Dr Martinez: So this field has just dramatically advanced in a short period of time. And so to be able to fit 20 minutes of discussion regarding therapy is really challenging, guys. So I am going to try to take you through some of the key components. I am going to try to split it into IPF and non-IPF. Remember what Corey said, IPF and then a whole series of other interstitial fibrosing disorders.

[00:50:50]

Algorithm for the Clinical Management of IPF

This is a summary that we created for a clinical practice guideline on the management of IPF. It is now outdated as of two weeks ago. In fact, it is outdated from the time we made these slides, Tyler.

And so I will give you a sense of where that outdating is taking place. As of 2022, when we published this guideline, the treatment of IPF was felt to include an anti-fibrotic agent. And the intended and prevented, I will show you some of the data for that.

For those of you that were answering pre-imposed test questions, notice steroids are not in there. And so the use of glucocorticoids for the chronic management of IPF is not a routine recommendation. It may be in the setting of an acute exacerbation, but not in this setting.

And so it is really anti-fibrotic management that is the cornerstone of pharmacological therapy. We will go through other components of this slide later on. So do not worry too much that I am glossing over key components.

[00:51:47]

INPULSIS-1: Nintedanib in Patients With IPF

Here are the data that led to that recommendation. These are studies that we completed about a decade ago. INPULSIS was a study of nintedanib. It is a multi-kinase inhibitor. It is originally developed for cancer. And these studies were performed in patients with IPF, as Corey alluded to in his, how you make the diagnosis.

They were randomized to drug or placebo and were followed for a year. The primary endpoint was what happened to lung function because IPF is felt to be a progressive disorder. The goal was to see whether you could attenuate that decrease, that worsening in lung function.

[00:52:23]

Nintedanib Reduces FVC Decline in IPF

Sure enough, FVC on the left-hand side, X-axis is the time in the study. Placebo patients had a steady deterioration in their for spinal capacity, a lung function parameter, and nintedanib attenuated it. It did not cure it. It did not resolve it, but it clearly decreased the slope of deterioration in that parameter. And so these were the key data that allowed us to say, okay, here is a drug that is affecting a marker of fibrosis, a lung function marker of fibrosis, FVC. That led to its approval by the FDA.

[00:53:00]

INBUILD: Nintedanib in Patients With Progressive-Fibrosing ILD

A few years later, one of my mentees actually from Michigan, Kevin Flaherty, published this study, which was the same drug, same kind of a study design, same dose, but this was not now in the non-IPF fibrotic disorders. And these were individuals predominantly that had chronic HP or connective tissue-associated disorders were the most common, that had already demonstrated evidence that they had progressed. So they had become more symptomatic. They had lung function declines. Their CT had worsened. So that was already a patient population sort of predefined for progression, randomized to the drug placebo, with the same idea looking at what happened to their lung function decline over time.

[00:53:42]

Nintedanib Shows FVC Decline in Progressive-Fibrosing ILD

Sure enough, in that setting, you noted on the top, is what happens with nintedanib in the overall population in black. Blue is those that had a UIP pattern. Corey has told you what that is. Below are the same groups that were on placebo.

So this study demonstrated that in patients with non-IPF fibrotic lung disease that had shown progression, you could attenuate that with nintedanib. That is the drug, the antifibrotic therapy that has now been approved for both of those indications. For those of you that use these drugs, you will know nintedanib is a challenging drug to use.

It has liver function abnormalities, it has some drug-drug interactions, it has quite a bit of GI side effects, and so it requires very careful management of the patient with a multidisciplinary approach to ensure that the patient can tolerate this drug and is able to achieve some of the benefits. So that is nintedanib.

[00:54:37]

ASCEND: Pirfenidone in Patients With IPF

Pirfenidone actually came out a little bit earlier. None of us are still sure exactly what pirfenidone does. It is clearly an antifibrotic. This was one of three large randomized control trials. It was the last one that really pushed the regulators to approve this drug. And this was an IPF study. So pirfenidone is well studied in IPF.

Same kind of study design. Patient with IPF meeting the criteria that Corey just gave you for how a diagnosis is established. Treatment with drug, placebo. What happens over the course of a year?

[00:55:07]

Pirfenidone Reduced Disease Progression in IPF

Sure enough, pirfenidone also attenuated the decline in lung function in patients with IPF. This study led to its approval in IPF. For those of you that have used pirfenidone, it is also a tough drug to use.

