Steven D. Nathan, MD, FCCP

Some practical tips to share with community physicians. IPF [idiopathic pulmonary fibrosis] can be a difficult diagnosis. Sometimes it’s black and white, clearly IPF or clearly not. But most of the patients fall in that gray zone of uncertainty. What I would say is if you’re uncertain, and this might be self-serving, contact your local ILD [interstitial lung disease] center. Get a second opinion and see what they have to say. I look to my colleagues all the time in our clinic, and I say, what do you think of this CT, or what do you make of this or that?

Talking among ourselves and putting these patients before multidisciplinary discussion, which typically happens at ILD centers, can be very important for validation of the diagnosis. Because probably the most difficult aspect of IPF is to make an accurate diagnosis first. The value of sending folks to ILD centers is that they can be looked at for clinical trials. Many ILD centers, such as ours, are transplant centers as well.

It becomes 1-stop shopping. You can get validation of the diagnosis concurrently. If you don’t want to start the therapy yourselves and leave it to the ILD docs, you can do it. They get looked at for clinical trials, and they get evaluated even in a cursory fashion as a potential lung transplant candidate.

To the community docs out there, don’t feel like you’re flying alone. I think I speak for all the ILD centers out there. We’re only too happy to partner with you in taking care of your patients and making sure they have the best possible outcomes.

I believe strongly that the primary care clinician should be the principal player in guiding patients and their caregivers through any disease process. I’ve had strong bias all along. I trained as a primary care physician years ago. My sense is that the primary care clinician needs to understand these disorders because of their severity and the implication for patient and their family members. That includes having a high index of suspicion of when this disease may be present.
So there have been a series of studies that are lovely and demonstrate that an older person presenting with a chronic cough is a tip-off to the primary care clinician that they should consider these disorders, and IPF in particular, as a potential diagnosis. Because it’s our suspicion that earlier diagnosis, particularly with these effective drugs, is likely going to be better in the long term. It makes sense, and the data would support that. Trying to work with our primary care clinicians to have a higher index of suspicion of when these disorders are present is crucial. The same thing for our radiologists, because we have a sense that early changes on a CT scan can be very instructive with regard to the early diagnostic process. 

That interaction has improved. If you think about how we consider optimizing the patient’s quality of life and survival, the importance of being able to address the potential tolerability issues of the drugs and how to manage them. The comorbid conditions and their interaction. In the middle of all that is a primary care clinician.

When we develop therapeutic plans with our patients and their caregivers, when we have a disease-management plan, it’s immediately transmitted to their primary care clinician, ideally by a phone call or a video chat, so the primary care clinician is fully aware of where we are at each stage and can aid the patient in making decisions at each stage.

The primary care clinician is a crucial player from the early diagnosis to the management at the end stage of disease. They are the quarterback in most of what happens with these patients.

Videos

Steven D. Nathan, MD, FCCP, and Fernando J. Martinez, MD, MS, share clinical pearls and advice for the management of IPF.

Clinical Pearls for the Management of IPF

Pirfenidone and nintedanib have been around for 7 years. What’s going to come down the pike next? I mentioned inhaled treprostinil is approved to treat complicating PH [pulmonary hypertension] being studied as a potential antifibrotic. There are many other drugs in various stages of development.

Drug development takes awhile, and inhaled treprostinil is in phase 3. There’s the drug that was owned by Promedior and is now owned by Roche, PRM-151. That’s being studied in a phase 3 clinical trial by Roche. There was the Galapagos study [ISABELA phase 3 trial], which got halted earlier this year for some reason. Data still have to be presented, but that was halted early so it’s not going to bear out as a therapy. There’s FibroGen’s anticonnective tissue growth factor infusion that’s being studied in a phase 3 trial as well.

It takes awhile for these drugs to go through phase 3, for the data to be scrubbed and analyzed, for patients to be followed, to go before the FDA. If any of the 3 agents I just mentioned that are on phase 3 do bear fruit and are shown to work in IPF, then it’s probably a minimum of another 2 years to maybe 4 years before 1 of them becomes available for clinical practice.

Many other drugs in phase 2 are even further behind. Many who will go on to phase 3 will depend on the phase 2 results, obviously. The next wave after these 3 that I mentioned is probably 7 to 10 years down the road. At this point, therefore, we have pirfenidone, nintedanib, and inhaled treprostinil that we can give our patients who have IPF [idiopathic pulmonary fibrosis]. We have to be patient, and our patients have to be willing to get enrolled and recruited into clinical trials. That’s important in our global management of these patients: the opportunity of being enrolled in a clinical trial because the availability of pirfenidone, nintedanib, and inhaled treprostinil is only through the good graces of the patients previously who were willing to participate in randomized controlled, placebo-controlled clinical trials.

There’s a tremendous push. It’s amazing to see how much advance is taking place in IPF over the last decade. It’s unbelievable. We have 2 agents that work, and dozens of clinical trials are ongoing with agents that span the spectrum of how the lung is injured and how it responds to that injury. Several drugs are in advanced-stage development, in phase 3, the traditional large, blinded, placebo-controlled trials.

There’s a drug being tested that specifically targets a very downstream pathway in the fibrotic pathway, which is pamrevlumab. It’s had impressive phase 2 results. It’s in a phase 3 program now. We’re all excited about how that looks. There’s a drug called ataxin-2 that targets a particular inflammatory process that’s been associated with progressive fibrosis, also with very impressive phase 2 data and in a phase 3 program. I’m 1 of the co–PIs [principal Investigators] of that study, so I’m biased. That study is now global and enrolling patients.

There was a recent study of inhaled treprostinil, which was more targeted to the pulmonary hypertension complication of ILD [interstitial lung disease]. But it suggested that it may improve lung function, so that’s being tested. There are 27 or 28 earlier-stage phase 2 studies that are ongoing. It’s dramatic how much advance we’ve made. The discussions that we have with patients at our center [Weill Cornell Medicine] are about not only the antifibrotics but the 5 or 6 active clinical trials that are present at any given time.

My suspicion is that within the next 2 or 3 years, the situation will be much more hopeful with combinations of these agents targeted to a specific patient. The overall approach and prognosis of patients is going to be markedly improved, and it’s not going to be 20 years. It’s going to be within the next few years. I am absolutely convinced that’s going to be the case.

Stem cells have been looked at for IPF, mostly just feasibility and tolerability. I know 

 sounds sexy for everything, but we don’t have efficacy data yet. There’s some promise to using stem cells, but I cannot endorse this in any way, shape, or form outside a clinical trial until we have the appropriate clinical trials to show that this is a strategy that works.

Expert pulmonologists comment on emerging therapies in the pipeline for the treatment of IPF.

Novel Agents for IPF Management

 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.

 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.

 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.

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.

Treatment Selection of Antifibrotic Agents for IPF

 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].

 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.”

Experts in pulmonology discuss the safety and efficacy of pirfenidone and nintedanib for the management of IPF.

Steven D. Nathan, MD, FCCP

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