While multiple trials assessing different mechanisms and approaches to treatment have proved negative over the past decade and a half, two drug therapies have recently become available for the directed treatment of idiopathic pulmonary fibrosis (IPF). Pirfenidone, a well-known anti-fibrotic drug already approved outside the U.S., and nintedanib, a tyrosine kinase inhibitor, both became available internationally in October 2014. The drugs mirrored each other in the number of phase III clinical trials leading to approval and slowing of forced vital capacity (FVC) decline, with pirfenidone touting a signal for improved mortality, and nintedanib suggesting decreased incidence of acute exacerbation in two of its three large trials.
While the availability of two agents for a progressive and fatal disease is welcomed, questions remain regarding indications and timing of initiation, side effects, and long-term outcomes. Clinical trials to date have excluded people with FVC of less than 50 percent predicted, leaving little understanding of how treatment affects people with more-advanced disease. The careful selection of trial participants limits applicability of outcomes to patients typically seen in practice.
For example, in clinical practice, up to 50 percent of patients with IPF may have "possible" usual interstitial pneumonia pattern on chest CT scans, while patients in clinical trials, subjected to diagnostic adjudication by committee, represent a purer diagnostic group.
In addition, trials often exclude concomitant emphysema on chest imaging, not an uncommon finding in clinical practice.
Side effects, including photosensitivity rash with pirfenidone and loose stools with nintedanib, may lead to drug intolerance and early discontinuation. As both medications are intended to slow disease progression, perhaps measured over months or years, drug adherence remains an important issue, particularly as clinical symptoms such as dyspnea or cough may not be expected to significantly improve.
When pooling data for two of the pirfenidone trials, 21 percent of participants still had FVC decline greater than 10 percent while on therapy. Furthermore, patient variables that predict a medication response are yet to be determined. Indeed, pirfenidone has been available for a number of years outside the U.S. for IPF treatment, yet few long-term follow-up studies exist and are limited to center-specific reviews of clinical experience. Unfortunately, such studies have been more equivocal than confirmatory of clinical or survival benefit. Finally, for some patients, disease stability (defined by a relative lack of symptoms or minimally changed FVC) may be justification for deferring initiation of drug therapy, though the expectation of future progression must be acknowledged.
At this time, use of both anti-fibrotic drugs is limited to the diagnosis of IPF but will likely see expansion to non-IPF interstitial lung disease in the near future. Where patients had little opportunity to fight disease in the past, current therapies offer a chance to slow disease progression and delay severity of symptoms. Research continues to optimize selection of the target population that will most benefit and experience the fewest side effects.