It has liver function abnormalities in a small proportion of individuals. It causes fatigue. It can associate it with a rash. It is tough to take. It requires, again, a lot of multidisciplinary management with the patient to ensure that you are adjusting the dose, you are getting the maximal tolerability.

I am not showing you any of the data of pirfenidone in non-IPF fibrosing disease because those studies have been inconclusive. And so it is not really approved for that indication. Pirfenidone is approved as an antifibrotic for IPF. So when I showed you that earlier slide that had pharmacological treatment, this is why nintedanib and pirfenidone are on that list.

[00:56:00]

FIBRONEER-IPF: Change in FVC at Wk 52 in Patients Taking Background Therapy

Now, what has happened this year has been this drug. So this is nerandomilast. Nerandomilast is a selective PDE4 inhibitor. You are familiar with PDE4 inhibitors. There are several on the market for COPD or for eczema. This is a targeted therapy in a fibrosing patient population.

So this is a study that we published earlier this year confirming that, in fact, actually several things came out of the study that were really quite important. Nerandomilast, this PDE4 oral inhibitor at two doses, also attenuated decline in lung function. Placebo is there. The two drugs are to the right-hand side. I mean, pretty significant attenuation of that decline. And almost 80% of these patients were already on an antifibrotic agent.

So that demonstrated that not only does nerandomilast attenuate the loss of lung function, but it can be done in addition to the other antifibrotics. One of the advantages of nerandomilast, at least in the studies, is that it is much better tolerated. It has some diarrhea, but less diarrhea in the clinical trials. It does not have the same liver function components. It does not have the same drug-drug interaction components. So nerandomilast, as of a couple of weeks ago, was approved by the FDA.

And I do not know about you, Corey, but this has become first-line treatment for IPF just because of its tolerability. One of the other interesting things that occurred with this nerandomilast study is that there was a drug-drug interaction that we were able to document with nerandomilast in the setting of a patient already on pirfenidone. And so when you look at the dosing and you look at this prior slide, you can go, both of those doses look pretty good. That looks pretty reasonable. The difference being, if you have a person on pirfenidone that is progressing and you want to add nerandomilast, that really does require the 18 mg dose because you will decrease drug exposure by 50% in that setting. So nerandomilast has now completely altered our prior recommendations because it is now no longer pirfenidone and nintedanib, but now nerandomilast is going to end up having to go up there.

And that guideline is actually in the process of being revised now because this data are now available and the drug's approved.

[00:58:12]

Nonpharmacologic Interventions for Managing IPF: Supportive Care

There are a whole series of non-pharmacological treatments you have to consider in parallel. Oxygen therapy supplementation is something that we have adapted from the COPD space, which is where the best data exists.

And we have made the assumption that the same sort of criteria relate to an ILD/IPF population. That is probably correct. Pulmonary rehab is also not well studied in this population, but also, is low-risk, and it likely does improve at least functional status.

And then, really, we have argued for years that the only intervention that has been demonstrated conclusively to improve survival is lung transplantation. I am not sure, Corey, that I would make that statement anymore with some of these antifibrotics, but it is certainly a therapy that is available that should be considered in patients with IPF because it is a progressive disorder. Even the therapies that I have shown you do not normalize lung function, do not resolve everything.

And so you always need to consider lung transplantation as a viable option in selective patients. I will come back to that again in a second.

[00:59:19]

Monitoring the Clinical Course of IPF

All right. I told you that I would come back to this slide and show you some of the other components. The right-hand side, which is how we monitor patients over time, is actually one of your pretest questions. So the idea that we will just follow patients every couple of years and we will only do follow-up if they are having symptomatic changes is not what is recommended.

The recommendation by pretty much every society that has taken a stand is that you really should be following patients on a regular schedule, anywhere between 4-6 months. And that includes symptomatic assessment. It includes pulmonary function assessments, particularly relevant now that we have data that you can actually combine antifibrotics. So if you document that there is progression, you have things that you may want to do at this point.

CT scan recommendation, it really is an annual CT scan. Not that CT progression dramatically alters what you do, but there is a significant increase in lung cancer and IPF population. And so this is an extension of the low-dose CT scan title that we use in smoking populations. This is an extrapolation into the IPF population. And so remember that the recommendation currently in an IPF population, I will show you the non-IPF in a second, really is regular follow-up on a regular schedule, monitoring symptoms, quality-of-life, lung function. It is not, "We will see you in a couple of years." And so for those of you that are going to answer the post test, remember that, not that I am trying to give you away answers.

