Rajan Saggar, MD - phaware® interview 515

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.

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