Redefining Pulmonary Fibrosis Care With Nerandomilast

In the final chapter of our pulmonary fibrosis webinar series, Dr Saad Ashraf discusses FDA-approved nerandomilast and what its introduction means for clinicians, payers, and patients living with interstitial lung disease.

Overview: Gain insight into the data behind nerandomilast’s approval for idiopathic pulmonary fibrosis, how it may fit into current treatment strategies, and what this milestone means for the future of disease management.  

Presenter:
Saad Ashraf, MD

Dr Saad Ashraf is a board-certified Pulmonary and Critical Care physician and the Critical Care Medical Director at Wellstar North Fulton Hospital in Atlanta, Georgia. He leads ICU performance and patient safety initiatives while mentoring physicians, APPs, and nursing teams. In addition to his hospital leadership role, Dr Ashraf practices tele-pulmonary and tele-ICU medicine, providing specialized care for patients with advanced and complex pulmonary diseases. His clinical interests include interstitial lung disease, pulmonary hypertension, and severe asthma/COPD. He also collaborates with the pharmaceutical industry on educational and advisory projects related to advances in pulmonary medicine. Currently pursuing an Executive MBA at Emory University’s Goizueta Business School, Dr. Ashraf is passionate about integrating clinical expertise, technology, and leadership to advance critical care and respiratory medicine. 

Transcript:

Dr Ashraf: All right. Good morning. My name is Dr Ashraf, and today we're going to be talking about the Clinical and Practical Insights on Nerandomilast, which is a new treatment in the idiopathic pulmonary fibrosis world. So, like I said, my name is Dr Ashraf. I'm currently working as the Medical ICU Director at Wellstar North Fulton at a facility in Atlanta, Georgia. My other interests include complex pulmonary disease as well. So, the learning objectives for today, we want to interpret the clinical evidence supporting the approval of this new medication for IPF, including the efficacy, outcomes, safety profile, and key information from the US Prescribing Information. We're also going to review recent peer-reviewed commentary to understand the role of nerandomilast in treatment decision-making for patients with IPF. And we'll also discuss practical considerations for selecting the appropriate patients for this new therapy. And then, the future potential indication of PPF, which may be coming soon, and how that may be integrated or sequenced into existing antifibrotic treatments in real-world clinical practice.

So, we're going to dive into why new treatment options were needed in regards to idiopathic pulmonary fibrosis.

So, IPF, it's a fatal, progressive ILD with a significant impact on daily life. So, patients generally have an insidious onset. There's a difficulty in diagnosing these patients, and usually by the time they are diagnosed by a specialist, there's been a significant delay in starting treatment. The overall general median survival once they have been diagnosed is anywhere from two to five years, usually due to an exacerbation or progression of the disease. For these patients, clinically their symptoms are very nonspecific. They may just have some dyspnea, some cough, fatigue. They will progressively have a loss of lung function. And they will have, as the disease progresses, a significant impact on their daily life that may lead to the need for oxygen, may lead to increased hospitalizations, and ultimately, unfortunately, it does lead to a premature mortality.

On top of the symptom burden, there's also a high economic burden as well to patients, payers, and the healthcare systems. IPF, as we just talked about, is a progressive disease with very limited treatment options. Usually, the cost associated per capita of patients with IPF in North America ranges $20,000 or more for hospitalization as well. That includes the majority of the expense. These patients generally need to be seen on a much more frequent basis. They require more advanced treatments to try to slow things down. And then, ultimately when they do end up in the later stages of their disease, repeated hospitalizations is a big cost, not only from a financial standpoint, but from an emotional standpoint for the patients as well.

Currently, there are some therapies that are standard of care for IPF. They have significant side effects, primarily GI side effects, that limit sometimes their use. The two medications are nintedanib and pirfenidone, also known as Ofev (nintedanib) and pirfenidone, which is Esbriet. Both of these medications do help with the slowing of the decline of lung function in their FVC and can help prevent exacerbations. The downside is that they do come with fairly significant side effects, primarily GI side effects related to nausea and diarrhea. Because of those side effects, it can lead to difficulty with adherence to the medication. And also, because of the dose reduction, sometimes you may not be getting peak effect. The other unfortunate effect of the medication is that while it does help with reduction of lung function and the decline of the FVC, it does not unfortunately change the underlying disease course. So, patients, despite these medications, will still have disease progression, and there has been no—to this point—any survival benefit with the medication. So, those two agents are used very commonly for IPF; however, we were very limited in terms of what we could do for IPF. The main point we're trying to get at here is that the current antifibrotics that were previously approved don't improve survival benefit, and there is still a high rate of progression despite the two medications that are on the market now.