[01:00:48]

Management of Comorbidities and Palliative Care for IPF

There are a series of comorbid conditions that are also quite common in IPF, in part because there are older patients. I will spend most of my time talking about pulmonary hypertension. Reflux is something that has been potentially argued as a biological rationale for developing IPF. And so I do not know about you, Corey, but I am very aggressive at asking about reflux, and any suspicion of reflux is going to trigger pharmacological therapy.

We in fact published a study a few years ago of surgical therapy in IPF patients with uncontrolled reflux. And there was a suggestion of improvement in survival. And so I am really aggressive about the reflux management.

If a person says, "Oh yes, no, I have heartburn," you are getting yourself on a pharmacological regimen and a dietary modification just in case. So IPF, the therapy of IPF is early institution of an antifibrotic. This slide, as I told you, is now updated because it now adds nerandomilast to that list up top.

Careful follow-up of the patient on a regular schedule, at least every four to six months, and then assessment for comorbidities, particularly reflux at this point. I will come to some of the other ones in a second.

[01:02:00]

2023 ACR/CHEST Guidelines: Treatment Algorithm for SARD-Related ILD

In non-IPF, guys, we do not have enough time in the remaining period of time that I have to be able to describe to you therapeutic interventions in non-IPF. It is just very complex, in part because there are a lot of treatments. And so in the autoimmune space, so this is, sorry, Corey, what you and I have called connected tissue in the past, but we will defer to our rheumatology colleagues. There is actually now a very complex schema.

This actually is a wonderful reference that you should look at. And it is being updated now, but this is the most recent version of it that really gives you a sense by different autoimmune disorders, what first-line therapy options are, what second-line therapy options are. And you can see that there are a lot of things in these boxes.

This is not just one drug. I mean, it has mycophenolate is standard for systemic sclerosis. Rituximab also seems to work. Nintedanib has been shown. So there is a lot of movement in this space, which is good for patients.

The bottom, high-dose, long-term use of steroids is no longer felt to be a standard treatment for these patients. It is now really targeted therapies that you start on first diagnosis when there is progression.

[01:03:08]

2023 ACR/CHEST Guidelines: Treatment Algorithm for Rapidly Progressing SARD-Related ILD

And in some patients that have very specific types of autoimmune disorders, for example, this anti-MDA5, which tends to progress very rapidly, there are now very specific therapeutic recommendations. This is one of the situations where you do see steroids plus combination immunosuppressive therapy.

So keep in mind now that the management of IPF and non-IPF has become much more complex in a good way because there are a breadth of therapeutic options that are available, which means that when you were thinking about what Corey was talking about in terms of approaches to diagnosis, it is really important to have a sense of what you are dealing with because the treatments really do differ now. And there are therapeutic options that are targeted to specific fibrosing ILDs. And it is up to all of us in a multidisciplinary fashion to try to figure out what do we think a patient has, because it is going to alter what you do therapeutically.

[01:04:03]

INCREASE: Inhaled treprostinil in Patients With ILD-Associated Pulmonary Hypertension

I told you that I would mention one other concomitant sort of comorbid component, and that is pulmonary hypertension. And the reason I mentioned that is that there is an approved therapy for pulmonary hypertension associated with ILD, broadly defined, IPF, non-IPF. And in this particular study published about four years ago, there was clearly a functional benefit as measured by a six-minute walk with inhaled treprostinil in patients with an ILD, fibrosing ILD, with evidence of pulmonary hypertension. And we have all used this in this setting.

[01:04:40]

INCREASE: Predicted FVC and Disease Progression

What is interesting is that in this particular study, there was an analysis that was done in parallel that suggested an improvement in lung function on the left-hand side and a decreasing time to disease progression, mostly driven by preserving lung function. This led to a study that I am going to talk about next under emerging treatments, because that is going to be the next thing that is going to alter what we do in a good way.

So we know that in patients with ILDs, fibrosing ILDs, the presence of pulmonary hypertension can be treated. So it has become now regular for us to assess for pulmonary hypertension, at least initially with a cardiography, because there is a therapy that you can use in that setting.

