Clinical Outcomes That Matter: FIBRONEER-ILD and the Future of PPF Management

In this expert commentary, Dr Toby Maher discusses the evolving treatment landscape in progressive pulmonary fibrosis (PPF) and the implications of the extended follow-up findings from the FIBRONEER-ILD trial. He explores the potential role of nerandomilast in addressing unmet needs in PPF, highlighting its efficacy, safety and tolerability, clinically meaningful outcomes—including disease progression, mortality, hospitalization, and acute exacerbations—and its potential place in treatment sequencing, combination therapy, and broader impacts on patients, providers, and health care systems.

Transcript

Kelly Conger: Hello and welcome to First Report Managed Care. I’m Kelly Conger, and on today’s podcast we are joined by Dr Toby Maher to discuss the results of the FIBRONEER-ILD extended follow-up study as well as the potential impact of nerandomilast on the treatment landscape for progressive pulmonary fibrosis. I’d like to introduce our guest, Dr Toby Maher.  

Dr Maher: Hi, I'm Toby Maher. I'm professor of clinical medicine and director of the Interstitial Lung Disease Program at Keck Medicine of the University of Southern California in Los Angeles.  

Kelly Conger: Thank you so much for joining us Dr Maher. To start us off, can you describe for our listeners the real-life disease burden of progressive pulmonary fibrosis. Are there any limitations that patients are currently facing, and how is this affecting disease management practices?  

Dr Maher: So progressive pulmonary fibrosis is a relatively recent concept, but I think it was generated to describe something that we all recognize in clinical practice, which is patients who have a diagnosis other than idiopathic pulmonary fibrosis that gets inexorably worse over time, characterized by worsening fibrosis of the lung and ultimately symptoms and a mortality rate that is akin to idiopathic pulmonary fibrosis. So this could be patients with connective tissue disease-associated ILD. It could be patients with hypersensitivity pneumonitis. It could be patients with other rarer ILDs. But the concept is that all of these conditions can occur in a proportion of individuals and be characterized by progressively deteriorating fibrosis of the lung. And that is what causes the majority of the morbidity and mortality. And so really it was with the INBUILD trial that we first saw effective treatment of progressive pulmonary fibrosis. So the use of nintedanib to slow the rate of disease decline. I think the major challenge with nintedanib has been the side effect burden. So although it has been an important change to be able to offer treatment to patients, the fact that the drug has been associated with significant diarrhea, often the need for major lifestyle change, patients to take treatment with food, the need for regular blood monitoring has limited its effectiveness in clinical practice.  

Kelly Conger: Alright, so tell us about nerandomilast. You’ve been involved in the FIBRONEER-ILD trials, seeing first-hand how this new drug impacts PPF patients. What is nerandomilast and why is it significant for this patient population?  

Dr Maher: Nerandomilast is a PDE4 inhibitor, so it blocks phosphodiesterase 4. It has a different mechanism of action to nintedanib. It's in clinical trials in the FIBRONEER-ILD study, both slowed the rate of FVC decline over 52 weeks, but also in the key secondary endpoint over the entire duration of the study, improved mortality for patients treated with nerandomilast compared to the placebo group, the hazard ratio would suggest that it halved the risk of death over that period of time. So this represents an important step forward for patients.  

And importantly, nerandomilast appears to be better tolerated than nintedanib. As a monotherapy, it tends to cause a lot less diarrhea. And again, in the trials for patients taking nerandomilast on its own, the discontinuation rate due to side effects was the same as we saw in the placebo group, again, suggesting that treatment was well tolerated. The other option that nerandomilast now gives us is the possibility of combination treatment. Again, in the trial, we saw that about 44% of patients were also taking background nintedanib, and those patients also got additional benefit from being on nerandomilast.  

So I think we are at an exciting position in the treatment of progressive pulmonary fibrosis. We now have two effective antifibrotic agents that we can potentially use for our patients, either as monotherapy based on patient choice and preference about side effects, or for patients whose disease continues to get worse over time as combination therapy, which is something that up until now we've not been able to do whatsoever.  

Kelly Conger: It certainly sounds like the treatment paradigm is changing with nerandomilast. Can you walk us through how the FIBRONEER-ILD trial was designed and what aspects are relevant to real-world PPF management?  

Dr Maher: So there were a number of important components to the FIBRONEER-ILD trial design. First off, with the inclusion criteria, we kept these as broad as possible. So as long as patients didn't have idiopathic pulmonary fibrosis but they had any other fibrosing lung disease, then they were potential candidates for the clinical trial. And so with those inclusion criteria, we were really trying to capture the sort of patients in clinical practice that we want to treat with antifibrotic drugs.  

Then for the trial itself, the primary endpoint was change in force vital capacity at 52 weeks, but people stayed in the study until the last patient reached the last visit, which means that some patients provided data over 114 weeks or more. And that really allowed us to assess the impact of nerandomilast, not just on lung function change, but also on endpoints of importance to patients. So mortality, hospitalization, and acute exacerbations.  

