An IPF Game-Changer: A Primer on the Newly Approved Drugs
Editor's Note: Idiopathic pulmonary fibrosis (IPF) is a disease of unknown cause, affecting mostly older adults. Confined to the lungs, the disease causes lung tissue to become thick and scarred over time, making breathing increasingly difficult. The disease is frequently fatal, and many people die within 3 to 5 years of diagnosis.

In October, the US Food and Drug Administration (FDA) approved two new drugs, nintedanib (Ofev®, Boehringer Ingelheim) and pirfenidone (Esbriet®, InterMune), to help manage this condition. Medscape Advisory Board member for Pulmonary Medicine, Steven Nathan, MD, was a principal investigator in studies on pirfenidone and nintedanib.

Dr Nathan recently spoke to Medscape about the importance of the new drug approvals, how the drugs work, and how physicians might use them to potentially extend the lives of their patients.

Medscape: Can you offer some background on these two newly approved therapies and how they came to be thought of as potential treatments for IPF?

Dr Nathan: Just to give you a little bit of a historical background, we've been doing trials in IPF for about the past decade and a half. Most of these trials have been negative and nothing has been approved by the FDA.

Pirfenidone has been around since the 1990s. I've been working with pirfenidone since the mid-1990s. At that time, the rights to the drug was held by a small organization called Marnac Inc. InterMune licensed certain rights to pirfenidone in 2002 from Marnac. Later, InterMune bought Marnac Inc., in 2007. Soon thereafter, InterMune embarked on the CAPACITY studies. These were concurrent phase 3 randomized, controlled studies with the goal of proving efficacy and attaining approval for pirfenidone as a therapy for IPF. Prior to this, another company, in Japan, Shionogi Ltd, had bought the rights to pirfenidone in that country. Japanese researchers conducted some studies there that were positive, and pirfenidone was subsequently approved in Japan.

The CAPACITY studies were completed successfully, but the issue with them was that one study—CAPACITY-2, I believe—was positive and CAPACITY-1 was negative. The cumulative data were positive and it was taken before an FDA panel. The FDA panel recommended approving pirfenidone, based on the results that they had on hand. But the FDA subsequently decided that they weren't going to approve it because the one study did not meet its endpoint. Therefore, a third study was undertaken, the ASCEND study, which was sort of the "tie-breaker" study.

The ASCEND study was completed earlier this year, and the results were presented for the first time at the American Thoracic Society (ATS) International Conference in May in San Diego. Concurrent with this, the article was published in the New England Journal of Medicine.

The nintedanib study was presented and published at the same time in the New England Journal of Medicine. That particular day in May was kind of a landmark day for IPF and led to the subsequent approval of both drugs by the FDA last month. Nintedanib doesn't have the long history that pirfenidone has. A phase 2 study was published in 2012 that looked very promising in terms of a lower rate of decline in lung function, as well as potentially impacting the incidence of acute exacerbations.

While tempting to do, the mistake not to be made is to compare one study to the other, and thereby try to make inferences about one drug being superior to the next. These were both very different studies. Although they had similar endpoints and durations, statistically they were evaluated very differently, while the patient populations were also slightly different because of nuanced differences in the inclusion and exclusion criteria.

Medscape: What is the specific mechanism of action for each of these drugs? Are they used together or separately?

Dr Nathan: They are used separately, although I think some folks will be tempted to use them together. And therein lies the unknown. Ultimately, where we are headed with IPF is toward some form of combination therapy, because neither of the drugs is the panacea. They both slow the rate of decline in lung function. Both likely work through different mechanisms in IPF, so to some it might make sense to use a combination, but this has yet to be subjected to a study.

We don't know how the two drugs might interact with one another—drug-drug interactions and how this might affect the pharmacokinetic profiles of each when used together. Both of them have gastrointestinal (GI) side effects, and we don't know whether the GI side-effect profile of both drugs together will be magnified or diminished.

As I mentioned, the mechanisms of both are different. Nintedanib is a triple kinase inhibitor. It inhibits vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF). The mechanism(s) whereby pirfenidone works specifically in IPF is not known. It is a pleotropic molecule and has multiple potential areas where it might be effective in IPF. It has activity against certain cytokines, including transforming growth factor (TGF) beta and tumor necrosis factor (TNF) alpha. It has also been shown to inhibit fibroblast proliferation and collagen synthesis in animal models of lung fibrosis and also has antioxidant properties. However, its exact mechanism of action in IPF is unknown. The pathogenesis of IPF is very complex, with multiple pathways, escape pathways, etc. If you put the two drugs together they might have some kind of additive or possibly synergistic effect. However, they could also conceivably have antagonist effects, and therefore this concept needs to be tested in the context of a clinical trial.

