Treatment selection of antifibrotic agents for IPF

Fernando J. Martinez, MD, MS: There’s a series of things that we put into play when we’re trying to make decisions and make recommendations to patients under caregivers regarding appropriate medications. This would include some of the comorbid conditions. If you are on blood thinners, one medication is less feasible than another. The level of underlying liver or kidney function can influence how we approach the recommendation of one medication or another.

There are a series of factors, especially in the elderly – patients with IPF [idiopathic pulmonary fibrosis] tend to be a bit older – we’ll take that into account. Is the patient underweight or losing a fair amount of weight? Remember, IM [gastrointestinal] toxicity is something you can see with these drugs. Is the patient very advanced in his disease? Are the patients taking a whole host of other medications, so we need to make sure the regimen is the simplest in terms of how many pills or capsules they take and drug interactions? It’s a much more complex set of discussions – in a good way – that we discuss and consider when interacting with the patient and caregiver in making decisions about therapy. All of this must be factored in when the patient makes the final decision about which agent they prefer to consider trying.

My experience has been that both drugs are well tolerated if you are careful how they are dosed and taken with food and monitor patients closely. Alter dose as needed for adverse effects. They are much better tolerated than what we initially saw or suspected. There are still patients who cannot tolerate one drug or the other, and we have removed patients from those drugs of their choosing. I feel like they are much better tolerated than years ago or seen in clinical trials.

Steven D. Nathan, MD, PCCF: I use both pirfenidone and nintedanib in my practice. I try to choose the drug that best suits the patient’s lifestyle or comorbidities. I’ll give you some extreme examples. Pirfenidone has, as one of its side effects, photosensitivity – a skin rash that can be caused by exposure to the sun. If I golf 6 days a week I might want to move them away from pirfenidone and towards nintedanib. Nintedanib has effects on coagulation through its anti-VEGF properties. Indeed, patients on anticoagulation were excluded from the INPULSIS studies, which got nintedanib approved. If someone comes in on anticoagulation, I could divert them from nintedanib to pirfenidone. You have to get to know the patients – what their lifestyle is, what their comorbidities are and the concomitant medications – to make the most appropriate choice for them.

The key to success with both antifibrotics is to choose the one that is most likely to be tolerated and the patient is most likely to continue as the key to success with both is to get patients on medication, preferably early , and keep them on drugs; otherwise, you are not going to have a positive result. Often it takes a lot of education, managing expectations in terms of what drugs do and don’t do, managing expectations with what adverse effects might result and how to manage them, and getting patients to buy in preservation of their lung function as a goal.

There needs to be some education on why preserving FVC [forced vital capacity] is important and why it might have long-term implications. What we’re seeing from longer term studies, as well as multiple registries around the world, is that patients who take antifibrotics, either pirfenidone or nintedanib, live longer than patients who don’t. are not treated with antifibrotics. What we’ve seen in the mid-term studies, 42, 72 weeks, in terms of what the two drugs do for FVC is relegated to long-term data. We observe a decrease in mortality in patients on antifibrotics. You can still poke holes in the registry data, but each registry reported the same thing. Some of our own analyzes that we have done with our patients have supported the fact that both drugs have a beneficial effect on long-term mortality.

We know that pirfenidone and nintedanib work in IPF. The next question is if they work alone, then what about together. Surely 2 is better than 1. There have been a few studies looking at the 2 drugs in conjunction with each other, mostly for safety rather than efficacy, safety and tolerability as well as pharmacokinetics. It has been shown that they can be given together. Not unexpected side effects are a bit more. Both can affect the gastrointestinal tract in particular. There isn’t much efficacy data to support that giving them both together will result in better results.

This is where the future lies: combination therapy. In fact, many of the clinical trials underway or in the process of being implemented now allow patients to undergo antifibrotic therapy. What we’re going to see in terms of the readings of these future studies is how pirfenidone and nintedanib work with drug X or drug Y, depending on which is being studied. I don’t think we will soon have a large randomized controlled study of the effectiveness of nintedanib and pirfenidone. I don’t think that study will ever happen, unfortunately.

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

Fernando J. Martinez, MD, MS: Unfortunately, in general, patients with IPF are a bit older. With age come age-related components and comorbid conditions. Comorbid conditions can clearly have an impact on the patient’s quality of life. Focusing solely on their REIT is not a good thing. You have to look at the patient holistically and make sure that because patients want a better quality of life and ideally longer survival, the combination of those is the ideal situation. Then you have to take into account all the components that influence those of an individual patient. We take certain approaches to ensure that the underlying IPF does not worsen the condition of a comorbid condition that requires active intervention. But there are also comorbid conditions that may be associated with the severity and progression of IPF.

For example, the most classic is gastroesophageal reflux. This has been associated in several studies with the potential to develop IPF or progress in IPF. We are very aggressive these days in questioning and managing reflux, including in some cases reflux surgery. Obstructive sleep apnea has been associated with IPF and worsening IPF, so we are very aggressive in looking for possible obstructive sleep apnea and screening for it, treating it if present. These are 2 conditions that have clearly been linked to IPF in terms of development and progression. The approach of comorbid conditions is the interaction between the lung disorder and all these other conditions, so that this or that does not make the situation worse. Consider all of this in its totality when managing a patient holistically, because you want that patient to have the best quality of life with the fewest symptoms for the longest period of time possible.

Transcript edited for clarity

Martin E. Berry