Forced vital capacity is important as a primary endpoint because it's essentially a surrogate for survival. If we can slow FVC decline, that will show that we're going to improve long-term outcome and survival for our patients. And that really is the reason that the FDA expect to see forced vital capacity as the primary endpoint in these sorts of studies. 

And then finally, at the end of study, patients were able to roll over onto the FIBRONEER-ON study, which is the ongoing open-label study of nerandomilast in patients with IPF or PPF. And that will continue to give us even longer-term data on the safety and efficacy of nerandomilast. 

So overall, I think that the trial was very realistic in terms of what we do in day-to-day practice. And additionally, it should be noted that patients were also allowed to be on background nintedanib. So reflecting what is likely to become practice going forward, which is to say that a proportion of patients will be on a combination of antifibrotic treatment. So with all of these design elements, I think it really is possible to integrate the results of the FIBRONEER-ILD trial into our day-to-day practice because it's not a select subgroup of patients. In fact, it is the majority of patients with PPF who were candidates for the trial and therefore the data is relevant to those same patients in our practice. 

Kelly Conger: You mentioned previously, that nerandomilast slowed the rate of FVC decline. Can you expand on the primary endpoint results and also tell us more about the key secondary endpoints that were assessed in the extended follow-up?  

Dr Maher: Well, we saw a significant slowing in the rate of FVC decline in both of the doses of nerandomilast that were tested, the 9 and the 18 milligram dose, compared to placebo. The relative rate of decline was reduced by about 50% in both treatment arms and when we follow patients to end of study that benefit of treatment was maintained over the duration of the trial so it wasn't just at 52 weeks but it was at end points beyond that including 76 weeks and I think this is vital for patients because it shows that treatment is durable. It shows that the benefit is achievable on top of background treatment. 44% of patients were on nintedanib, and we still saw FVC benefit in that group of patients. And the expectation is that, of course, that will ultimately improve survival for these patients living with this devastating set of diseases. 

So added to what we see on the primary endpoint, the change in FVC over time, these key secondary endpoints really highlight that the slowing of FVC is not the sole benefit of treatment with nerandomilast, that we are having an impact on these events of real meaning to patients.  

What we saw over the duration of FIBRONEER-ILD was a reduction in the incidence of all of those events, the hospitalizations, the acute exacerbation and the deaths in patients taking nerandomilast compared to those taking placebo. The risk of death was reduced by almost 50% in patients on active treatment, particularly those taking the 18 milligram dose of nerandomilast. 

Ultimately, hospitalization, acute exacerbations are often life-changing events for patients when they happen. They signal a worsening in prognosis, and clearly death is the worst possible outcome for patients with fibrotic interstitial lung disease. We see the high death rate associated with progressive pulmonary fibrosis in the placebo group, and therefore it's vital that we now have a treatment that improves outcomes for this devastating set of diseases.  

Kelly Conger: Now, shifting gears from efficacy to safety — how do you interpret the safety and tolerability profile of nerandomilast, particularly in the context of long-term treatment of PPF?  

Dr Maher: An important aspect of any new drug coming to market is for us to understand the safety and tolerability profile. Reassuringly, the results of FIBRONEER-ILD were incredibly reassuring in this regard. We've come to expect antifibrotic drugs to be associated with significant side effects. For the last decade, we've dealt with issues including diarrhea, upper GI disturbance, and photosensitive rashes. However, the results of FIBRONEER-ILD suggest that overall nerandomilast is extremely well tolerated by patients. When we look at patients taking nerandomilast as monotherapy, so on no background antifibrotic treatment, the rate of drug discontinuation was balanced between placebo and the two different dosing arms of nerandomilast, the 9 milligram and the 18 milligram groups.  

If we look at the subset of patients who were already taking nintedanib, we do see that the combination of nintedanib and nerandomilast was associated with a higher frequency of diarrhea. And that was the one situation where we did see some discontinuations was patients taking the combination of nintedanib and nerandomilast, particularly at the 18 milligram dose. But diarrhea aside, the tolerability profile and the adverse events are otherwise balanced in patients who are already taking nintedanib compared to the placebo group who were taking nintedanib alone. There were also some adverse events of special interest that were assessed in the trial. So in the past, phosphodiesterase inhibitors have been associated with mood disturbance and suicidal ideation. And as part of the FIBRONEER-ILD trial, a lot of effort was gone to assess both mood and suicidal ideation. And there were no differences observed between placebo and active treatment, either with the 9 or 18 milligram dose of nerandomilast, suggesting that there was no effect of nerandomilast on these outcomes of special interest. Similarly, in animal models, phosphodiesterase inhibitors have been associated with vasculitis. And again, that was an area of special interest within the FIBRONEER-ILD trial. There was even an external adjudication committee to look at any reported episodes of vasculitis. And fortunately, we did not see any signal in that regard. So on the areas of special interest where there were prior concerns, the data were incredibly reassuring. And as I've said, the safety tolerability profile over the duration of the study looked excellent. And furthermore, there was no signal of liver injury, meaning that nerandomilast does not require monitoring of liver function tests in clinical practice, in contrast, for instance, to nintedanib.  

