Idiopathic pulmonary fibrosis (IPF) is the most frequent and the most lethal among the idiopathic interstitial pneumonias: with a 3 to 5 years estimated average survival after diagnosis and lung transplant as the only ‘therapeutic’ option so far, this disease represents, without any doubt, a major challenge for any pulmonary physician worldwide. However, the good news is in the exponential increase over the last decade in the number and the methodological quality of placebo-controlled randomized controlled trials (RCT) assessing the safety and the efficacy of new potential IPF treatments. Over the last few years, several thousands of persons affected by IPF had the opportunity of being part of different RCT enrolling patients in different geographic areas of the globe. Recently, the first fruits of these combined global efforts involving physicians, industries, funding agencies and patients are becoming available. In this issue of the journal, Hilberg and co-workers focus on the results of a series of studies evaluating the impact of pirfenidone, the first drug approved for IPF.
Assessing the effect of the first therapeutic intervention in any disease is a challenge in itself, due to the lack of previously approved benchmarking drugs and the intrinsic lack of knowledge because of the lack of long-term data; IPF does not make an exception to these problems, having been largely treated empirically until now. It is remarkable that the most widely used approach used in IPF so far, the so-called triple therapy (i.e. a combination of prednisone, azathioprine and N-acetylcysteine), has been recently shown to be not only ineffective but also harmful (by significantly increasing mortality compared with placebo) in a properly designed RCT, sponsored by the US National Institutes of Health . These unpredictable results stress once again the importance, highlighted for the first time four decades ago by Archie Cochrane , of using the evidence derived from placebo-controlled RCT in daily clinical practice, simply because the results of these studies are likely to provide much more reliable information than any other source of evidence. In this context, the results available today for pirfenidone, which are based on the comprehensive evaluation of at least three different RCT and on related meta-analyses , are undoubtedly encouraging. This drug might not be the ‘magic bullet for IPF’ (a likely unrealistic concept for such a complex disease), but it certainly represents a major advancement, in particular, when compared with the ‘toxic’ empiric treatments used until now and probably still largely in place in many areas of the world. The fact that pirfenidone has been approved for clinical use in Japan, India and Europe, but not in the United States, underscores the existing differences in the evaluation of efficacy of drugs across different regulatory agencies and the many existing gaps of knowledge in IPF. Because we are still at the early ages of IPF therapies, we cannot be sure on which approach will be the best one in assessing effect of IPF treatments. As a reflection of these uncertainties, an ongoing debate on clinically meaningful endpoints in IPF is currently ongoing . Nonetheless, we should reaffirm the fact that the methodologies used to assess the safety and the efficacy of pirfenidone are proper and adequate: as such, the existing degree of uncertainty is most likely due to the still unpredictable heterogeneity of the disease course and the lack of knowledge about factors impacting disease progression over time (e.g. the genetic factors). In this context, the ongoing further RCT currently enrolling patients in the United States (the ASCEND study) will add to our existing knowledge, although being probably unlikely to answer the fundamental questions on the effect of this treatment, i.e. its impact on overall survival.
Opening a new pathway in drug discovery for a disease without a cure is undoubtedly a major challenge: although the chances of failure would be high, the potential impact on the life of patients would be even higher. For this reason, it is important that the search for new drugs in IPF does not stop but move forward as soon as possible, starting from the first solid step represented by pirfenidone.