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Dr. Raj Parikh from Hartford Hospital discusses the development of the PH-ILD Detection tool, a screening tool designed to help detect pulmonary hypertension (PH) in patients with interstitial lung disease (ILD) at an early stage. Early detection is critical, as there is often a significant delay in diagnosis of PH in ILD patients, leading to worsened outcomes.

This Special Edition episode is sponsored by Liquidia.

My name is Raj Parikh. I'm the Director of the Pulmonary Hypertension Center at Hartford Hospital in Hartford, Connecticut. I did a lot of my training kind of all over. I went to medical school in New Orleans, Chicago, ended up in Boston, and then made my way back home to Connecticut where I grew up. I've been at Hartford Hospital for the last four years. I started the Hartford Hospital's Pulmonary Hypertension Program from scratch, and I've been building it up since then.

I got involved in Pulmonary Hypertension really during my fellowship at Boston. I really wanted to get involved in the rare disease space of PH, where patients are far and few between, but the ones that are there, they have pretty significant morbidity, mortality, and a poor prognosis. There's limited treatment options and there's limited specialty care for these patients. I really wanted to come back home to my state of Connecticut and build up a program in sort of the area that I grew up in.

Today, I want to talk to you about the PH‐ILD Detection tool that Hap Farber, MD and I have been working on for a couple years. Now, it's in the community. We're encouraging all interstitial lung disease, ILD specialists, general pulmonary docs who see ILD patients to really use this as a way to work on early detection of pulmonary hypertension in interstitial lung disease patients. The reason behind developing the PH‐ILD Detection tool was to really focus on early detection and early screening for pulmonary hypertension that's associated with ILD. The impetus behind that was the development of the first and only FDA approved therapy for PH-ILD, which is inhaled Treprostinil. That was FDA approved back in 2021 after the INCREASE clinical trial.

The PH-ILD Detection tool, the real spirit behind it is patients with interstitial lung disease that develop pulmonary hypertension carry extremely poor prognosis. They need more oxygen. Their quality of life is worse. Their longevity of life and their mortality is worse, as well. These are things we know. We've studied the PH-ILD population for years and years. This is well-established stuff. The key now that we have a therapy that can A, improve the patient's walk distance and therefore their quality of life. B, keep them from having any sort of clinical worsening like ending up in the hospital or having more right heart failure. These are all findings based on the INCREASE trial. So the key really is to detect the pulmonary hypertension as soon as possible in ILD, not just screen for it once a year, or test for it when you meet the patient for the first time and then test for it again every five years.

This is not like colon cancer screening or lung cancer screening. This is active assessment every time you see an ILD patient, you should be thinking, “Okay, do they now have signs of pulmonary hypertension? Should I now be concerned about pulmonary hypertension or should I not be?" There is no standard protocol or standard practice when it comes to screening and detecting for pulmonary hypertension in ILD patients.

Back in 2022, Hap and I really developed eight parameters for PH-ILD detection. We base these parameters off of things that you should routinely already be using to assess a patient's interstitial lung disease. We're talking about 6 minute walk tests, physical exam, pulmonary function testing, assessing whether the ILD patient needs oxygen or not, blood tests, CAT scans, and their prior history and comorbidities. If we take these eight parameters and we assess, okay, which parameters have a higher weight compared to lower parameters that have maybe not as much of a weight in terms of predicting for pulmonary hypertension? We took these eight parameters and basically created a 12 score tool. The score can be anywhere from zero to 12. Four parameters have a weighted score of two points. Four parameters have a weighted score of one point, therefore equaling a max score of 12 points.

Basically, depending on what you score from zero to 12, you are stratified into either low risk for pulmonary hypertension ILD, intermediate risk for PH-ILD, or high risk for PH-ILD. A score of three or below is low risk. A score of four to five is an intermediate risk. A score of six or higher is actually high risk for PH-ILD. What does that mean? What does it mean if you're low versus intermediate or high? Well, that should really dictate what are your next steps. 

If you're low risk, you should reassess the patient at your follow-up visit, whether that's at three months or six months or whatever. If you're intermediate risk, you should get a screening echocardiogram for that patient to make sure there's no signs or development of pulmonary hypertension or right ventricular disease on that echo. If you're high risk, that's a score of six or higher on the PH-ILD Detection tool, you should not only order an echocardiogram, but you should be calling your nearby your local pulmonary hypertension specialist or pulmonary hypertension center and say, "I have a patient with interstitial lung disease. I have a high suspicion for pulmonary hypertension, can you get them into your clinic? Can you get them in for a right heart catheterization for a definitive diagnosis?" 

When we developed this score, we not only first developed it internally retrospectively, but once it was initially published, we discussed it and presented it at an oral presentation at CHEST back in Nashville, so that was a couple of years back. We then actually had seven centers used the score prospectively, and we validated the score by doing a multi-center validation cohort study. That study actually upheld a very significant area under the curve, very significant sensitivity and specificity for a score of six or higher to really strongly predict pulmonary hypertension in interstitial lung disease patients.

As a result of this, we've been working on promoting the use of this PH-ILD Detection tool with local ILD specialists, local general pulmonologists. We use this score not only to predict or increase suspicion for pulmonary hypertension, we've done some other data and we actually presented this information at CHEST, this past year at Boston, where the higher the score you have, the worse your right heart cath hemodynamics are, and therefore the worse your prognosis may be. Some of that is almost common sense, but it's nice to kind of see pen to paper and see that correlation, as well.