[01:05:22]

Emerging Therapies

Now, when I come to emerging therapies, I am going to talk about three things. I could spend another 45 minutes, Corey and Tyler, talking about emerging therapy, because I do clinical trials for a living. I mean, my God, there are 106 active studies going on right now. I do not have enough time, Tyler, to show you 106 studies in five minutes. So I am only going to touch on three things.

[01:05:44]

FIBRONEER-ILD: nerandomilast in Patients With Progressive-Fibrosing ILD

The first is nerandomilast. This is the same PDE4 inhibitor that I showed you earlier in IPF. This was the parallel non-IPF study. We also published this in May of this year in the New England Journal. And this was a study that looked very similar to that nintedanib study in non-IPF that I showed you earlier.

That is, these were mostly chronic HPs, autoimmune disorders, or NSIP that had progressed. So these were already established as a progressive non-IPF fibrosing ILD. And they were treated with placebo and the gray and the two doses of nerandomilast.

There was no doubt that you clearly can decrease lung function decline with this drug. More importantly, Corey and Tyler, if you guys looked at this, we were able to demonstrate an improvement in survival over only 52 weeks with a selected PDE4 inhibitor. This is now at the FDA and we anticipate that FDA approval for this drug will be in probably January or so.

I do not know exactly the time frame, but that is what that suspicion is. So I put it here, Tyler, under emerging therapies, but this, by the time we do the session next, is going to be an established therapy, and it is going to be a really important therapeutic advance in this field.

[01:07:02]

TETON-1/2: Inhaled treprostinil in Patients With IPF

Remember I showed you that in inhaled treprostinil study with the pulmonary hypertension, suggesting that there was an improvement in lung function? So those, that group of investigators, that company actually completed a study in IPF that read out about three or four weeks ago, suggesting that that finding is in fact correct. That inhaled treprostinil, even in patients without pulmonary hypertension, can actually preserve lung function.

I put it here under emerging therapies because this is not published yet. I am sure that this company will go to the FDA and ask them, if they have not already, to modify their current indication to expand it beyond just an IPF with pulmonary hypertension. Their pulmonary, their progressive pulmonary fibrosis non-IPF study is ongoing. I cannot imagine that is not going to read out as positive as well.

So by the time we do this presentation in a few months, you will have to choose between multiple antifibrotic approaches that can be combined in our fibrosing population. Corey, for some of us that have been doing this for a long time, this is like a completely different field right now than it used to be. So it is really pretty exciting.

[01:08:17]

Admilparant: An LPA1 Antagonist

This drug, admilparant, which is an LPA1 antagonist, is another oral drug that seems to be well tolerated. There are two Phase III studies ongoing. I am fortunate to be leading these.

And this was the Phase II study in IPF. It looked similar in the non-IPF progressive pulmonary fibrosis population, with a suggestion that you could, in fact, at least with that 60 mg dose, decrease lung function decline. So we will read out the IPF study at the very beginning of next year, followed later in the year by the progressive pulmonary fibrosis.

We will see what happens if this study is positive. Corey, we will have five antifibrotics that we will be dealing with and trying to decide how to use and how to combine. And so it is really a dramatically, just an exciting field because there are so many good therapeutic interventions.

And so, unfortunately, guys, it makes our life more difficult because it is going to make it more challenging for us to make decisions. But that in this space is actually a good thing because it means we have really good therapeutic options.

So with that in mind, taking you through a whirlwind in 20 minutes of what is occurring in this field, I am going to turn it back over to Tyler.

[01:09:32]

Skill Building and Feedback

Dr Kershaw: We have come a long way from when we were trying to give people interferon gamma about 20 years ago, you know.

Dr Martinez: Oh my God. Tyler, the days of combining immunosuppressive therapy.

Tyler Kuhk: Yes.

Dr Martinez: Corey, you will remember azathioprine, prednisone. I mean, we have debunked that. I mean, we were killing people with what we were doing before.

Dr Kershaw: But there was that, you know, that one trial from the, you know, the Dutch that published, and we got to do this; we got to do this. And thankfully Panther came out pretty quickly and said, please, stop doing that. So that was good.

Dr Martinez: Yes. So one of the key things, Tyler, for people to realize is that in a simplistic point of view in the IPF population, it is not immunosuppression, it is antifibrotic therapy. In the non-IPF progressive population, it is a much more complex interaction with multiple different therapeutic approaches.

