Treatment Selection of Antifibrotic Agents for IPF

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Insights | <b>Management of Idiopathic Pulmonary Fibrosis</b>

Fernando J. Martinez, MD, MS, and Steven D. Nathan, MD, FCCP, share their personal experiences using pirfenidone and nintedanib in clinical practice and discuss the role of managing comorbidities for the treatment of IPF.

Fernando J. Martinez, MD, MS: There are a series of components that we put into play when we’re trying to make decisions and recommendations to patients under caregivers with regard to which medication is appropriate. That would include some of the comorbid conditions. If you’re on an anticoagulant, 1 of the drugs is less feasible than another. The level of underlying liver or kidney function can influence how we approach recommending 1 drug or the other.

There are series of factors particularly in older adults—patients with IPF [idiopathic pulmonary fibrosis] tend to be a little older—that we will take into account. Is the patient underweight or losing a fair amount of weight? Remember, GI [gastrointestinal] toxicity is 1 thing that can be seen with these drugs. Is the patient very advanced in their disease? Do the patients take a whole series of other medications so that we need to ensure that the regimen is most straightforward with regard to the number of pills or capsules they take and any drug interactions? It is a much more complex—in a good way—series of discussions that we discuss and consider as we’re interacting with the patient and caregiver with regard to making decisions regarding therapy. All that needs to be incorporated as the patient makes the final decision regarding which agent they prefer to consider trying.

My experience has been that both drugs are well tolerated if you’re careful in terms of how they’re dosed and they’re taken with food and you monitor patients closely. Alter the dose as needed for adverse effects. They’re much better tolerated than we initially saw early on or suspected. There are still patients who can’t tolerate 1 drug or the other, and we’ve taken patients off these drugs at their choice. My sense is they’re much better tolerated than we saw years ago or that were seen in the clinical trials.

Steven D. Nathan, MD, FCCP: I use both pirfenidone and nintedanib in my practice. I try to pick the drug that’s most suited to the patient’s lifestyle or comorbidities. I’ll give you a couple of extreme examples. Pirfenidone has, as 1 of its adverse effects, photosensitivity—skin rash that can be brought out by going in the sun. If 1 plays golf 6 days a week, I might want to steer them away from pirfenidone and toward nintedanib. Nintedanib has some effects on coagulation through its anti-VEGF properties. In fact, patients who are on anticoagulation were excluded from the INPULSIS studies, which got nintedanib approved. If someone comes in on anticoagulation, I might steer them away from nintedanib more to pirfenidone. It takes getting to know the patients—what their lifestyle is like, what their comorbidities and concomitant meds are—to make the most appropriate choice for them.

The key to success with both antifibrotics is to choose the 1 that’s most likely to be tolerated and that the patient is most likely to continue on because they key to success with both is to put the patients on drug, preferably early, and to keep them on drug; otherwise, you’re not going to have a successful outcome. A lot of times it takes a lot of education, managing expectations in terms of what the drugs do and don’t do, managing expectations with what adverse effects might ensue and how to manage those, as well getting the patients to buy into preservation of their lung function as the goal.

It takes some education on why preservation of the FVC [forced vital capacity] is important and why this might have long-term implications. What we’re seeing from more long-term studies, as well as multiple registries around the world, is that patients who are on antifibrotics, either pirfenidone or nintedanib, are living longer than patients who aren’t treated with antifibrotics. What we saw in intermediate-term studies, 42, 72 weeks, in terms of what both drugs do for the FVC is being relegated with long-term data. We’re seeing a lower mortality in patients who are on antifibrotics. You can always punch holes into registry data, but every registry has reported the same. Some of our own analyses that we’ve done with our patients have supported the fact that both drugs have a long-term mortality benefit.

We know that pirfenidone and nintedanib work in IPF. The next question is if they work by themselves, then what about together. Surely 2 are better than 1. There have been a couple of studies looking at the 2 drugs in conjunction with one another, mostly for safety rather than efficacy, safety and tolerability as well as pharmacokinetics. It has been shown that they can be given together. The adverse effects not unexpectedly are a little more. Both can affect the GI tracts in particular. There isn’t much in the way of efficacy data to support that giving them both together will result in improved outcomes.

That’s where the future is: combination therapy. In fact, many of the clinical trials coming down the pike or that are being implemented now allow patients to come in on antifibrotic therapy. What we’re going to see in terms of readouts from these future studies are how pirfenidone and nintedanib do with drug X or drug Y, whichever is being studied. I don’t think we’re going to have a big randomized controlled study looking at the efficacy of nintedanib and pirfenidone anytime soon. I don’t think that study will ever happen, unfortunately.

But combination therapy clearly will be the way of the future. If you look at the recent approval of inhaled treprostinil, patients can get inhaled treprostinil already on pirfenidone or nintedanib, and then inhaled treprostinil is used to treat their complicating pulmonary hypertension. There’s even some evidence that inhaled treprostinil may have an impact on the FVC, and inhaled treprostinil has now been studied clearly for its antifibrotic properties rather than for its vasodilatory properties.

Fernando J. Martinez, MD, MS: Unfortunately, in general, patients with IPF are a little older. With age comes age-related components and comorbid conditions. The comorbid conditions can clearly have an impact on the patient’s quality of life. Just focusing on their IPF is not a good thing. You have to look at the patient holistically and ensure that because the patients want a better quality of life and ideally a longer survival, the combination of those is the ideal situation. Then you have to consider all the components that are influencing those for an individual patient. There are approaches that we take to ensure that the underlying IPF is not worsening the status of a comorbid condition that requires active intervention. But there are also comorbid conditions that can be associated with IPF severity and progression.

For example, the most classic is gastroesophageal reflux. That’s been associated in multiple studies with the potential of developing IPF or progressing in the IPF. We’re very aggressive these days at querying and managing reflux, including in some cases surgery for reflux. The obstructive sleep apnea has been associated with IPF and worsening IPF, so we’re very aggressive at querying for potential obstructive sleep apnea and screening for it, treating it if it’s present. Those are 2 conditions that clearly have been linked to IPF in terms of its development and progression. The approach to comorbid conditions is the interplay between the lung disorder and all these other conditions, so that this or that these don’t make this worse. Consider all that in totality as you’re holistically managing a patient, because you want that patient to have the best quality of life with the least number of symptoms for the longest period of time possible.

Transcript Edited for Clarity