We've actually been working on seeing if we can create an app for this score. Now, Hap and I are creating an abbreviated version of the PH-ILD Detection tool to take it instead of eight parameters with 12 points, can we make it three parameters? Can we simplify it even further and make it as simple as possible so that the community pulmonary doctor, the community ILD specialist -- all of them can really focus on how simple it can be to detect and screen for pulmonary hypertension. Mostly because we know that once patients develop PH with ILD, the prognosis is so poor that we want to really act fast. We want to get them diagnosed soon. If we can diagnose them quickly, we can treat them with inhaled Treprostinil. We can mirror some of those outcomes that we saw with the INCREASE clinical trial, and get these patients having a better quality of life, better walk distance, lower proBNP scores, keep them out of the hospital, so on and so forth.

We know from PAH pulmonary arterial hypertension and the REVEAL registry, there's almost a three year delay in diagnosis from the time a patient develops cardiopulmonary symptoms to the point B, which is when they actually have a formal PAH diagnosis. Three years. Those three years are met with seeing different specialists, being in and out of the hospital, having a worsening quality of life because they’re always short of breath and overall just poor more prognosis. If we take that, do we have that exact number when it comes to PH-ILD? No, but we do have an extremely wide range of epidemiology when it comes to PH existence with ILD. PH can range anywhere from 12% to 86% in ILD patients. Why do you have such a wide range? That's because we don't know when to look. We don't know how to look. A lot of times we don't even look and we're getting a lot of that data that 86% is sometimes showing up on autopsy results and transplanted patients.

Then, we're looking back at those autopsy or transplanted lungs and saying, "Oh wow, those patients not only had ILD, they actually had PH as well." That's not something to necessarily be proud or happy about. So it kind of is in the same boat as, what is our delay in diagnosis? What is the window of opportunity that we need to really diagnose and intervene so we can make a difference? There will be a point of no return when it comes to ILD patients with PH. The same way there is sometimes a point of no return with PAH where the patients get so advanced that they're meeting them in the intensive care unit and they're meeting them really on what we call rocket fuel. These patients are looking for the Hail Mary to get better. You're not meeting them in the office, you're not trying to do a 6 minute walk test on them these patients can't even do a 6 minute walk test when they're sometimes at that point of no return. So really what is the sweet spot? I think it is trying to mirror what we went through with PAH several years ago. Developing a registry, understanding more of the referral patterns for PAH and we're trying to extrapolate all of that information and bring it now into this PH-ILD space, as well. 

I know I'm speaking to a lot of the providers and doctors who are involved with taking care of ILD patients, but really switching gears and thinking about it from the patient perspective. If you're a patient who has been diagnosed with any of the many subtypes of interstitial lung disease, I think it's important to be aware of this concomitant process that can occur and that can develop, which is pulmonary hypertension. It is difficult to tease out when you have worsening cardiopulmonary symptoms, worsening breathing symptoms. Is that the interstitial lung disease? Or is that something new such as pulmonary hypertension? I think it's important to think about that and be open with your provider, with your specialist, with your pulmonologist and say, "I'm now feeling this way, and I'm now using this much more oxygen, and wasn't my 6 minute walk distance this far last time and now it's down to this time? Could this be something else? Is this just not necessarily worsening interstitial lung disease or is this a second process?" A second process that now we know we can treat and we can make better. I think that's important to sort of think about. You can be your best advocate when it comes to going into your provider's office and really telling them exactly how you're feeling, and what you're feeling, and how it's different from prior.

My name is Dr. Raj Parikh, and I'm aware that my patients are rare.

Learn more about pulmonary hypertension trials at www.phaware.global/clinicaltrials. Engage for a cure: www.phaware.global/donate #phaware Share your story: [email protected] Like, Subscribe and Follow us: www.phawarepodcast.com. #phawareMD @HartfordHealthC @Liquidia_Corp @teamphhope #PHILD

Dr. Raj Parikh from Hartford Hospital discusses the development of the PH-ILD Detection tool, a screening tool designed to help detect pulmonary hypertension (PH) in patients with interstitial lung disease (ILD) at an early stage. Early detection is critical, as there is often a significant delay in diagnosis of PH in ILD patients, leading to worsened outcomes.

This Special Edition episode is sponsored by Liquidia.

Learn more about pulmonary hypertension trials at www.phaware.global/clinicaltrials. Engage for a cure: www.phaware.global/donate #phaware Share your story: [email protected] Like, Subscribe and Follow us: www.phawarepodcast.com. #phawareMD @HartfordHealthC @Liquidia_Corp @teamphhope #PHILD

Dr. Ron Zolty delves into groundbreaking advancements in treating pulmonary arterial hypertension. From the historical use of vasodilators to the revolutionary promise of sotatercept and seralutinib, Dr. Zolty unpacks how science is moving closer to halting—and possibly even reversing—PAH.

This Special Edition episode is sponsored by Gossamer Bio.

