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Editorial |

Improving Survival in Idiopathic Pulmonary Fibrosis: The Race Has Just Begun FREE TO VIEW

Harold R. Collard, MD, FCCP
Author and Funding Information

FINANCIAL/NONFINANCIAL DISCLOSURES: The author has reported to CHEST the following: H. R. C. has served as a scientific consultant and advisory board member for Boehringer Ingelheim and as an advisory board member for Roche/Genentech for the past 3 years.

Department of Medicine, University of California, San Francisco, San Francisco, CA

CORRESPONDENCE TO: Harold R. Collard, MD, FCCP, Department of Medicine, University of California, San Francisco, 505 Parnassus Ave, Campus Box 0111, San Francisco, CA 94143


Copyright 2017, American College of Chest Physicians. All Rights Reserved.


Chest. 2017;151(3):527-528. doi:10.1016/j.chest.2017.01.007
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Published online

Jockeys hoping to squeeze more out of an exhausted thoroughbred at the end of a race often whip the horse’s thigh with a riding crop. By that point, the poor beast often has nothing left to give. After the recent publication by Nathan et al in the Lancet Respiratory Medicine, any additional pooled or meta-analyses of the impact of pirfenidone on 52-week mortality in patients with idiopathic pulmonary fibrosis (IPF) will be similarly futile. The issue is settled. It is time to move on.

Pirfenidone improves survival time over 52 weeks (its impact beyond 52 weeks is less clear due to limited data). There are now at least six articles that demonstrate qualitatively similar findings.,,,,, This conclusion has proved remarkably contentious in the IPF academic community; this is regrettable. In practice, most of us have tacitly accepted it as true—why else would we recommend a medication with significant tolerability issues and cost? To preserve FVC? Patients only care about preserving FVC because of its presumed (and now established) relevance to improved survival time. We should no longer argue against this rationale.

The demonstration of pirfenidone’s impact on survival time has important implications for IPF clinical trials. The field’s most heated debate of the past decade was about the “clinical meaningfulness” of FVC as an end point.,, It centered on the concept of end-point validation—specifically whether treatment-related differences in FVC decline reliably reflected treatment-related differences in survival time. A disconnect could occur for a variety of reasons, most directly because FVC decline might not be in the “causal pathway” of survival time. In other words, there might be an association but not causation. The findings from the pirfenidone program (combined with the qualitatively similar findings seen in the nintedanib data,) suggest that this is not the case. Perhaps the US Food and Drug Administration said it best in its editorial describing the approval process for pirfenidone and nintedanib: “the relationship between FVC and mortality trends in both sets of clinical trials strengthened our ability to rely on FVC as a clinically relevant measure in IPF.”

Since the approval of pirfenidone and nintedanib, there have been several high-profile disappointments in IPF clinical trials,, and there is a growing unease among potential sponsors with the lack of efficient clinical development pathways and feasible regulatory end points. There is a real risk that investment and innovation in the field of IPF drug discovery will wane. I cannot emphasize enough the importance of moving beyond the debates of the past few years to address the significant challenges facing future IPF drug developers. This means accepting that pirfenidone, and probably nintedanib, are important therapies that prolong survival time in IPF, emphasizing that they are both insufficient as monotherapy and that there remains a large unmet medical need in the field, and accepting that FVC is an appropriate end point for future registration trials of novel IPF therapies.

The IPF community needs to collectively search for more efficient end-points and cohort enrichment strategies that allow for reasonable sample sizes and reliable signals in early-phase clinical trials. I believe this is the number one priority for drug development in IPF, and it will require a new level of collaboration among clinical scientists, industry sponsors, regulators, and other key stakeholders. There are powerful incentives across stakeholder groups to avoid this push; this would be a huge mistake. The IPF community has an obligation to push forward—to agitate for a renewed urgency in drug development. One need only look to the patients who continue to die of this awful disease despite approved therapies to see why.

To risk extending the analogy that I began with too far, the IPF community needs to stop beating the dead horses of the past, switch saddles, and sprint out of the gates together toward the next set of challenges facing the field. This is the only way we will reach the most important finish line—curing IPF—toward which we are all so desperately racing.