Tyler Kuhk: Lots of great information. I think, yes, I mean, the last several years, I think for a lot of pulmonary things, especially ILD has just been, there has been like just everything's just blown up. So we are going to kind of move into another case here for the next 15 minutes, maybe try to get to a couple questions and some discussion.

So now we have Mr. Miller, and he is a 55-year-old bank employee who visits your clinic for a routine follow-up. He reports ongoing issues with cough and dyspnea on exertion and that shortness of breath is worse with hills during walks. He does not have any wheezing or edema, and he was diagnosed with rheumatoid arthritis about three years ago.

So his rheumatoid factor was positive, CCP positive. He is a former smoker, his joint disease is well controlled, and he has had an unremarkable cardiac workup, including negative stress testing and a normal echocardiogram. And so in retrospect, he has also had a chest X-ray from three years ago that was clear.

So we have some PFT data on the slide here. So we have got an FVC of 110% predicted and a DLCO of 67% predicted. Before we move to the next slide, I just want to know if Dr Martinez, if you have anything to add to this case on what you might be thinking before we get into what his imaging looks like.

Dr Martinez: Well, so you remember what Corey told you earlier, that there are a series of these autoimmune disorders that have clearly been associated with a likelihood of developing ILD and rheumatoid arthritis is clearly one of those. And so, Corey already told you this so that you have got to hear a person who has a diagnosis of rheumatoid arthritis, who is coming to you with cough and dyspnea. Guys, remember what Corey told you. Cough and dyspnea should trigger in your mind the potential of ILD. Most ILD, most cough and dyspnea is not ILD. Got you, Corey. I understand the cardiologists and, you know, going through the nasal steroid. Yes, I got all that. And it is appropriate to do that.

But here you have a different situation because you have a person that, as Corey has told you before, has an underlying disorder that already predisposes that person to having an ILD. So if you are sitting there in your office and you are seeing this person: cough and dyspnea in a 55-year-old. Oh, and they have rheumatoid arthritis. Corey is going to be there telling you, ILD, ILD, ILD. And it is your pulmonary function test. And the DLCO has decreased. Oh, my God. More push.

[01:12:37]

Mr. Miller’s Imaging

Tyler Kuhk: So what do we think? And here is his imaging. So here are some CT images from Mr. Miller.

Dr Martinez: So great job in ordering imaging.

Corey Kershaw: Yes.

Dr Martinez: Corey, you are a radiologist. We will give you the high bucks for radiology.

Dr Kershaw: Oh, boy. Let me make my screen a little bigger so I can. Okay, so we have, again, a basilar predominant CT scan here, right? Because we have actually got a couple of images now. We are a little south of the carina on the top two images. And then we have one more toward the base there.

I already see an esophagus that concerns me. So as pulmonologists, we are always looking at the esophagus because there is, like Fernando said, there are worries about acid reflux here. But this is also somebody whose esophagus may not be working very well. And boy, we have got a lot of ground-glass, do not we? A lot of haziness in both lung bases. I have a bit of traction bronchiectasis down there. It is some dilated airways, but I do not see any honeycombing, right, guys? No honeycombing here at all.

Are you showing me expiratory images side by side there, perhaps? I am not sure. One left to right. But I also kind of get a little bit of a hint of some peripheral sparing in that upper left-hand corner, but it is not so much so at the bottom. This is an alternate diagnosis pattern, right? Lots of ground-glass, even though I am basilar predominant. But there is so much ground-glass here. This is not going to be in the UIP family here.

Dr Martinez: One thing I realize is you are very sharp because I made the slide, and you are right. Right hand is inspiration. Left side is expiration.

Corey Kershaw: Not my first time.

Dr Martinez: You are a radiologist, buddy.

Tyler Kuhk: All right. Maybe just for the audience, maybe you want to just touch on inspiratory versus expiratory images, what we are seeing on a CT scan, and why they look so different.

Dr Kershaw: Am I still the radiologist?

Tyler Kuhk: Yes, you are.

Corey Kershaw: So an important maneuver we do with an HRCT scan is we ask the patient to do a supine CT scan with a full breath in, and then we repeat the scan with a full breath out.

And the reason I suspected this was inspiratory-expiratory because air images black on an X-ray in a CAT scan. So if I empty the air out, I am number one, increasing the tissue volume of the lung by getting rid of the air. So anything that is denser than air on scan will then be more toward white.