My name is Ron Zolty. I'm a cardiologist working in advanced heart failure and heart transplantation. In my training, I had to do a lot of catheterizations in patients with pulmonary arterial hypertension. I trained at the University of Colorado in Denver, which is considered one of the best centers in pulmonary arterial hypertension. Working with patients in the cath lab, I fell in love with PAH, now leading a pulmonary hypertension program here in Omaha, Nebraska. Today, I would like to speak about some innovations in the field of pulmonary hypertension. As you may know, pulmonary arterial hypertension is a progressive, lethal disease. Patients, unfortunately, die from pulmonary hypertension if not treated. We should go back a little bit to the pathogenesis at the mechanism of what we believe causes pulmonary arterial hypertension. We know that when patients suffer from pulmonary arterial hypertension, they have what we call endothelial disruption. Endothelial is the inner layer covering the vessel of any vessel and especially the pulmonary arterial tree. If you have any damage of this endothelial layer, you are going to make some small thrombi, some small clots. One of the initial treatments of pulmonary hypertension was in the eighties to treat these patients with anticoagulation. Unfortunately, there was never any prospective study looking at the benefit of anticoagulation, only retrospective studies. Most of them showed that there is some benefit of anticoagulation blood thinner. However, because there was never any prospective study, it's just a 2b indication, not everyone needs to be on anticoagulation because again, it hasn't been shown really to improve survival in patients with PAH. The second main phenomenon that patients have with pulmonary hypertension is vasoconstriction. Vasoconstriction, meaning that the vessels tighten when you do have the disease. That's the reason for the three classic pathways we treat today. Pulmonary arterial hypertension, we know that patients with PAH have too much endothelin, which is one of the most potent vasoconstrictors we have in our body. So we block this endothelin causing less vasoconstriction and vasodilator effect. We also know that patients with PAH don't have enough prostacyclin, so we do substitute this lack of prostacyclin with some prostacyclin. We do have IV, inhaled, and oral prostacyclin to give to patients. The third pathway, which is also a vasodilator pathway, is the lack of nitric oxide. Patients with pulmonary hypertension have a lack of nitric oxide, and therefore we give them a PDE5 inhibitor like sildenafil or tadalafil or a SGC stimulator like riociguat to increase the nitric oxide pathway, increasing cyclic GMP. Cyclic GMP, really vasodilates. But all these therapies, these classic therapies do not stop the progression of the disease. They slow down the progression of the disease without stopping the disease. We also know, and that's the last point and the newest point I want to make, when patients do have pulmonary arterial hypertension, the wall of the vessel gets thicker. If the wall gets thicker, the lumen where the blood travels gets smaller and smaller. That's the reason why patients get less blood, less oxygen, less hemoglobin, less oxygen, more shortness of breath. This thickening of the wall gets what we call an increase in the resistance, leading to right side heart failure. About 15 years ago, there was a paradigm shift in the understanding of pulmonary arterial hypertension thinking, why do these patients have a thickening of their wall? It's because there is proliferation of endothelial cells, smooth muscle cells like neoplasia, like a tumor. Maybe if we block this progression, this proliferation, we may stop the disease and maybe even regress the disease in making the wall thickness less thick and smaller. Therefore, about 15 years ago, there was a very interesting clinical trial with a drug called Imatinib or Gleevec. Gleevec has, for patients with chronic myelocytic leukemia has been a revolution. Patients with CML in the past needed to have a bone marrow transplant. With the administration today of Gleevec it’s been a revolution and patients can live with CML, with this chronic myelocytic leukemia for years and years with absolutely no progression of their disease. Similarly to CML, the idea was maybe if we give an agent like Gleevec or Imatinib to these patients, we may stop the proliferation of endothelial cell and smooth muscle cells in the wall of the vessel and stop or even regress the disease. This trial, called IMPRES, was done about 13 years ago. The results of the study were absolutely beneficial. However, more than 30% of patients quit the study because of side effects, and also patients on anticoagulation, on blood thinners developed some intracranial hemorrhage. The FDA, because of the side effect, decided not to approve this drug for pulmonary hypertension. Just to give you a background that there is really a paradigm shift in the understanding of the disease. The new drug that has recently been approved by the FDA is being called sotatercept. That's another mechanism. We know that in our system, every cell has like a yin and a yang. There is activin, a system which stimulates the gene while the bone morphogenetic protein system is slowed down. The activin slowed down the proliferation of cells. In our system, in a normal system, you do have a balance between BMP and activin. We also know in patients with pulmonary hypertension, they do have too much activin. This new medicine, sotatercept blocks the activin. Activin is like an accelerator. It does promote proliferation of cells on the gene. If you block the activin, you recalibrate the BMP and the activin, reducing this proliferation of cells. Sotatercept was shown really to improve patient pressure as well as improving their six-minute walk distance as well as their quality of life. Sotatercept has been approved by the FDA for the last year and really has changed the field of PAH. Another group similar to the Gleevec, but as I said, Gleevec was not approved by the FDA because of the side effects. The idea was maybe if we could give a Gleevec as an inhaler without systemic effect, patients would absorb the drug into the lungs without having any side effects. There was a clinical trial with inhaled imatinib, inhaled Gleevec if you want. Unfortunately, the study was not positive, because most likely Imatinib was not absorbed by the lungs. However, another company was able to produce a super imatinib, which is being absorbed by the lungs called GB002 or seralutinib showing a significant improvement in the pressure, as well as the PVR. Currently, there is a Phase 3 with this drug as an inhaler. So, in summary, I just want to say the drugs we have currently until now were vasodilators, they do slow down the progression of the disease but don't stop the disease. Now, we do have one drug approved by the FDA. Hopefully, a second one will be approved. These two drugs stop the proliferation that occur in pulmonary hypertension and hopefully will stop the disease and potentially even regress the disease. We are getting closer to maybe a cure of the disease with agents like sotatercept and seralutinib. 

Thank you for listening. My name is Ron Zolty and I'm aware that my patients are rare.