References

Nathan S.D. .Albera C. .Bradford W.Z. .et al Effect of pirfenidone on mortality: pooled analyses and meta-analyses of clinical trials in idiopathic pulmonary fibrosis. Lancet Respir Med. 2017;5:33-41 [PubMed]journal. [CrossRef] [PubMed]
 
King T.E. Jr..Bradford W.Z. .Castro-Bernardini S. .et al A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2083-2092 [PubMed]journal. [CrossRef] [PubMed]
 
Loveman E. .Copley V.R. .Scott D.A. .Colquitt J.L. .Clegg A.J. .O'Reilly K.M. . Comparing new treatments for idiopathic pulmonary fibrosis—a network meta-analysis. BMC Pulm Med. 2015;15:37- [PubMed]journal. [CrossRef] [PubMed]
 
Aravena C. .Labarca G. .Venegas C. .Arenas A. .Rada G. . Pirfenidone for idiopathic pulmonary fibrosis: a systematic review and meta-analysis. PLoS One. 2015;10:e0136160- [PubMed]journal. [CrossRef] [PubMed]
 
Canestaro W.J. .Forrester S.H. .Raghu G. .Ho L. .Devine B.E. . Drug treatment of idiopathic pulmonary fibrosis: systematic review and network meta-analysis. Chest. 2016;149:756-766 [PubMed]journal. [CrossRef] [PubMed]
 
Rochwerg B. .Neupane B. .Zhang Y. .et al Treatment of idiopathic pulmonary fibrosis: a network meta-analysis. BMC Med. 2016;14:18- [PubMed]journal. [CrossRef] [PubMed]
 
Raghu G. .Collard H.R. .Anstrom K.J. .et al Idiopathic pulmonary fibrosis: clinically meaningful primary endpoints in phase 3 clinical trials. Am J Respir Crit Care Med. 2012;185:1044-1048 [PubMed]journal. [CrossRef] [PubMed]
 
Wells A.U. .Behr J. .Costabel U. .et al Hot of the breath: mortality as a primary end-point in IPF treatment trials: the best is the enemy of the good. Thorax. 2012;67:938-940 [PubMed]journal. [CrossRef] [PubMed]
 
du Bois R.M. .Nathan S.D. .Richeldi L. .Schwarz M.I. .Noble P.W. . Idiopathic pulmonary fibrosis: lung function is a clinically meaningful endpoint for phase III trials. Am J Respir Crit Care Med. 2012;186:712-715 [PubMed]journal. [CrossRef] [PubMed]
 
Richeldi L. .du Bois R.M. .Raghu G. .et al Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2071-2082 [PubMed]journal. [CrossRef] [PubMed]
 
Richeldi L. .Cottin V. .du Bois R.M. .et al Nintedanib in patients with idiopathic pulmonary fibrosis: combined evidence from the TOMORROW and INPULSIS(®) trials. Respir Med. 2016;113:74-79 [PubMed]journal. [CrossRef] [PubMed]
 
Karimi-Shah B.A. .Chowdhury B.A. . Forced vital capacity in idiopathic pulmonary fibrosis—FDA review of pirfenidone and nintedanib. N Engl J Med. 2015;372:1189-1191 [PubMed]journal. [CrossRef] [PubMed]
 
Raghu G. .Brown K.K. .Collard H.R. .et al Efficacy of simtuzumab versus placebo in patients with idiopathic pulmonary fibrosis: a randomised, double-blind, controlled, phase 2 trial. Lancet Respir Med. 2017;5:22-32 [PubMed]journal. [CrossRef] [PubMed]
 
Behr J. .Bendstrup E. .Crestani B. .et al Safety and tolerability of acetylcysteine and pirfenidone combination therapy in idiopathic pulmonary fibrosis: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Respir Med. 2016;4:445-453 [PubMed]journal. [CrossRef] [PubMed]
 
Collard H.R. .Bradford W.Z. .Cottin V. .et al A new era in idiopathic pulmonary fibrosis: considerations for future clinical trials. Eur Respir J. 2015;46:243-249 [PubMed]journal. [CrossRef] [PubMed]
 