So, FVC, it's a reliable and a valid parameter for evaluating pulmonary function and disease status in patients with IPF. Your forced vital capacity, that is a measure of your maximum volume of air that can be expired from the lungs during a forced and complete expiration from a position of full inspiration, and that's measured with a spirometer. We do this very frequently, on a daily basis in our office, and it's the mainstay of disease monitoring. It is reported as either liters, and it's also reported as a percentage of a reference value (predicted) for someone of the same age, sex, height, and ethnic group. A decline of 10% or greater, it is recognized as a clinically significant predictor of mortality. Some studies suggest that the minimal clinically important difference for percent-predicted FVC is between 2% and 6%. For myself, I don't really use an absolute marker when I'm monitoring my patients with IPF. For me, if I see a decline in FVC at any percentage when I'm checking my PFTs on a regular basis, that, to me, is a marker of disease progression.

So, we'll dive now into the approval of nerandomilast, which is also known as JASCAYD, and kind of how it plays into the future of treatment of IPF patients.

So, the FDA approval of JASCAYD was the first time in over a decade that a new medication was approved for IPF. It was approved based on the fact that there was a statistically significant reduction in FVC decline versus placebo. There also were some long-term outcomes and real-world impact that are currently under evaluation. The mechanism of the medication is that it's a selective PDE4 inhibitor, which drives down pulmonary inflammation and fibrosis while avoiding the off-target PDE4D side effects related to the gastrointestinal side effects. So, the benefit of this medication, just from this slide that we can tell, is that we're going to have improved compliance, decreasing the inflammatory processes and cascade that drive the disease process, while also limiting some of those side effects.

So, this is going to go into the mechanism a little bit more. The preferential inhibition of PDE4B results in the anti-inflammatory and antifibrotic effects, which leads to the improved safety profile versus the other PDE4 inhibitors that are more kind of pan affected. So, currently the pirfenidone and nintedanib, they are antifibrotics and anti-inflammatories. However, for pirfenidone, the downstream targets aren't necessarily known. Nintedanib is a tyrosine kinase receptor inhibitor, which inhibits the growth of fibroblast growth factor and vascular endothelial growth factor as well. So, the mechanism of JASCAYD, it's a little different. And while I won't go into the exact pathway, it is important to know that the mechanism of JASCAYD is different from the current two medications approved on the market for IPF.

The FIBRONEER-IPF trial was the main trial that looked at nerandomilast or JASCAYD, and that's how it was approved based off of the primary endpoint. They were looking at the change in FVC, compared to placebo, and it did show a clinically meaningful slowing of disease at the 52-week point. So, the FIBRONEER-IPF trial was a 52-week trial, and what they saw at 52 weeks at the 18 mg dose, there was a decline in FVC by 106 mL versus placebo—was almost doubled at 170 mL. That did represent a 28% to 38% slowing of the FVC decline versus placebo. There were some secondary endpoints evaluated as well. They signaled an exacerbation reduction along with patient-reported outcomes that suggested overall improvement and a real-world benefit. Now, you may be thinking, you know, what's the difference between 106 mL versus 170 mL? When it comes to lung function, while there's no number out there that says what is clinically meaningful, any reduction, even 10 to 15 reduction of mL of FVC, that can have a meaningful benefit for patients. Every little bit of lung function that is preserved will be reducing the symptom burden for these patients. And then, the secondary endpoint of reduction of exacerbation potential also can help keep these patients then out of the hospital.

One of the other things that is a benefit of JASCAYD versus some of the other medications was the improved GI tolerability. So, looking at the two doses that are approved, the 18 mg and the 9 mg, you can see that the diarrhea discontinuation rate was lower compared to the other medications. There weren't any treatment discontinuations due to diarrhea, with patients who are already on antifibrotic plus JASCAYD, compared to placebo as well. So, overall, the sense is that the medication will probably have improved GI tolerability compared to patients who are currently on Ofev and Esbriet. And I can speak to this from a personal standpoint as well. I have probably over 40 to 50 patients with IPF who are on antifibrotics right now. I would say over 30% to 35% of them have had tolerability issues. So, the potential of a new medication that works in a different pathway that can help reduce the decline of lung function with improved tolerability is very exciting for someone who treats these patients on a regular basis.