Learn more about pulmonary hypertension trials at www.phaware.global/clinicaltrials. Engage for a cure: www.phaware.global/donate #phaware Share your story: [email protected] Like, Subscribe and Follow us: www.phawarepodcast.com. #phawareMD @UNMCCOM @NebraskaMed @GossamerBio #clinicaltrial #PROSERA 

Dr. Ron Zolty delves into groundbreaking advancements in treating pulmonary arterial hypertension. From the historical use of vasodilators to the revolutionary promise of sotatercept and seralutinib, Dr. Zolty unpacks how science is moving closer to halting—and possibly even reversing—PAH.

This Special Edition episode is sponsored by Gossamer Bio.

Learn more about pulmonary hypertension trials at www.phaware.global/clinicaltrials. Engage for a cure: www.phaware.global/donate #phaware Share your story: [email protected] Like, Subscribe and Follow us: www.phawarepodcast.com. #phawareMD @UNMCCOM @NebraskaMed @GossamerBio #clinicaltrial #PROSERA 

For decades, researchers have sought better treatments for pulmonary hypertension in interstitial lung disease, a condition that drastically impacts patients’ quality of life. In this episode, Dr. Rajan Saggar dives into the latest advancements, including new inhaled medications, upcoming clinical trials, and the push for more personalized treatment approaches.

This Special Edition episode is sponsored by Gossamer Bio and Pulmovant.