Figures

Tables

References

Nathan S.D. .Albera C. .Bradford W.Z. .et al Effect of pirfenidone on mortality: pooled analyses and meta-analyses of clinical trials in idiopathic pulmonary fibrosis. Lancet Respir Med. 2017;5:33-41 [PubMed]journal. [CrossRef] [PubMed]
 
King T.E. Jr..Bradford W.Z. .Castro-Bernardini S. .et al A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2083-2092 [PubMed]journal. [CrossRef] [PubMed]
 
Loveman E. .Copley V.R. .Scott D.A. .Colquitt J.L. .Clegg A.J. .O'Reilly K.M. . Comparing new treatments for idiopathic pulmonary fibrosis—a network meta-analysis. BMC Pulm Med. 2015;15:37- [PubMed]journal. [CrossRef] [PubMed]
 
Aravena C. .Labarca G. .Venegas C. .Arenas A. .Rada G. . Pirfenidone for idiopathic pulmonary fibrosis: a systematic review and meta-analysis. PLoS One. 2015;10:e0136160- [PubMed]journal. [CrossRef] [PubMed]
 
Canestaro W.J. .Forrester S.H. .Raghu G. .Ho L. .Devine B.E. . Drug treatment of idiopathic pulmonary fibrosis: systematic review and network meta-analysis. Chest. 2016;149:756-766 [PubMed]journal. [CrossRef] [PubMed]
 
Rochwerg B. .Neupane B. .Zhang Y. .et al Treatment of idiopathic pulmonary fibrosis: a network meta-analysis. BMC Med. 2016;14:18- [PubMed]journal. [CrossRef] [PubMed]
 
Raghu G. .Collard H.R. .Anstrom K.J. .et al Idiopathic pulmonary fibrosis: clinically meaningful primary endpoints in phase 3 clinical trials. Am J Respir Crit Care Med. 2012;185:1044-1048 [PubMed]journal. [CrossRef] [PubMed]
 
Wells A.U. .Behr J. .Costabel U. .et al Hot of the breath: mortality as a primary end-point in IPF treatment trials: the best is the enemy of the good. Thorax. 2012;67:938-940 [PubMed]journal. [CrossRef] [PubMed]
 
du Bois R.M. .Nathan S.D. .Richeldi L. .Schwarz M.I. .Noble P.W. . Idiopathic pulmonary fibrosis: lung function is a clinically meaningful endpoint for phase III trials. Am J Respir Crit Care Med. 2012;186:712-715 [PubMed]journal. [CrossRef] [PubMed]
 
Richeldi L. .du Bois R.M. .Raghu G. .et al Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2071-2082 [PubMed]journal. [CrossRef] [PubMed]
 
Richeldi L. .Cottin V. .du Bois R.M. .et al Nintedanib in patients with idiopathic pulmonary fibrosis: combined evidence from the TOMORROW and INPULSIS(®) trials. Respir Med. 2016;113:74-79 [PubMed]journal. [CrossRef] [PubMed]
 
Karimi-Shah B.A. .Chowdhury B.A. . Forced vital capacity in idiopathic pulmonary fibrosis—FDA review of pirfenidone and nintedanib. N Engl J Med. 2015;372:1189-1191 [PubMed]journal. [CrossRef] [PubMed]
 
Raghu G. .Brown K.K. .Collard H.R. .et al Efficacy of simtuzumab versus placebo in patients with idiopathic pulmonary fibrosis: a randomised, double-blind, controlled, phase 2 trial. Lancet Respir Med. 2017;5:22-32 [PubMed]journal. [CrossRef] [PubMed]
 
Behr J. .Bendstrup E. .Crestani B. .et al Safety and tolerability of acetylcysteine and pirfenidone combination therapy in idiopathic pulmonary fibrosis: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Respir Med. 2016;4:445-453 [PubMed]journal. [CrossRef] [PubMed]
 
Collard H.R. .Bradford W.Z. .Cottin V. .et al A new era in idiopathic pulmonary fibrosis: considerations for future clinical trials. Eur Respir J. 2015;46:243-249 [PubMed]journal. [CrossRef] [PubMed]
 
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