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Experts in pulmonology discuss the safety and efficacy of pirfenidone and nintedanib for the management of IPF.
Steven D. Nathan, MD, FCCP: The 2 antifibrotic drugs we have available for IPF [idiopathic pulmonary fibrosis], pirfenidone and nintedanib, have been around for about 7 years. It’s interesting that both are pleiotropic molecules, meaning that they have multiple targets that they potentially address in the context of the pathogenesis of IPF. If you look at nintedanib, it’s a triple kinase inhibitor that inhibits VEGF, fibroblast growth factor, and connective tissue disease growth factor. It has other TKI [tyrosine kinase inhibitor] effects as well, but those are the 3 main ones.
Pirfenidone is also pleiotropic. It has antioxidant properties, it affects TGF-β pathway, and it has other properties that aren’t well worked out. How it works in the context of IPF is uncertain, but the reason that both drugs might be effective antifibrotics is because they’re pleiotropic and don’t target just 1 pathway. Because IPF is such a complex disease, drugs that target multiple pathways might be an effective way to manage the diseases. For both, it’s like giving multimodality therapy with 1 pill.
There’s a third agent that recently got approved, inhaled treprostinil, specifically for pulmonary hypertension complicating the course of interstitial lung disease, including IPF. We look to start antifibrotics early—either nintedanib or pirfenidone, and I use both—but later on in the disease course we maintain our vigilance if and when they develop pulmonary hypertension. One can regard that as a complication of the IPF or as a comorbidity, but once it sets in then we have a third option through inhaled treprostinil which was approved last year on March 31 as a therapy for PH-ILD [pulmonary hypertension associated with interstitial lung disease].
Fernando J. Martinez, MD, MS: It’s crucial to understand that for some of us who have been in this field for 30 years, the field has totally changed in the last 6, 7 years because we have effective antifibrotic therapies. Two have been approved, pirfenidone and nintedanib. Both agents clearly ameliorate, decreasing the progression of lung function abnormality in patients with idiopathic pulmonary fibrosis. That’s a massive improvement. We also understand that those drugs can be—not always, but can be—difficult to tolerate. Nintedanib has its major concern being stomach upset and potentially diarrhea. Pirfenidone can be associated with feeling blah, anorexia, and nausea. It clearly has the potential to cause photosensitivity. What’s become very clear is that both drugs have the potential to cause liver toxicity. They can have interactions with drugs that cause liver toxicity.
The advantage is those drugs clearly work. They clearly can have a beneficial effect on our patients. But we have to understand their tolerability. Because these drugs have been available for several years and lots of patients have used them, we’ve developed a lot more expertise. It’s clear that the level of difficulty in tolerating these drugs in clinical practice is much less than we initially suspected from the clinical trials. That’s a good thing, and that’s because we’ve become very good at understanding how to mitigate some of the diarrhea concerns with nintedanib or the photosensitivity component of pirfenidone. We’ve gotten quite good at knowing how to monitor liver function studies, how to alter drugs, how to potentially provide drug holidays if people require those. So the drugs are much better tolerated than when we started doing this. We’ve become much savvier at understanding how to tolerate these drugs from a patient’s and caregiver’s perspective.
One of the interesting things of having 2 drugs is that they work differently, and they’re both effective. They’ve never been compared head-to-head, but there has been a statistical approach to try to compare them. My sense is that the drugs are very similar in terms of their efficacy. When we consider these drugs in clinical practice, since all of us are trying to be much more adherent to this shared decision-making philosophy, it’s a discussion with the patient and their caregiver because the drugs are dosed a little differently. The adverse-effect profile, as I mentioned, is a little different. Drug interactions are a little different, so some drugs interact with anticoagulation, for example. Others may have more of an interaction with skin disorders.
I suspect that my own bias is the drugs are remarkably similar. How we choose to recommend 1 for the patient is based on the patient’s desire with regard to adverse effects, drug-drug interactions, and how often you have to take the medication. That’s usually a much longer discussion than it used to be when we saw patients. That’s a good thing because that means that we’re describing to the patient and their caregiver what we know about these drugs, and having them play a key role in, “I want that 1 or that 1.”
Trancsript Edited for Clarity