I am Dr. Rajan Saggar. I'm Co-Director of the Pulmonary Hypertension Program at UCLA, and my Co-Director is Dr. Richard Channick. We work at that program together. One of my main interests, actually, is pulmonary hypertension, complicating interstitial lung disease. Sometimes, interstitial lung disease can progress and become pulmonary fibrosis. So, along that spectrum of disease, pulmonary hypertension, which is Group 3. There's basically five types of pulmonary hypertension. There's five different groups. The one related to lung disease ... and again, that lung disease could be COPD or emphysema, or it could be interstitial lung disease - pulmonary fibrosis. Any type of lung disease is considered Group III pulmonary hypertension. The focus that we have right now is specifically with patients who have interstitial lung disease or ILD and pulmonary fibrosis. This is a field that I've been interested in for a couple of decades. There's been a lot of failed studies over the years. There's been a lot of attempts to use drugs that have clearly worked and are now FDA approved for the much rarer form of Group 1 pulmonary hypertension, which is also called pulmonary arterial hypertension. Those drugs, which are now FDA approved and thriving and doing well have been used or tried to be used in the Group 3 pulmonary hypertension setting. Unfortunately, the majority of them have failed. But the good news is recently, as of April of 2021, there is a medication that now is FDA approved, specifically pulmonary hypertension in the setting of interstitial lung disease or what we call PH-ILD. That is inhaled treprostinil. It's an inhaled medication that's taken four times a day. What's exciting now is that that started off a chain of events, which I think re-lit interest in this type of pulmonary hypertension. Now, there's several pharmaceutical companies that have shown interest, and more than that, have actually started clinical trials looking at the potential for other inhaled therapies. I say inhaled, because most of the therapies being looked at are inhaled therapies. The rationale there being you have a lung disease, specifically affecting the lung and you happen to have associated pulmonary hypertension. The idea being that if you inhale something as opposed to taking something orally or something through the vein, you might have more of an effect. You're delivering the drug to the area of interest. There's a lot of people and rationale for doing that and maybe sparing patients from the side effects of these drugs, when you inhale it, as opposed to giving it what we call systemically, either orally or through the vein. There's a lot of interest in the inhaled approach. Another product being looked at, and the reason I'm bringing it up is it's maybe close to being available and being launched, is a drug called Yutrepia. Again, another formulation of inhaled treprostinil made by a company called Liquidia. We are recording this before the potential for launch, but it's possible that this drug could be launched as early as May of 2025. Again, the potential benefits of that drug, because one could ask, "Well, what's the point? You already have an approved medication that's inhaled treprostinil, as well." The touted benefits of that drug may be a decrease in side effects, particularly cough, which may allow more up-titration of that particular medication in terms of actual absolute dosing. What we do know is that more is better of this medication, inhaled treprostinil, in the setting of PH-ILD. If we can get to higher doses without having side effects, that would be the ultimate goal. Then, even a further goal would be to do that with, let's say, once a day dosing, for instance, to make the frequency less. That would be pie in the sky. But the point is there's motion here and there's movement, so we look forward to that. There's another formulation of inhaled treprostinil being looked at, which is by a company called Insmed, and they're also looking at a once-a-day formulation of inhaled treprostinil. Again, specifically in pulmonary hypertention with interstitial lung disease. That's not as far along as the Liquidia product, but that's also exciting, because again, you would be going to once a day, which would be a game-changer for a lot of patients. There's other companies looking at other formulations of inhaled treprostinil and trying to make that better, if you will. The reason I say that is because the current approved medication, inhaled treprostinil, is a drug which is four times a day and also can have cough associated with it, which is not atypical for an inhaled medication, but a lot of these patients have cough even from their interstitial lung disease to begin with. So, when we introduce a medication which sometimes exacerbates their pre-existing cough, it can become quite difficult. At four times a day, it can be a little cumbersome. There are other companies trying to improve the side effect profile perhaps, but also the frequency of how often they take it, trying to build on what's already out there. In addition to reformulating the treprostinil product there, there's also other companies looking at other mechanisms, just brand-new mechanisms. For instance, there's a drug called Seralutinib, which is made by Gossamer Bio. This is a drug also inhaled, a dry-powdered inhaler, which blocks certain molecules in the body called tyrosine kinases. It blocks several of these and has a lot of promise in PAH, so that's Group 1 pulmonary hypertension, but they've extrapolated that and now are looking at it actively in Group 3 pulmonary hypertension, specifically this PH-ILD, pulmonary hypertension with interstitial lung disease. That's exciting. The other medication that's being looked at is a drug made by Pulmovant, which is called Mosliciguat, which is reminiscent of another pulmonary hypertension medication that we have in Group 1 disease, which is called Riociguat. But this is specifically being looked at, much like the Seralutinib product is being looked at in both Group 1 pulmonary hypertension as well as Group 3 pulmonary hypertension. Again, specifically pulmonary hypertension with interstitial lung disease. So again, you can see that the people are making newer medications not just for the Group 3 necessarily, but they're looking at it in Group 1, the more traditional pulmonary hypertension, the pulmonary arterial hypertension, but also looking at it in Group 3 pulmonary hypertension. That product with Pulmovant is also an inhaled medication. There is a protocol in motion, as we speak, looking at PH-ILD, which is exciting. It's a guanylate cyclase activator. It works in the nitric oxide pathway, which has been an old pathway used in pulmonary hypertension. It has some interesting benefits that are touted in terms of how it works in that pathway specifically. But without getting into the details, it is an old mechanism, but looking at it with new parts, if you will. That's Pulmovant. Again, that's their new medication, Mosliciguat. That's out there, as well. There's some other ones in the pipeline that are not as far along. There is a aldehyde dehydrogenase stimulator, which is being looked at. Again, very early. There's a drug that blocks hyaluronan synthesis, which is a drug that's coming out of Stanford actually, which is also very early in the mix. Nothing really ready for patients to engage in just yet. But again, the pipeline's pretty deep. It's very exciting because pulmonary hypertension with interstitial lung disease has really been a type of pulmonary hypertension yearning for a drug that we can actually give patients and actually get some relief. It turns out that this particular type of pulmonary hypertension, it causes a lot of illness, much more than the other types of pulmonary hypertension. These patients are unfortunately dealing with pretty much two lung diseases, they have pulmonary hypertension and they have this interstitial lung disease, so they tend to need oxygen. They tend to be very functionally limited. As anyone knows, living with oxygen in the house is hard enough. Leaving the house with oxygen, it becomes extremely difficult. Unfortunately, us in the respiratory world and the pulmonary world, we haven't really figured out how to best give oxygen outside of the house just from a comfort standpoint, and just making it easy for patients. It's still, I think, relatively cumbersome. I think that's another area that we should be focusing on to make living with oxygen easier, particularly outside of the home. So yeah, I'm happy to report that there's a lot going on in this field. From a clinical trial standpoint in the PH-ILD space, luckily so far, knock on wood, there's been sort of minimal overlap in terms of the trials being available. In other words, we don't have two trials or more going on at the same time for PH-ILD. For instance, I mentioned the Liquidia product, Yutrepia is farther along, so their study is finishing while the Pulmovant study with Mosliciguat is ramping up. So luckily, we haven't had the problem of having to try to figure out which study to go into, or which one to consider, or having choices in that matter. That really hasn't happened just yet, but I suspect it will, given the pipeline we just discussed. At that point, I think it's just an individual patient discussion, one-on-one discussion with the pros and cons, and probably has a lot to do with the side effects they're dealing with at some point, or inclusion/exclusion criteria. I think it gets into some of the details that we'd have to have an individual discussion with that particular patient to make the best decision with them. From a physician standpoint and trying to understand disease, any disease, not just pulmonary hypertension with interstitial lung disease, once we get more and more into it, we often start realizing that things can't just be lumped. Patients can't just be lumped into one category that you have PH-ILD and everyone will respond to drug X or drug Y. We all know that not everyone responds to available therapies. Or if there is response, there's a spectrum of response. Some are no response, some have mild response, some have significant response. But what makes this even more, I guess in some ways, difficult, but also exciting from a medical standpoint is that we are learning that there is an extreme amount of heterogeneity within PH-ILD. By that, I mean there's so many different causes and etiologies of ILD, and each of those patients with ILD has a different natural history of that specific ILD in terms of how it progresses. Some people are much more stable than others. Some people are progressively getting worse faster than others, and it has a lot to do with the type of ILD. Then, when you throw the pulmonary hypertension on top, the pulmonary hypertension itself has a heterogeneity to it in terms of how it progresses. Does it stay stable or does it tend to progress? Then, you can understand that when you're dealing with two diseases which are heterogeneous in their natural history, then it becomes a little bit more difficult to understand in terms of lumping people in one category. That's important, because the physicians in this space, and I being one of them, one of our tasks is to make sure that we understand what we call phenotypes. A patient's phenotype is not always the same with PH-ILD. Phenotype means the set of characteristics specific to that patient. There'll be patients just like that patient that fit into a certain phenotype. There's going to be multiple phenotypes in this PH-ILD space. We're learning about those. The reason it's important is because not only do they have different rates of progression or changes in their ILD and PH, but it also predicts who's going to need a lung transplant sooner perhaps, or who may be more responsive to a medication. Perhaps a patient who has idiopathic type of disease responds better to something than someone who has a connective tissue disease or vice versa. Those are the things that we need to learn about, so then we can inform patients better. Sometimes, that might trigger us off into saying, "Hey, you probably should think about this clinical trial, because the data with your type of phenotype may not be as predictable or as wonderful as we want." That's just the reality of the situation. Some people are going to have better responses than others. But that's important for us to identify that a priori so we can actually have a discussion with some real data so the patient can be informed, so we are not just making up stuff. We want to actually have real data, that hard data so we can actually help the patient make the best decision. I think that's really important. I'm Dr. Rajan Saggar, Co-Director of the Pulmonary Hypertension Program at UCLA in Los Angeles, California. And I'm aware that my patients are rare. Learn more about pulmonary hypertension trials at www.phaware.global/clinicaltrials. Engage for a cure: www.phaware.global/donate #phaware Share your story: [email protected] Like, Subscribe and Follow us: www.phawarepodcast.com. #phawareMD #PHILD @UCLAHealth @GossamerBio #Pulmovant #PROSERAstudy #clinicaltrial #PHOCUSstudy

