Beyond FVC: What FIBRONEER-ILD Means for Outcomes, Patients, and Access in PPF

In this expert commentary, Toby Maher, MD, PhD, discusses the evolving treatment landscape in progressive pulmonary fibrosis (PPF) and the potential implications of the longer-term FIBRONEER-ILD trial findings. He explores how nerandomilast may address key unmet needs in PPF, with a focus on disease progression, clinically meaningful outcomes, treatment sequencing, and the broader impact on patients, providers, and health care systems. 

Transcript

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.  

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, in a proportion of individuals, be characterized by progressively deteriorating fibrosis of the lung. That is what causes the majority of the morbidity and mortality. Really, it was with the in-build 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. Although it has been an important step 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. 

In that regard, the introduction and recent approval of nerandomilast as a treatment for patients with progressive pulmonary fibrosis has been an important step forward. 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. This represents an important step forward for patients.  

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 in nintedanib, and those patients also got additional benefit from being on nerandomilast. I think we are at an exciting position in the treatment of progressive pulmonary fibrosis. We now have 2 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. 

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. 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. 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 forced 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. 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.  

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. That will continue to give us even longer-term data on the safety and efficacy of nerandomilast. Overall, I think that the trial was very realistic in terms of what we do in day-to-day practice. 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. 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.  

The key primary endpoint from the FIBRONEER-ILD study was change in forced vital capacity over 52 weeks, although we continued to measure FVC for the duration of the study. Forced valve 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. That really is the reason that the FDA expect to see forced vital capacity as the primary endpoint in these sorts of studies.  

So, what did we see in FIBRONEER-ILD? 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. 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 endpoints beyond that, including 76 weeks. 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. Forty-four percent of patients were on nintedanib, and we still saw FVC benefit in that group of patients. The expectation is that, of course, that will ultimately improve survival for these patients living with this devastating set of diseases. 

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. If we look at the Kaplan-Meier curves, we see a statistically, nominally statistically significant benefit of treatment compared to placebo. 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. Ultimately, hospitalization, acute exacerbations are often life-changing events for patients when they happen. They signal a worsening in prognosis. 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. 

In FIBRONEER-ILD, patients were allowed to be on background treatment with nintedanib. About 44% of patients who went into the study were taking nintedanib. We saw that those patients, when we look at the placebo group taking nintedanib alone, that those patients had an appreciable rate of FVC decline over the study. In fact, the rate of decline in those patients was faster than that seen in patients on no background treatment. Furthermore, we saw that nerandomilast slowed the rate of FVC decline when used on top of nintedanib, so there was an added benefit to rate of disease decline when the drugs were used in combination compared to nintedanib alone. We saw that, in general, the drugs were well tolerated, so patients obviously who went into the study on nintedanib were, we presume, already tolerating nintedanib. When we added nerandomilast, we did see a slight increase in the rate of diarrhea, particularly when patients were taking 18 milligrams of nerandomilast with nintedanib.  

However, in general, the combination appeared to be fairly well tolerated within the trial, with relatively few dropouts due to gastrointestinal upset, and other side effects remained well balanced across groups. In summary, the combination of nintedanib and nerandomilast appears to be feasible and beneficial for patients, and I think was an important insight from some of the subgroup analysis that was done with the trial. I think the results of FIBRONEER-ILD now give us the opportunity to use nerandomilast and nintedanib either as monotherapy or in combination. Certainly, for patients newly diagnosed with progressive pulmonary fibrosis, either drug would be an acceptable option from an efficacy perspective.  

I suspect when the pros and cons of both drugs are discussed, many patients may opt for the better tolerated option. However, if patients do progress over time, then that option to use combination therapy, I think, will become very important. I think the only unknown at the moment is whether we should be offering our patients upfront combination therapy. At least in theory, using both drugs together at the time of identifying progressive pulmonary fibrosis might offer extra benefit. However, in the absence of trials designed to specifically answer that question, it is harder for us to know whether that is actually going to be the case or not.  

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 2 different dosing arms of nerandomilast, the 9-milligram and the 18-milligram groups.  

We did, when we dive in, see a little bit of diarrhea in the nerandomilast treatment groups that was more marked in the 18-milligram group, but that did not lead to extra discontinuations when nerandomilast was taken on its own. When we look at other side effects that are listed, we don't see many major differences between nerandomilast and placebo. There was perhaps a slight increase in the number of weight loss events reported with nerandomilast compared to placebo. But otherwise, adverse events were balanced between 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. That was the one situation where we did see some discontinuations, patients taking the combination of nintedanib and nerandomilast, particularly at the 18-milligram dose. 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. In the past, phosphodiesterase inhibitors have been associated with mood disturbance and suicidal ideation. As part of the FIBRONEER-ILD trial, a lot of effort was gone to assess both mood and suicidal ideation. 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. 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. 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. As I've said, the safety/tolerability profile over the duration of the study looked excellent. 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.  

I think the approval of nerandomilast now gives us a very important treatment option for patients with progressive pulmonary fibrosis. Certainly, in my experience over the last decade, since we've had antifibrotic drugs available, many clinicians have hesitated to start early treatment because of concerns about side effects and tolerability with nintedanib. I think nerandomilast now changes the equation. As we've seen, nerandomilast was very well tolerated in patients in the FIBRONEER trials. Our expectation is that that should be true in real-life clinical practice. As such, it removes one of the barriers to early treatment of patients once we've identified progressive pulmonary fibrosis.  

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. 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 step decline, both in their functional level but also, importantly, in their quality of life. Often, patients who are hospitalized will spend protracted periods in hospital, and this contributes to their overall morbidity associated with their disease. 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. 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 healthcare system with reduced overall burden of disease for patients living with PPF.  

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. 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. 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. 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. 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. 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. 

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. It also reduced the risk of hospitalization and acute exacerbations. Finally, I think the third key takeaway from the study was how well tolerated nerandomilast was. In pulmonary fibrosis trials, we've become accustomed to seeing high discontinuation rates due to side effects. 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. 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. 

Toby Maher, MD, PhD, is Professor of Medicine and Director of Interstitial Lung Disease at Keck School of Medicine, University of Southern California, Los Angeles.  

Dr Maher has spent over 20 years specializing in the management of interstitial lung disease. Since June 2020, he has been director of ILD at Keck Medicine of University of Southern California. He previously ran the ILD unit at Royal Brompton Hospital in London and was a professor of ILD at Imperial College London. His research interests include biomarker discovery, cellular senescence in the pathogenesis of IPF, and clinical trials. He has been involved in over 100 trials in fibrotic lung disease from phase 1b through phase 4 and including those assessing IPF, sarcoidosis, scleroderma, rheumatoid arthritis, and inflammatory myositis. He is an associate editor for American Journal of Respiratory and Critical Care Medicine. He has authored over 420 papers on pulmonary fibrosis.