So, just to compare, the side effect profile of JASCAYD versus nintedanib and pirfenidone. In nintedanib, the diarrhea was reported in 62% of patients. And then, in pirfenidone, it was 36% of patients. So, an improvement for JASCAYD.

Some of the pooled analysis from FIBRONEER-IPF and FIBRONEER-ILD also showed a significant reduction of death, which was not shown in the other antifibrotics. So, looking at the pooled analysis, what we see is that 43% of patients taking JASCAYD 18 mg had a reduction of their death potential, 59% of patients taking JASCAYD without background therapy, and then 41% of patients taking JASCAYD plus Ofev. So, that is a significant number. When I look at this trial, having a reduction of a risk of death of over 33% is significant. And if that can keep my patients alive longer and live healthier lives, it's definitely a positive for me.

Diving into the prescribing information a little bit, we talked about the mechanism. It's a PDE4 inhibitor. It is currently approved for the treatment of idiopathic pulmonary fibrosis in adult patients. For dosage, the recommended dosage is 18 mg twice a day, 12 hours apart. For patients who do have the inability to tolerate the medication, there is a dose reduction indication of 9 mg twice a day. As we talked about the data earlier, the 9 mg still has an improvement in their FVC decline along with the mortality. Most common side effects, like with any antifibrotic, you're going to have some diarrhea, some upper respiratory tract infections, depression, weight loss, decreased appetite, nausea, fatigue, headache, vomiting, back pain, dizziness as well. It is important to remember that the disease state in itself can also cause some of these adverse reactions. Usually with an increased metabolic demand from worsening oxygenation, hypoxemia, you're going to lead to a weight decrease and a decreased appetite from that as well. So, it'll be important to monitor nutritional status while patients are on therapy. Some certain drug interactions for strong CYP3A inhibitors, you want to reduce JASCAYD to 9 mg twice a day. If you're on a strong CYP3A inducer, you want to avoid concomitant use with JASCAYD.

Diving into the practical application, what does this mean for clinicians like myself and payers? So, finally, after a decade, we have a new option for patients who have disease progression or who are not on any therapy at this time. For patients with a suboptimal response to current antifibrotics who've been on Ofev and pirfenidone, along with patients with a decline in FVC despite being on those medications, those are the patients you really want to target. Starting this new medication, it is approved for use with or without other antifibrotics right now. You can consider as a monotherapy on a new start or in combination with other antifibrotics, basing that off of the current patient profile, treatment goals, and tolerability. My current practice, given that the medication is still fairly new, I have started a couple of patients on JASCAYD, and all of them right now have been on nintedanib or Ofev. So, my current practice is to go ahead and add on the therapy, given that all of them have had a decline in FVC in the last one to two years, despite being on therapy. As I get more patients with IPF who are maybe treatment naive, there's likelihood that I would be reaching for nerandomilast, probably first, given that the data shows to be a little more promising for this one, this medication compared to some of the older ones.