For decades, researchers have sought better treatments for pulmonary hypertension in interstitial lung disease, a condition that drastically impacts patients’ quality of life. In this episode, Dr. Rajan Saggar dives into the latest advancements, including new inhaled medications, upcoming clinical trials, and the push for more personalized treatment approaches. This Special Edition episode is sponsored by Gossamer Bio and Pulmovant. Learn more about pulmonary hypertension trials at www.phaware.global/clinicaltrials. Engage for a cure: www.phaware.global/donate #phaware Share your story: [email protected] Like, Subscribe and Follow us: www.phawarepodcast.com. #phawareMD #PHILD @UCLAHealth @GossamerBio #Pulmovant #PROSERAstudy #clinicaltrial #PHOCUSstudy

Eric Austin, MD, MSCI discusses early detection among people who are at risk of pulmonary arterial hypertension (PAH), particularly those who would have genetic susceptibility, or who may have congenital heart disease, or who may have connective tissue disease or other features that would make them more at risk of developing pulmonary arterial hypertension than the rest of the population.

My name is Dr. Eric Austin. I'm a physician and physician scientist at Vanderbilt University Medical Center. I direct the Pediatric Pulmonary Hypertension Program at Vanderbilt and have done so since 2012. I have studied children and adults with pulmonary hypertension, in particular pulmonary arterial hypertension, but other forms as well, for nearly the last 20 years, with a particular interest in people who are at risk of pulmonary arterial hypertension for various reasons or are resilient to its development for reasons. 

I have great interest in the topic at hand today – early disease detection among people who are at risk of pulmonary arterial hypertension, particularly thinking about people who would have genetic susceptibility, or people who may have congenital heart disease, or people who may have connective tissue disease or other features that would make them more at risk of developing pulmonary arterial hypertension than the rest of the population.

When you think about people who are at risk of developing pulmonary arterial hypertension, the most commonly thought about group in the current era are individuals who actually have familial disease; that is to say they have pulmonary arterial hypertension, or PAH, that occurs in families. This would be two or more family members with truly documented pulmonary arterial hypertension. We and others here at Vanderbilt and others around the world have been interested in studying families who are impacted by pulmonary arterial hypertension as a way to investigate the factors that lead to disease expression or presentation of PAH among people who are at risk.

Years ago, in 2000, the initial genetic discovery was the association of bone morphogenetic protein receptor type II, or BMPR2 gene, with PAH. This association was discovered by several groups working in concert and several groups working independently, who discovered that single-gene mutations or rare variations in the BMPR2 gene can associate with pulmonary arterial hypertension. I intentionally said associate, because while I think they cause PAH, we don't actually definitively know that those mutations, ”cause pulmonary arterial hypertension.” We just know that beyond a shadow of a doubt, families with BMPR2 mutations are much more likely to have people with PH in them than the general population. 

Other genes have emerged over the past 20 years associated with pulmonary arterial hypertension, including mutations in the gene TBX4, mutations in ALK1 and endoglin, which actually also associate with hereditary hemorrhagic telangiectasia, SOX17, and several other genes. There's a smattering of genes that are now known to put a person at risk of developing pulmonary arterial hypertension. You may ask, "Well, what's the risk?" Well, that's the hard part. If you look at families who have individuals who have mutations but are healthy, it does appear that not everyone with a mutation in the genes that we think essentially “cause” pulmonary arterial hypertension will ever develop pulmonary arterial hypertension in their lifetime. Stated another way: a person with a mutation in one of the ‘PAH genes’ will not necessarily develop PAH.

Most of this data actually is from BMPR2 mutation-carrying families, because mutations in this gene are by far the most common--about 75% of families that have PAH due to BMPR2 gene mutations. So most of our data emerges from those people. We know that on average, about 20% of all people who carry one of those mutations will develop PAH in their lifetime. But that's not a yearly risk; that's in their lifetime. We also know that mutation-associated PH can develop not only at any point in the life; but, it's actually different from men and women. People of female sex are much more likely to develop PH than those in male sex who have BMPR2 mutation. In fact, it's about a 42% lifetime risk for a female to develop PH if they have a BMPR2 mutation and about a 14-16% lifetime risk for men.

For reasons we don't totally understand yet, although a lot of work has gone into this, as you can imagine, BMPR2 mutations don't equally cause PH between biologic females and males. That's a point of interest that makes you think, "Well, are the people of male sex resilient in developing PH, or are the females more susceptible, or somewhere in between?" It's probably somewhere in between, but we don't know for sure.