So I have emptied out, some of the black stuff. So I have got more white stuff on the left than I do on the right. But the main thing I am looking for on an expiratory film is, does the air empty uniformly? Are there areas where the air is stuck in some lobular spaces to suggest air trapping? And when I see that, that suggests to me that not only is there involvement of the alveolar space, but there is also involvement perhaps of the airway compartment too. Is there scarring there that is keeping air from leaving? And when you have multi-compartment diseases like that, you think of a couple of things. Number one, hypersensitivity pneumonitis would do that because you have airway scarring because I have inhaled the antigen causing scarring there. The other thing I think about is connective tissue disease because connective tissue disease is likely to affect multi‑compartments, pleural space, vascular space, airway space, alveolar space.

So that is why we do those images.

Tyler Kuhk: Beautiful explanation. I think it is just really important too, especially for our audience, and good wide variety of experience, the importance of a high-resolution CAT scan and the differences between getting a high-resolution versus just a regular. So that was very helpful.

[01:16:18]

Skill Building and Feedback: Case Continued

So Mr. Miller's on multiple immunosuppressants. He is on rituximab, mycophenolate for his RA and his ILD. And he has a mild restrictive defect and moderately decreased diffusion capacity. And we saw that the high-resolution CAT scan with NSIP and connective tissue disease features. And so the diagnosis is a multi-connective tissue disease. So he was admitted to the hospital with acute increase in shortness of breath and cough, does not have a fever, is on high-flow oxygen, does not have a clear infection, and improves with steroids.

So what would be the next best step for Mr. Miller?

[01:17:01]

Poll 7: Which of the following is the most appropriate management strategy for Mr. Miller?

So we can go into the question that we can get into the discussion. So which of the following is the most appropriate management strategy for a patient like Mr. Miller?

1. Start antifibrotic therapy on and then monitor lung function;
2. Continue immunosuppressive therapy and monitor lung function;
3. Discontinue immunosuppressive therapy and observe; or
4. Begin high dose corticosteroid monotherapy.

And I will give you guys a couple of seconds to answer that.

Okay, so we got about 60% that want to start antifibrotic therapy and monitor lung function. And then 22% want to continue immunosuppressive therapy and monitor the lung function.

[01:17:52]

So the correct answer is to start antifibrotic therapy and monitor lung function. Dr Martinez, you want to talk about the correct answer and why that is correct?

Dr Martinez: Yes, so this is a difficult case because it is not something that I can tell you that has the strongest evidence base for. The fact that the person was treated for an acute exacerbation, got steroids, makes perfect sense. This is where you can use steroids in some of these fibrosing disorders, particularly when it is non-IPF. Even if this person had IPF, he probably would have been treated with steroids for an acute exacerbation.

And so what we now know from the most recent studies, particularly the FIBRONEER, that nerandomilast study, is that in patients that are on other therapies that are progressing, there is an advantage to adding an antifibrotic agent. And in the setting of connective tissue disorder, that FIBRONEER PPF study, the one that I showed you that was published a few months ago, waiting for the FDA to act upon, suggests that in that setting, the addition of an antifibrotic, in this case nerandomilast, is associated with further preservation of lung function and likely improved survival.

And so I think that you are not going to just stop immunosuppressive therapy because this person has an underlying inflammatory disease. So the idea of I am going to stop immunosuppressive therapy is just clinically not something that is practical to do. You are not going to say, well, you know what, let us just see what happens because the guy on the current therapy just got hospitalized, for God's sake.

So clearly this guy's got active disease. And having high-dose corticosteroid monotherapy implies you are going to get rid of the other immunosuppressive therapy. So that sort of violates what I have said in terms of, well, he has got an underlying inflammatory disease.

And so, given that you already know that there is fibrosing disease on that original CAT scan that Corey read for you as a radiologist, and you now know that this guy has worsened, it is adding an immunosuppressive, I mean, an antifibrotic agent on top of that.

Corey, what do you think? Do you agree with that assessment?

Dr Kershaw: Yes, no, you have got to, again, you cannot do nothing here, right? I mean, this guy's in trouble. There is a great subset study that I love to quote that looked at patients in the original nintedanib IPF study on no therapy and showed their rate of progression laid on top of patients who were in the INBUILD study, which is a nintedanib study for progressive pulmonary fibrosis, and they are identical. So you take away from that, that patients who begin to progress with a non-IPF diagnosis, they have similar prognostic implications as patients with IPF that you are not treating at all, which is bad. So you have got to be on top of these guys if this happens.