So, integrating JASCAYD into the IPF patient journey. We talked about this a little bit the last time, but generally your diagnosis is done radiologically with a high-resolution CT scan, and then there is plus or minus a multidisciplinary review. For myself, at our health system, we have an ILD conference that we have on a monthly basis where we discuss patients' high-resolution CT scans. UIP is the pattern that would be seen on a CT scan that is diagnostic of IPF. Generally speaking, a biopsy is not needed for the diagnosis of IPF. You can do that with a high-resolution CT scan. You also want to be getting a baseline forced vital capacity, DLCO, six-minute walk test, because you can use those as a marker of disease progression as you see these patients regularly. My current practice is to generally see IPF patients on a one- to three-month basis, depending on where they're at. Usually, once the diagnosis is made or if they come in with a high-resolution CT scan, I will be starting therapy kind of upfront. Usually, I don't like to delay starting antifibrotic therapy. For monitoring for FVC decline, for me, I don't really use 5% to 10%. I use any sort of decline in their FVC on PFTs. And then, I also monitor symptoms. Are you having worsening shortness of breath? Do you have a cough? Have you lost any weight? Things like that. Obviously, we need to be monitoring treatment adherence and tolerability. In terms of treatment optimization, that's kind of where there'll be more of a stylistic change for clinicians. If your patient is already on Ofev and they're showing decline in their FVC or they're having a worsening symptom burden, that's where maybe JASCAYD would be an adding point. If you have a new start patient or a new diagnosis of UIP, there's a possibility that maybe you reach for JASCAYD first, given the improved side effect profile and significant reduction in FVC decline along with improvement of mortality. And then, ongoing care and monitoring. You know, obviously seeing these patients regularly. I usually don't do more than three months in my general practice for follow-up. Obviously, that's going to be different for different clinicians, given schedules and availability of subspecialists for these patients. So, generally speaking, the documentation pathway or access of the medication, obviously you need to have a high-resolution CT scan showing evidence of a UIP pattern to confirm the diagnosis of IPF. You want to document progression or intolerance of medications. You want to submit medical necessity for JASCAYD coverage. And then, you want to continue outcome tracking for payer reauthorization.

So, clear medical-necessity criteria, flexible coverage policies, and evidence-based utilization can support appropriate and timely patient access. Aligning nerandomilast coverage with real-world need will require clear PA criteria that will recognize disease progression, antifibrotic intolerance, and patient variability. So, current policies that are in place for PAs for antifibrotics, obviously you need a high-resolution CT scan. For step therapy, there are some PAs that require failure or intolerance of other antifibrotics, placement on higher tiers with higher copays, narrow progression criteria, limited flexibility for combination or sequencing approaches, and then frequent reauthorization and strict documentation requirements. For me, for my practice, when I do my PAs, generally we've been able to get antifibrotics approved for a year before we have to do another PA. Given the frequency that I see these patients, it's fairly easy to document any disease progression, antifibrotic intolerance, things like that, given that they're seeing me at a minimum four times a year, if not more. So, streamlined PA criteria for nerandomilast, it could include approval for disease progression or intolerance to other antifibrotics. It may not require a mandatory step therapy. And that's kind of the key, kind of moving forward as more information comes out about the medication, more real-time clinical data comes out for patients is that—should JASCAYD be the first line of treatment for patients with IPF, given that it does show a better safety profile from side effects and also improvement with the exacerbation reduction along with the mortality? I think that will be kind of a moving target as time goes by and we get more information.

We'll dive into PPF or progressive pulmonary fibrosis next, which is an evolving clinical landscape.

So, PPF is a distinct form of fibrotic disease outside of IPF. So, PPF can fall into any of the other interstitial lung diseases that can lead to pulmonary fibrosis that is not idiopathic. So, approximately 13% to 40% of non-IPF fibrosing ILDs progress within two years despite appropriate management. The clinical trajectories, including rate of decline in FVC and transplant-free survival, for these patients closely resembled those seen in IPF. So, there are quite a few ILDs that are associated with PPF. You have your idiopathic interstitial pneumonias. So, these are your AIPs, your PPFEs, your NSIPs, your cryptogenic organizing pneumonia. In the pulmonary world, everything is an acronym. So, there's over 100 ILDs out there, and everything has an acronym. But these patients can progress to PPF, and that's where their clinical trajectory kind of changes from their underlying disease state to more of an IPF state. And I will say from a personal standpoint, that I definitely see more PPF ILD than IPF, given that there's just so many more diseases, particularly the connective tissue disease-associated ILDs. There's so many of those, and it is a big disease burden for patients.

So, the FIBRONEER-ILD trial looked at adjusted mean FVC decline in patients who have PPF ILD. And there is significant potential in applying this medication to these patients as well. So, in FIBRONEER-ILD, what we saw was a statistically significant decline of FVC at the 52-week mark of almost 100 mL versus 165 mL in the placebo group. This actually represented a greater slower decline of FVC compared to what they saw in FIBRONEER-IPF. So, 41% to 49% slower decline. FIBRONEER-ILD was a global, Phase three, randomized, placebo-controlled study, looking at over 100 patients with an ILD that was not IPF. Nerandomilast was granted Breakthrough Therapy Designation by the US FDA for the treatment of PPF in April of 2025. And the NDA in PPF has been filed with the FDA. And I'm very excited as a pulmonologist who sees these patients regularly that we may have another option for PPF ILD. And the data is very promising for this medication.