Kelly Conger: The combined efficacy and tolerability associated with nerandomilast certainly seems to be changing expectations for patient outcomes. In your mind, what do the FIBRONEER-ILD findings suggest about the potential to alter the disease course of PPF?  

Dr Maher: So I think one of the key learnings from the FIBRONEER-ILD trial, particularly when we just look at the placebo arm in the trial, is how impactful the diagnosis of progressive pulmonary fibrosis really is. And it must be remembered that what we know from the clinical literature is that when patients with pulmonary fibrosis have acute exacerbations or they have hospitalizations, there is often a steep decline, both in their functional level, but also importantly in their quality of life. And often patients who are hospitalized will spend protracted periods in hospital, and this contributes to their overall morbidity associated with their disease. And so I think the fact that we saw reductions in all of these critical events in patients on treatment in the FIBRONEER-ILD trial speaks to the added value of treatment in real-world clinical practice.  

Clearly, patients want to live longer and they want to live better quality lives. They want to avoid hospitalizations and they want to avoid living in fear of acute exacerbations. And I think being able to reduce all of those with treatment is a very important potential benefit of therapy and is certainly something that should be explained to both patients and payers. If we can reduce some of these acute episodes, if we can reduce acute exacerbations, and we can reduce hospitalizations, then we bring not only benefit to the patient, but also to the health care system with reduced overall burden of disease for patients living with PPF. 

Kelly Conger: After seeing the results of the extended follow-up study, what do you feel is missing, or what questions remain regarding the role of nerandomilast?  

Dr Maher: So I think there are still a number of evidence gaps that need to be addressed as we move forward. Clearly with any new medication, we do want to see longer term data. And importantly, patients from both the FIBRONEER-IPF and the FIBRONEER-ILD studies have gone into a long-term open-label study, FIBRONEER-ON. And that should give us important data about the longer-term safety of treatment with nerandomilast. And it should also give us some indication of long-term lung function trajectories for patients on treatment. I think the other unanswered question is how and when we should use combinations of therapy for patients with progressive pulmonary fibrosis. So as we've said, nerandomilast has opened the door to combination antifibrotic treatment. Intuitively, it would seem that upfront combination treatment may afford our best option of preventing further fibrotic decline in patients with progressive pulmonary fibrosis. However, we are going to need trial data to support that supposition so that we can justify early upfront treatment.  

I think we also struggle to define treatment failure. So for patients who are already on antifibrotic therapy, there is no evidence-based trigger for when we should initiate second-line treatment or add in a combination treatment. And again, I think we need to do work, both trial work with nerandomilast itself, but also observational studies to understand the optimal time for considering switching or adding antifibrotic therapies. There is some work to be done to understand better the effect of nerandomilast in specific interstitial lung diseases, for instance, autoimmune or connective tissue disease-associated, ILD, and the effect of combining nerandomilast with immunosuppressive agents, for instance, or even the potential role for nerandomilast as an early treatment before progression of fibrosis to see if we can truly modify disease outcomes in a group of patients at high risk of subsequent future progression. And then I think there is also an opportunity to better define the broader health care benefits of antifibrotic therapy with nerandomilast to try and understand whether treatment with a better tolerated drug that doesn't require regular monitoring perhaps reduces health care utilization for patients on treatment compared to those on alternative antifibrotics or no antifibrotic therapy at all. 

Kelly Conger: Dr Maher, if you could summarize for our audience, what are three key takeaways from the FIBRONEER-ILD study and what it means for patients, for the future of nerandomilast, and for the PPF treatment landscape?  

Dr Maher: So I think there were a handful of key learnings from the FIBRONEER-ILD studies. The first is the devastating and dangerous nature of progressive pulmonary fibrosis. The condition when left untreated is associated with a high mortality, as we saw in the placebo group, and a high risk of hospitalization or acute exacerbations, both of which are devastating events for patients. The second key point is that nerandomilast at the 9 and 18 milligram doses reduced lung function decline, but it also reduced the risk of some of these very important outcomes for patients. It reduced the risk of mortality, the hazard ratio suggesting that treatment halves the rate of mortality for patients on the 18 milligram dose, and it also reduced the risk of hospitalization and acute exacerbations. And finally, I think the third key takeaway from the study was how well tolerated nerandomilast last was. In pulmonary fibrosis trials, we've become accustomed to seeing high discontinuation rates due to side effects. And that was simply something we didn't see in the FIBRONEER-ILD study, suggesting that for the first time, we actually have a well-tolerated antifibrotic therapy. So this is a devastating disease. Nerandomilast slows decline and reduces the risk of death and hospitalization. And importantly, it does so whilst being well-tolerated. 

Kelly Conger: Thank you so much, Dr Maher for sharing your expertise and insight with us today. And thank you to our audience for listening to this First Report Managed Care segment where we discussed nerandomilast and the results and impact of the FIBRONEER-ILD extended follow-up study.