And Fernando, I agree completely. You were asking this question about nerandomilast. I mean, it is the safety profile alone, and the really strong data for PPF is going to make this be the number one therapy for it.

Dr Martinez: That is my bias as well. You know, it is a conflict, guys. I was involved in these studies. I work with BIs, so I am conflicted on all of this.

One other component about this particular case title, this guy's 55 years old. I would also have a lung transplant evaluation started.

Tyler Kuhk: Yes, good point.

[01:21:02]

Faculty Discussion

And that leads us into how we discuss these kinds of treatment options with patients. I am sure, especially in a case like this, probably some extensive conversation on the complex nature of what is going on and how you break that down for patients and have those conversations.

Dr Martinez: Yes, actually, I was just laughing because Luann just posted a question. It is really a good question. It is an interesting era that we are in right now.

So look, guys, I have been at this for 30-odd years. I mean, I did some of the original studies. I was involved in the original interfering gamma study style, I mean, way back. And so the space for fibrosing ILD was a space that was nihilistic. There was nothing you could do. It was all just lung transplant evaluation.

And the situation that you now have is that you have three approved antifibrotic agents. It is hard for me to imagine this is IPF, that treprostinil will not have an extension of its indication. And so you will have four agents.

I hope that admilparant is positive. So early next year, you have five agents that you will have. That creates complexity, but it is good complexity because it means you have multiple options that you can use right now.

One of the challenges, Corey, that you and I have talked about before is all of these drugs are expensive. I mean, nerandomilast is $190,000 a year. Treprostinil is $240,000 a year. I mean, these are really expensive medications. And so part of the question that I think we are all going to have to wrestle with, and this is actually a study, Corey, that I am going to drag you into that we are planning, which is a comparative effectiveness study of what we do after initial therapy, because I do not think any of us have any idea of exactly what we are going to do now when a patient comes in and they are worsening. Are you going to stop or change, add?

And I think that we now can do that and contemplate that study to give some of the people that have asked great questions on this Q&A here a definitive answer, because we have multiple things. In the non-IPF, Tyler, you saw that slide I showed you with the autoimmune disorders. I mean, it is mycophenolate, rituximab, cyclophosphamide.

I mean, it is multiple immunosuppressants, plus now a couple of antifibrotic agents that are going to be thrown on top of that. And so what that now tells me is that the complexity of the field requires a multidisciplinary discussion. Corey will talk to you about that next, including non-pulmonary people, rheumatologists, for example.

And it really, really requires the patient and their caregivers to weigh in, because these drugs are all complex drugs that have their own unique adverse event profiles, and it requires all of us working together. And I meet with the nurse practitioner in my ILD clinic that really runs the show, Tyler. I mean, we meet every day, going over even outside of the formal MDD structure, because these are really complex situations.

But in this case, guys, complexity is a good thing. We used to have nothing we could do for these patients.

Tyler Kuhk: It is a great question. I think just in the interest of time, going to move into the posttest question for this particular section.

[01:24:13]

Posttest 2: A 68-yr-old man with a history of progressive dyspnea and dry cough is diagnosed with IPF after HRCT confirms a UIP pattern and other causes of ILD have been excluded. PFTs show an FVC of 65% predicted and DLCO of 45% predicted. He has no cardiovascular disease, is a former smoker, and is not currently on any therapy. Which of the following is the most appropriate next step in managing this patient?

So a 68-year-old man with a history of progressive dyspnea and dry cough is diagnosed with IPF after an HRCT, confirms a UIP pattern and other causes of interstitial lung disease have been excluded. We have got those PFTs showing that FVC of 65% predicted and a DLCO of 45% predicted, and he has no cardiovascular disease, and is a former smoker, and is currently not in any therapy. So which of the following is the most appropriate next step in managing this patient?

1. Initiate systemic corticosteroids as first-line therapy;
2. Begin nintedanib as first-line therapy;
3. Start immunosuppressive therapy with azathioprine and prednisone as first-line therapy; or
4. Begin first-line therapy with systemic corticosteroids followed by nintedanib.

I can give you guys a few moments to answer that question. And good. And so if we can see the pretest here, it was a pretty big spread among most of them.

Most of you guys in the posttest picked answer B, which is the correct, right? One of the two FDA-approved antifibrotic therapies. I think you all took a listen there.