You may then ask, "Well, what is the risk of a person to develop it in a given year if they have a mutation?" I told you there's a lifetime risk of about 42% for females and about 16% for males, but what is the yearly risk? Some of that work has now emerged from groups in Paris and in the Netherlands who have been studying individuals who have pulmonary arterial hypertension in families. Recent data from the French registry of these individuals suggests that about 2 to 3% of people per year in their cohort convert and develop PAH every year. If you take a group of people and they say to you, "Well, what's my likelihood of developing PH in the next year," it's probably about 2% to 3%. We don't know specifically yet. That's the best indicator we have. 

Here at Vanderbilt, we follow about 250 families who have pulmonary arterial hypertension in their family, and many of those have a BMPR2 mutation, and that's probably about the data that we have as well, though we have not published that. We also are now excited to be studying individuals who have BMPR2 or other mutation-associated PAH and then their family members who have those mutations but are healthy. We call that the RARE study, R-A-R-E. It's funded by the National Institutes of Health. I'm pleased to work on this with my collaborators and friends, Drs. Anna Hemnes and Evan Brittain, where we're studying people who have PH in the family, looking at healthy and unaffected as well as PH-affected people. We're interested not just in what makes the person who has the disease develop the disease, we're interested in what helps the person who is healthy stay healthy. By studying genomic and transcriptomic information, which tells us about their DNA and RNA, and then protein-based factors in their blood that may ultimately associate with whether they develop the disease or whether they stay healthy, we hope to learn more about ‘resilience’ to and ‘susceptibility’ to PAH.

We hope that one day if we can figure out what factors are more present in the healthy people who should be sick and are less present in the diseased people who should not be sick, we can harness that to both prevent disease, but also maybe someday develop treatments built around that. You can imagine if there's something that... We find a protein that really helps someone stay resilient to or prevents them from developing PH even though they ought to have it, what if we could harness that as a therapy in the people who already have the disease? We're really interested in this notion, both here at Vanderbilt and around the world, of using people who have genetic susceptibility to understand the disease better and to understand how to prevent it and how to treat it better. 

You see a great example of this in the recent approval of sotatercept in the EU and in North America by the FDA. The drug sotatercept really emerged because of the genetic discoveries around BMPR2 and the associated pathways that go with it. We think that there's a lot more opportunity to learn a lot more from our genetically susceptible and genetically resilient people. 

There are also other forms of disease that associate with PAH. We know that individuals who have an illness known as HHT, or hereditary hemorrhagic telangiectasia, we know those people also are at higher risk of developing PAH in their lifetime. It's still quite rare for those people. It's not a common presenting symptom, but all of our PH clinics have multiple people with PAH and HHT, so it's common enough that we see at a fair amount. There are actually two different genes that most strongly associate with HHT, and that's endoglin and ALK1, or ACVRL1, and a few others. You probably don't care the names about them per se, but just to know that there are families of individuals who have HHT that courses through the family, and those people are also at risk of PAH.

For people who have genetic susceptibility, whether it's HHT families or families with BMPR2 or other gene mutations, there's a little bit of controversy onto how often to screen the healthy people for pulmonary arterial hypertension. You may ask me, "Well, what do you do?" Most people would recommend that first-degree relatives, that is a mom, a dad, or a son or daughter, or a sibling, of a PAH patient due to a mutation like BMPR2 or HHT PH be screened every one to three years with a clinical evaluation and an echocardiogram for pulmonary arterial hypertension. I told you earlier, I direct the Pediatric PAH Program here at Vanderbilt, and here at Vanderbilt we actually tend to see the children who are at risk about every year with a clinical exam and an echocardiogram. I also like to get spirometry with DLCO to look at their diffusion capacity. If they seem at all impaired, we'll do a full six-minute walk test and lung volumes as well.

But what we're doing is we're trying to screen them and perhaps detect PH earlier. If their echocardiogram is abnormal, you can imagine we would activate a full PH workup, including ultimately cardiac catheterization, because we think that earlier therapy will probably lead to better outcomes. We don't actually have that definitively proven, though, in clinical studies. But we also know that every year we have people who have syncopal events or pass-out events or other dangerous events that occur with their pulmonary arterial hypertension. I would be devastated to know that someone was at risk and we never looked for PH and then they died or had a bad event in the community because they passed out. So we screen our people who are children every year. In the adult world, you may see it more commonly every one to three years of screening those at risk.

Another form of at-risk population would be the individuals who have connective tissue disease. The most common connective tissue disease that we know associates with pulmonary arterial hypertension is scleroderma or systemic sclerosis. But you can actually see PH in other forms, including lupus, mixed connective tissue disease and the like. So individuals, and they're usually but not always adults, who have connective tissue disease but are not known to have PH should be screened for pulmonary arterial hypertension every one to three years as well with a clinical evaluation and echocardiogram.

Now, the reality is if you have connective tissue disease and you're well-connected, you're probably seeing your provider every three to six months, and part of the evaluation at every visit is considering progression of disease; is it possible the person has a new diagnosis of PAH? It's not extremely common in those groups to develop PH, but it certainly can happen. They can also develop pulmonary hypertension due to what we call Group III PH, which would be more lung-disease-driven, perhaps due to interstitial fibrotic changes in their lungs that can cause low oxygen tension and can cause PH, as well. So it's not always a pure pulmonary arterial hypertension Group I phenomenon.