Medscape: Both of these formulations were fast-tracked for approval under the FDA's orphan and breakthrough drug designations. Why are these drugs so important to the treatment of IPF?

Dr Nathan: They are the first treatments to be FDA approved for IPF; previously we didn't have anything. So they bring hope to the patient and they give physicians options for trying to slow the progression of this disease.

Before, our options were limited; we could enroll patients in clinical trials or refer them for lung transplantation. This latter option was only available to a small subset of patients who met the transplant candidacy criteria. Neither of these drugs is a panacea, and this is just the start. But they do demonstrate—and this is where they are also game-changers—that we can impact and modulate the course of the disease in a positive fashion. This is just the beginning; hopefully we will see future drug regimens coming out that will have an even greater impact on the course of IPF.

Medscape: Because these are new formulations, many physicians are looking for a better understanding of how and when to prescribe them. What advice would you offer them?

Dr. Nathan: That is obviously the $64 million question: How do clinicians decide which drug to use? We don't know whether one is better than the other. There might be nuanced differences in individual patients that might make physicians inclined to use one over the other. For example, for pirfenidone, the recommended dose is three capsules three times a day, whereas with nintedanib the recommended dose is one capsule twice a day. So, for example, say that a patient has an issue and feels like he can't manage nine pills a day or like he is not going to be compliant on that daily dose; then it might make more sense to go with nintedanib. I have to caveat this by saying that in all the years I have been using pirfenidone in the research arena, the pill burden has not been an issue for most patients.

You might have another patient who has a little bit of baseline diarrhea; the major side effect of nintedanib is diarrhea, in almost two thirds of patients. That might be enough to sway the physician to go with pirfenidone instead of nintedanib. I think there will be subtle nuances to each individual case that can turn a physician in one direction or the other, but there will be cases where, quite frankly, it will be a coin flip as to which one to use.

IPF is also a difficult disease to diagnose, so this certainly raises the bar in terms of wanting to be sure that the patients we are treating do have IPF and have been diagnosed correctly.

Medscape: What are your hopes for patients receiving these drugs? Will there be a mortality benefit beyond the estimated 3- to 5-year survival rate for most patients diagnosed with IPF? Could the approval of these two drugs lead to the development of even better treatments?

Dr. Nathan: As far as expectations, these drugs are not like drugs you can take for other conditions— for example, when you put an asthma patient on a bronchodilator and they come back and say, "Gosh, I feel better after exercise." What they will do is preserve lung function for a longer period. So patients won't necessarily notice any difference on a visit-by-visit basis. Also, if they do eventually deteriorate, it's not to say that the drug is not working, because all these drugs do is slow the rate of deterioration; they do not reverse the disease course or restore lung function. What also makes it difficult is that the rate of deterioration is difficult to predict and differs on a patient-by-patient basis.

Will there be a mortality benefit? It is noteworthy that the combined CAPACITY and ASCEND patient groups did show a mortality benefit for pirfenidone at 52 weeks. This was alluded to in the NEJM publication. However, there is no mention of a mortality benefit in the prescribing information for pirfenidone because, for the FDA analysis, to my understanding, all the patients were followed out for as long as they continued in their respective studies. Whereas the ASCEND study had follow-up to only around 52 weeks, those patients in the CAPACITY studies had follow-up well beyond 72 weeks. When the groups were looked at in terms of total follow-up, there was no demonstrable mortality difference.

It is going to be very difficult to say that we are achieving something specific in individual patients because the natural history of progression is so difficult to predict in individual patients. If one believes the data from these studies (which I do), that both of these drugs work to preserve lung function in cohorts of patients with IPF, then as we prescribe these agents, we will be doing the community of IPF patients a good service. Ultimately, hopefully one day we can go back and look at how these patients have done with using one or both of these drugs, and we'll see that they have survived longer and performed better over a specific period of time. This is something we might only appreciate in retrospect, by looking at large cohorts of patients who have been treated with the drug(s).

In terms of future drug development, I think this is just the first shot across the bow, and there is certainly room for other drugs to be developed and come to market. These are just the start to coming up with more effective regimens that will effectively treat this condition and hopefully reverse the disease course in many patients. I don't see these drugs being approved as an impediment to future drug development. If anything else, this will accelerate interest in the development of other drugs for IPF.

You only have to look at other conditions, like pulmonary arterial hypertension (PAH), which is a much smaller-market disease. The availability of the second drug for this condition was about 12 years ago, and today in the United States we have 13 available therapies for PAH. IPF is probably 15 to 20 years behind the world of PAH, and there are many more patients who would benefit from a multitude of therapies for IPF when they come to market. Certainly the availability of these drugs just marks the end of the beginning and is reason for optimism for this devastating condition.