So, diving into some expert perspectives, there was some commentary published in the New England Journal of Medicine that stresses the importance of contextualizing the clinical relevance of these findings. So, Dr Singh quoted that “FVC is a commonly used surrogate marker in trials. There is still a need for data showing reduction in hospitalizations, improved survival, and improved quality of life.” While Dr Yuji said that “In the FIBRONEER-ILD trial, the rationale for exclusion of the patients who were taking mycophenolate is not clear, and its potential effect on applicability of the trial results to clinical practice is not discussed.” So, just to comment on those quotes. So, FVC is a commonly used surrogate marker. I will say that the secondary endpoints that showed the possibility of reduction in hospitalizations and improved survival is a positive, in my opinion. Improved quality of life can be very subjective. It can be hard to measure that in a clinical trial. But the reality is, if you are slowing the decline of FVC in these patients, you are then improving the patients’ quality of life because they will be able to breathe more easily and remain more symptom-free as the disease progresses. So, a longer follow-up period may be needed to show effects on these outcomes. But again, like the data showing the objective slowing of decline of FVC, that in itself, in my opinion, shows that your quality of life will be improved. And in regards to Dr Yuji's comments, the use of mycophenolate was excluded from FIBRONEER-ILD to enable a robust assessment of the efficacy and safety of nerandomilast. Definitely further investigation is warranted, given that it is a novel medication. But, at the same time, for the FIBRONEER-ILD, for PPF ILD, CellCept is not a medication that is a one-stop shop for those patients. They can be on a variety of medications. And for nerandomilast to be showing the benefit that it did while excluding the use of CellCept, to me, demonstrates that the medication works with or without background therapy. And I think that's a very important takeaway of the data that will be coming out from the FIBRONEER-ILD trial. Patients with connective tissue ILD, there's a variety of medications that I have them on outside of CellCept. And if there's an improvement of the patient who is just taking nerandomilast outside of any other immunomodulatory therapy, I think that kind of shows you the standalone ability of nerandomilast as a medication.

Some key takeaways, it's the first selective PDE4B inhibitor and the first new IPF therapy in over a decade. It's a novel mechanism that's going to slow down FVC decline, and it'll probably have improved GI tolerability compared to current antifibrotics. The study showed that it can be used as a monotherapy or in combination with the current two antifibrotics that are on the market. It offers an option for patients with disease progression or intolerance to current therapies. Patient selection monitoring and payer alignment will be the key to help optimizing these outcomes. For PPF and other fibrosing ILDs, there is support in it showing a move to more phenotype-driven, combination-based, early treatment strategies across those fibrotic lung diseases. And while clinical trials show meaningful efficacy, extended follow-up and real data are always needed to confirm impacts on survival exacerbations, quality of life, and to refine treatment sequencing over time. That's the case with really any new medication that, as time progresses, real-world data and anecdotal from treatment of patients will be very helpful as time goes by.

So, a couple cases that we'll go into that may highlight the use of JASCAYD. So, for case one, we have Mr. J, who's a 68-year-old male. He was diagnosed with IPF approximately 14 months ago, has a history of GERD, hypertension, a former smoker with a BMI of 27. He was initially started on nintedanib 150 twice a day. However, he developed persistent diarrhea within the first month, which was refractory to any sort of medication for the diarrhea. He was dose reduced to 100 twice a day, but his symptoms unfortunately continued. He lost eight pounds unintentionally over three months, and he frequently has missed doses due to intolerance. He has had a decline of his FVC in 5% over nine months. He's had increasing subjective complaints of exertional dyspnea and fatigue. His CT remains stable, but his symptoms are starting to affect his daily activity. The clinical issue with Mr. J is that unfortunately he's been intolerant to nintedanib despite the dose adjustments, and he is also demonstrating a physiologic decline in therapy. So, the decision point for this patient, he would be someone who is a strong candidate to transition over to JASCAYD due to the persistent intolerance, ongoing symptoms, and documented decline in FVC despite attempted adherence.