That's a quick once-over of the main types. The other things you see in children but not as much in adults, although you certainly can, is congenital-heart-disease-associated pulmonary arterial hypertension. So people who maybe had profound severe congenital heart disease that was operated on when they were young, such as a tetralogy of Fallot, or people who have less severe congenital heart disease, such as an atrial septal defect or a ventricular septal defect that's being monitored or was repaired, can all develop PAH at any point in their lifetime, as well. There's not strict guidelines for pulmonary arterial hypertension or pulmonary hypertension screening for repaired individuals who have had congenital heart disease in the past, but certainly if you were a provider and you saw a person with a history of congenital heart disease repaired that presents with unexplained shortness of breath or difficulty in breathing or other features that could be suggestive of pulmonary hypertension, then you would certainly want to activate some sort of more aggressive screening evaluation for pulmonary arterial hypertension for those people.

Lastly, this is a group that may be less likely to seek care until they're very sick, or they may be depending on the scenario, would be people who are using recreational or other forms of drug use, such as amphetamines or cocaine. Those people are at higher risk of developing pulmonary arterial hypertension. So too are people who use the dietary drug fenfluramine, which has largely gone away in the United States and in Europe, but is known to associate with pulmonary arterial hypertension. This is not the diet drug that you're seeing now that's so popular across the world right now. Ozempic would be a common name for semaglutide and related GLP agonists. Those drugs do not, to our knowledge, associate with pulmonary arterial hypertension. But a traditional weight loss drug called fen-phen, or fenfluramine, did associate with pulmonary arterial hypertension. We still see it's used sometime among people with seizure disorders, by the way. I recently had a patient with this exposure, and we decided to stop that for safety reasons for that person.

If you think about people who are at risk of developing pulmonary arterial hypertension, as I mentioned before it's pretty rare. Thankfully there's a lot more common diseases out there than pulmonary arterial hypertension. But it's really challenging to develop that disease because pulmonary arterial hypertension can significantly impact someone's quality of life and their survival over time, and so we like to be vigilant about it.

If you ask the question, "How would one use the information we know about people at risk in a day-to-day basis," what I would say is that certainly for those individuals who are in a family known to have people with PAH in the family, two or more people in particular, of pulmonary arterial hypertension, it would be great for the family to be aware of it as a group and understand that, “Hey, cousin Jimmy died of pulmonary arterial hypertension and his son or his daughter also has it. I should think that if I ever feel short of breath, or if my daughter ever feels short of breath or has difficulty with walking or not really the same cardiovascular fitness that one would anticipate, that person should go be screened and seen by a medical professional.”

One great way is to be aware of it on your own. It can be hard for families, because sometimes some of the people who are impacted in the family may be multiple branches of the pedigree or multiple branches of the tree away from the person who's actually at risk; that can happen. For individuals who have other risk profiles, like if they have connective tissue disease, if they have congenital heart disease, it's that partnership with your provider or your physician or your nurse practitioner or your PA or whoever you're working with for your care, and both of you together being aware that not only are you being cared for your current problems, but being vigilant for the associated conditions that can occur in the setting of your current diagnosis. 

If you have connective tissue disease, having a good discussion with your provider about, "Hey, Dr. so-and-so, thank you so much for your care of my rheumatoid arthritis, but what other things should I be thinking about as we move along through life? Do I need screening for pulmonary hypertension? Do I need screening for such and such?" Having that dialogue with your provider can be really helpful. Obviously, we're hopeful that would never actually come about and you would not be impacted by PH, but we would want to be on top of it in the event that you did have that happen.

A thing that we're finally becoming a little more aware of in the PH community is the incorporation of people of all backgrounds, shapes, and sizes. For whatever reason, for many years, a lot of the individuals who we were studying at least, and even the people in our clinic, skewed toward a Caucasian population. But we've recognized in the last 10 years in particular that that needs to be rethought and more sensitively thought about. There are people in disadvantaged groups, individuals who are native people of the region, individuals who have African ancestry, individuals from LGBTQ+, who may not be seeking care or receiving care with the frequency with which other populations are. 

Many of us have worked with many groups to improve our distribution of information about pulmonary hypertension across all providers and into populations of individuals, as well, because that is a really important thing. I know Dr. Vinicio de Jesus Perez at Stanford has worked very closely with disadvantaged people across the world, which is another issue that's important. The PVRI (Pulmonary Vascular Research Institute) has been working on this ,as well, spreading the information about screening and about notification of PH and awareness both within North America, but also around the world in places that may be less able to access care or less able to access screening.

Right here at home, I think we've done a much better job in the last 10 to 15 years of being aware of this and made sure that we are getting into all communities. Just like any other medical condition, if you don't have access to the care or you're not receiving care that's aware of the problem, you can miss it. I think through the years we've been not as aware of that as a group as we can be, and we've seen a real improvement of that over the last 10 years or so. I absolutely know that I have learned a lot about that, and so that's a really important point and it’s something that we, as providers, need to be thoughtful about.

My name is Dr. Eric Austin, and I'm aware that my patients are rare.

Learn more about pulmonary hypertension trials at www.phaware.global/clinicaltrials. Follow us on social @phaware Engage for a cure: www.phaware.global/donate #phaware Share your story: [email protected] #phawareMD @VUMCDiscoveries @pphnet @VUMCchildren

Eric Austin, MD, MSCI discusses early detection among people who are at risk of pulmonary arterial hypertension (PAH), particularly those who would have genetic susceptibility, or who may have congenital heart disease, or who may have connective tissue disease or other features that would make them more at risk of developing pulmonary arterial hypertension than the rest of the population.

Learn more about pulmonary hypertension trials at www.phaware.global/clinicaltrials. Follow us on social @phaware Engage for a cure: www.phaware.global/donate #phaware Share your story: [email protected] #phawareMD @VUMCDiscoveries @pphnet @VUMCchildren