address the underlying mechanism in a way that's just beyond vasodilatation. We felt like there was a need to have this conversation across our community, and that's what led to the paper.

Initially, it was like, let's figure out what the outline of conceptualizing this phrase is. What does it mean to all of us? How do we measure it? How do we test it? That's the main thing. We are trying to also police ourselves and the community and how that term is being used. We're getting this group together and we said there's two important things that we need to have.

We need to have a perspective from someone who has experience from a regulatory perspective. We ought to test this concept. So we need someone who has know-how knowledge experience with part of EMA or FDA or whatever. The second thing was, it's imperative that we have the patient voice in this conversation, because the kind of maneuvers that we're thinking about and we proposed in our manuscript will require feedback from patient community, because they'll be in those clinical trials.

I have a patient of mine who is a dear patient of mine who is a physician, also. I thought that was really great, because then we would have someone with medical knowledge involved. We engaged her. She blew us away. If you look at the paper, you'll see, we talk about what is the definition of this concept, how do we approach it and how we think about it medically. She was like, "Hey guys, I don't care. What I care about is how does that feel to me." That was really sobering.

In fact, I want to give a shout-out to the American Journal of Respiratory Critical Care Medicine, the Blue Journal. We basically said, "Here's a section of what the patient said. We're not going to make it into Medicalese. It's going to read like a first-person what the patient is telling you." And they allowed us to put that in. This is the first time that this medical journal, for me at least, allows really the voice of the patient speaking through all the medical jargon of the paper.

I think it's really important because one of the critical items I believe, and this is an opinion, to test this idea of whether a drug is modifying the disease, is to test withdrawing the drug for a period of time to see how much effect it has had. If I could biopsy your pulmonary arteries to say how much reduction in vascular remodeling there's been or biopsy your right heart on a routine basis, we would do that. Those are not easy maneuvers. Those are not without risk. No one ever biopsies the pulmonary arteries. Short of that, we strongly believe in this manuscript, we wrote this, that we can't just because the drug works really well, we can't say that that drug is changing the disease at a pathology level reversing it, because we don't have evidence of that.

So our manuscript calls for ways to test it. One of the cornerstones of testing get is to withdraw the drug. The patients have a very strong opinion about what that means, and we have to be careful about explaining that construct carefully enough in a clinical trial setting. So, it was really important to have the voice of that patient in a manuscript.

Just to be fully transparent, there are other manuscripts that are being published or have been published. I'm not sure if they're out yet or not by other colleagues, and they may say similar things to us or different things to us, but the reality of it is, it was not part of the clinical trial. Now, we think the idea should be tested in the clinical trial. We know, and we're very strong in the opinion that just because a drug can be very impactful in reducing pulmonary artery pressures, it doesn't mean that it is somehow changing the underlying pathology of the disease.

For example, Flolan, (Epoprostenol), life-saving drug, has profound ability to reduce pulmonary artery pressures, but in the long term, it doesn't change the disease pathology, doesn't change the fact that patients end up needing a heart-lung transplant. Hopefully they never do.

In our thinking, this idea was to really outline how we think about a term that shouldn't be used willy nilly and a concept that should be tested in clinical trials. As this concept gets air and people were discussing it at the World Symposium on Pulmonary Hypertension through our task force, which was the clinical trial's task force. But in the broader sense, how it fits into the community, I think there are different opinions. I think generally people see this as a good concept to understand and people I think do agree now that we should be testing it. We're at a place in PH that we could test it.

Most people are sensitive to the idea of withdrawing a drug. I'll tell you in a very simple way, first of all, we're no longer at a place where there isn’t experience managing patients on already background therapies. We're talking about in the setting of a clinical trial, right? We're not saying that someone should test this in clinical practice.

In clinical trial, all clinical trials now require patients to be on background therapy, require patients to be closely monitored. So, I think it is the right environment to take a patient through a period of time where you take the drug off and see how patients do. I think people are open to it, but we always have to start with the primary construct. A lot of patients, and even some physicians I think have reluctance about this concept or may have reluctance around this concept, because they feel that the drug that they're getting, and maybe they're already on it or they're on placebo, who knows? Right? Is going to be effective. But that's what the clinical trial is testing.

So it doesn't mean we're asking patients to withdraw immediately from an effective drug. We're asking them, at least in our manuscript, we ask that whether the drug that's being tested, before it's proven to be effective, is withdrawn during a period of time and evaluated for this idea of disease modification. There are people in this field that think you could also withdraw background therapies, so they go on a drug. If that drug is really helping them substantially, then you should be able to take away some other already approved background therapy drug that are on. There are different permutations to it, but that's been the entirety of the discussion.

The biggest point of the discussion has been can this be safe and tolerable for patients to do in a clinical trial? I think a lot of people believe it is. In this day and age of pulmonary hypertension care, it's viable. Then, the second part of it is what signals do we look at to say something is disease modifying or not? What are the, if you will, endpoints? Is it the six-minute walk distance? Is it the PVR? Is it some surrogates of the PVR? Is it blood tests? What is it that we're looking at?

I think there is going to be a lot of exciting innovation in that front that people can look forward to. But that's been the discussions both at around the World Symposium on Pulmonary Hypertension. I know we're going to talk about this at the PVRI meeting in Brazil. I'm sure people are talking about it either at regular conferences or between themselves, but it's exciting. I've been in this field since the early 2000s and it's exciting to be in a place in time where we can think about testing something like this. It feels like progress to be even in a position to test it.

I'm Roham Zamanian and I'm aware that my patients are rare.

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