For case two, this is an IPF patient with nintedanib, who's had physiologic progression as well. So, this is Ms. L, who's a 72-year-old female. She has a UIP pattern on high-resolution CT. The diagnosis of IPF was confirmed via a multidisciplinary evaluation. A history of rheumatoid arthritis, which is inactive, and hyperlipidemia. So, this patient was started on nintedanib 150 twice a day for 18 months, tolerating it with minimal GI side effects, and had had a stable early course. However, over the last six to 12 months, despite tolerance to the medication, there has been a decline in the FVC by 8%. FEV1 has declined 10%. Six-minute walk test is down 40 meters, and the CT scan is now showing interval progression of the fibrosis. The clinical issue for Ms. L is that there's been progressive physiologic decline despite standard antifibrotic therapy. Decision point for this patient is—you know, this patient would be a candidate for JASCAYD—to transition to JASCAYD from nintedanib or adding it on as a secondary therapy supported by the FIBRONEER-IPF data showing benefit with or without background of antifibrotics. The goal for Ms. L is to slow further decline and stabilize lung function.

I'll now open it up for a Q&A session. Thank you, guys, for your attention. I hope you guys came away with some new information that you may have not known about this new medication for IPF. And, again, if you have any questions or concerns, feel free to ask. Thank you, guys.

Moderator: Thank you, Dr Ashraf, for that wonderful presentation. So, we are now able to get into some audience questions. So, the first question we have for you is, are there specific patient phenotypes where nerandomilast provides the clearest early benefit?

Dr Ashraf: Thank you, guys, for having me. So, right now, the data suggests fairly consistent benefit across a pretty broad IPF population, patients with or without background nintedanib or pirfenidone, that was studied in the FIBRONEER trial. I think where we will maybe see the clearest early benefit in practice are possibly newly diagnosed IPF with relatively preserved lung function, where our main goal is going to be to slow down FVC decline from day one. I think the other population where it should be considered is patients who are progressing already on antifibrotics or have had a decrease in FVC. Because there was a statistically significant reduction in FVC decline versus placebo, I'm thinking of it as a drug where earlier use may give the most lung preservation.

Moderator: That's helpful, thank you. And along those same lines, what clinical markers or early signs of progression should trigger consideration?

Dr Ashraf: You know, in general, I follow the same progression signals we already use in IPF management, such as a drop in FVC. Even a reduction of 5% over a 12-month period will get my attention or definitely more than 5%. Worsening symptoms, so if the patients are having worsening shortness of breath, cough, dyspnea, a reduced six-minute walk distance, all of those I think would be a trigger. Obviously, a progression on your high-resolution CT scan or if they've been hospitalized with an exacerbation.

Moderator: Thank you. So, maybe shifting gears a little bit, but we have a question about additional or add-on therapies. So, someone asked, what about including adipose stem cell therapy?

Dr Ashraf: So, that still is a hotly debated topic right now. Really, right now what is approved for IPF at this point are two antifibrotics, nintedanib and pirfenidone. Obviously, with nerandomilast being the newest version, newest molecule that's come out, I think there's a lot of promise with this. And there's the possibility in the future that maybe a targeted treatment like that may be of benefit.

Moderator: Definitely. That makes sense. And so, maybe a few more questions that are starting to get into some of the data that you shared for nerandomilast. First, how do you explain the less, or lower mortality with combination therapy as compared with monotherapy?

Dr Ashraf: That's a good question. When I dive into that, I think right now there's no head-to-head trial of nerandomilast versus nintedanib or pirfenidone. So, any comparison is going to be indirect and should be interpreted individually. But I do think where you look at the trial with FIBRONEER, they looked at—the patients were included who were already on background antifibrotic therapy. And that just means that, to me, at least, that the nerandomilast may have superimposed additional benefits as compared to just your nintedanib and pirfenidone. So, I think from an efficacy standpoint, the nerandomilast is in probably the same conversation as the older antifibrotics. But the difference is that in that study, the benefit was seen with background antifibrotic there as well. So, it's not just another option, it's a drug with evidence of additional FVC preservation on top of our current standard of care.

Moderator: Wonderful. And this next question, we may ask you to see into the future a little bit, but if nerandomilast slows the progression of the disease, do you think long-term studies may show improvement in life expectancy?

Dr Ashraf: You know, I do think so. Given its mechanism being different from the current antifibrotics, it's a novel mechanism. And it's definitely a possibility where, as more data comes out, we see a benefit not only with preservation of lung function, but also possibly improvement of symptoms along with mortality as well. So, I do think that as more data comes out, as the drug gets used more, I think there may be a benefit that we see in the future.

Moderator: Yes. And future studies will, I'm sure, give us that answer. Let's see, what do we have next? I think, let's talk a little bit about adherence. As we know, that being an important consideration, do you anticipate better adherence compared to current therapies based on the trial tolerability data that we have?

Dr Ashraf: So, I think in IPF what a lot of the physicians and providers deal with is adherence. That's the issue. So, with JASCAYD or nerandomilast, it is a twice-daily tablet, which is simpler than some of the older regimens. Primarily, I’m talking about pirfenidone. When we looked at the FIBRONEER data, the discontinuation rate due to adverse effects was in the low- to mid-teens, which wasn't that much different from placebo. Main tolerability issue, again, with this drug was diarrhea. But the pattern was a little different, especially in patients who are already on background therapy with nintedanib. So, I'm cautiously optimistic that adherence would be comparable, and maybe for some patients better than our current options who struggled with maybe more severe GI side effects or photosensitivity. But I would leave it as we probably need more real-world data before making strong claims, but I am optimistic about it.

Moderator: And that makes complete sense. And speaking of real-world data, what real-world evidence do you think would be most valuable to support broader access and earlier use of something like nerandomilast?

Dr Ashraf: So, I think earlier use, I think where we would see it primarily is if it's a newly diagnosed IPF patient. And if we extrapolate the data seen in FIBRONEER, what we could see is that given that this saw patients with a reduction in FVC that was lower in patients who were already on background therapy, monotherapy may be useful in patients who are naïve to treatment at this point. And also, add-on therapy in patients who are already on an antifibrotic. So, I think over time as registry and outcomes data come out more, I think we'd be able to look at that a little bit better and see where it would be an option to start maybe kind of upfront.

Moderator: Thank you. One more question related to monotherapy versus combination therapy. So, in your clinical opinion or in your experience, should nerandomilast be paired with those other antifibrotics or as standalone used alone?

Dr Ashraf: So, I think there's not a wrong answer at this point, given what FIBRONEER showed us. I will say, in my current practice, I have about four to five patients who've been started on nerandomilast. And all of them have been on background therapy already with nintedanib. And given that the data showed that there was a reduction in FVC in patients who were on combination therapy, I think that just speaks to how the medication works with or without background antifibrotic. So, I think in my practice I'll be adding it on to patients who have had a reduction in their lung function, but also for new evaluations for IPF. I don't think it's unreasonable to be starting them upfront on nerandomilast.

Moderator: That makes sense. Thank you. All right. I'm just looking through to see if there's any more questions coming in here. I think we can maybe have time for one or two more questions. Maybe thinking about some of your case examples that you shared toward the end, we have an audience question that is sort of a specific case example, and I know you won't have all the details to make a determination. But if you were considering treatment for an otherwise healthy, 65 or so year old who can hike several miles per day and has been diagnosed with IPF, is this a good drug for that patient?

Dr Ashraf: I think it would depend on what their clinical trend has been. If they're on antifibrotic therapy already and there's been minimal to no reduction in their FVC over the last six to 12 months or just trending it out even longer, I think it's probably okay to wait to start. Now, if the patient has had even a 5% reduction in their FVC, despite them clinically being okay still, the goal is overall lung production, as we know that IPF is a progressive disease. I will say in one of the patients who has started the medication—they've been on Ofev for about, I would say, three years now, a relatively similar profile, very healthy, active. But my goal is to prevent progression of the disease. And given that the data showed that there was an improvement in lung function with or without concurrent therapy, I went ahead and started the patient on it after having a discussion with the patient. So, I think it kind of comes down to what the patient's comfortable with. But I do think that there would be benefit starting it earlier in some patients.

Moderator: Awesome. Thank you so much. And I think that's actually all the questions that I see coming in at the moment. So, I think we can go ahead and wrap it up. So, first of all, thank you to Dr Ashraf again, for that wonderful presentation. And thank you, of course, to our audience for joining us today on First Report Managed Care.

Dr Ashraf: All right. Thank you for having me.