Currently Viewing:
Supplements A Managed Care Perspective:Treatment of Idiopathic Pulmonary Fibrosis

Evaluating New Treatment Options

Steven D. Nathan, MD
Data pertaining to nintedanib, compared with other more selective TKIs, demonstrate benefit in terms of patient-important outcomes in IPF, although no overall mortality benefit was seen. Patients should be warned about the AEs associated with nintedanib, specifically diarrhea, to make an informed decision about therapy. Available evidence does not outline optimal duration of therapy, and it remains to be seen how long the treatment effect endures with ongoing drug therapy.6 As noted earlier, a mutual decision between patient/caregiver and treating clinician, with an emphasis on expected benefits, AE profiles, dosing, frequency, drug interactions, and patient preference, is crucial for successful therapy and patient management with either nintedanib or pirfenidone.12

Comparing the Agents, and Should All Patients With IPF Be Treated With Antifibrotics?

Both pirfenidone and nintedanib have been approved by the FDA for treatment of IPF, independent of disease severity. Currently, there is no definitive evidence to preferentially recommend either of these agents over the other.12 One network meta-analysis of RCTs of pirfenidone, nintedanib, and N-acetylcysteine found that of the 3 treatments, only pirfenidone and nintedanib produced a statistically significant slowing in the rate of FVC decline as compared with placebo. An indirect comparison suggested that nintedanib is statistically significantly better than pirfenidone in slowing FVC decline, while mortality rates favored pirfenidone but were not statistically significant. However, of 1076 references in this analysis, 67 were pulled and only 11 studies were included, and limitations to indirect comparisons such as these must be considered.18 In addition, clinical trials combining these agents are ongoing.12,19

A major question remains in IPF therapy: Should antifibrotic agents be administered to all patients with IPF, including those with more than moderate pulmonary impairment? As noted earlier, clinical trials for these novel agents tended to exclude patients with more severe FVC impairment (Table20).20

The effect of nintedanib and pirfenidone is to slow disease progression in IPF, reducing the rate of decline in FVC.6,8,15,20 For those patients with more severe disease, it remains biologically plausible for these drugs to have the same effect on FVC.20 Subgroup analyses of the major trials suggest that both agents had similar salutary effects in patients with both milder or more severe disease.20-22 Because there is no gradient of disease severity in the studies, it could be inferred that similar treatment effects may be seen in those with disease severity that differs from that seen within the limits of the major RCTs. The actual labeling for these agents states simply “...approved for the treatment of IPF,” without mention of disease severity. This could be interpreted as a tacit endorsement to use them beyond the inclusionary and exclusionary criteria of the clinical trial in well-informed patients with well-established IPF as part of individualized, shared decision-making management.20 An algorithm for patient evaluation and potential therapy has recently been proposed. 23

Conclusion

There has been a sea of change in the management landscape of patients with IPF since the approval of the 2 antifibrotic agents. Their availability has raised the bar for an earlier and accurate diagnosis so that the option of therapy can be addressed with patients before significant loss of lung function, which invariably punctuates the course of this deadly disease. While neither drug is a cure, the availability of both represents hope for patients in terms of modulating the disease course. Their successful clinical development also establishes that the disease can be modified, with the further hope for other, more effective therapies in the future.

Author affiliation: Medical Director, Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, Falls Church, Virginia.
Funding source: This activity is supported by educational grants from Genentech and Boehringer Ingelheim Pharmaceuticals, Inc.
Author disclosure: Dr Nathan has the following relevant financial relationships with commercial interests to disclose:
ADVISORY BOARDS
  Roche and Boehringer Ingelheim
SPEAKERS BUREAUS
  Roche and Boehringer Ingelheim
Authorship information: Concept and design, acquisition of data, analysis and interpretation of data, drafting of the manuscript, and critical revisions of the manuscript for important intellectual content.
Address correspondence to: steven.nathan@inova.org.
Acknowledgment: Elizabeth Paczolt, MD, FACNM, provided medical writing and editorial support for this manuscript.
1.        Raghu G, Collard HR, Egan JJ, et al; ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183(6):788-824. doi: 10.1164/rccm.2009-040GL.
2.        Bonella F, Stowasser S, Wollin L. Idiopathic pulmonary fibrosis: current treatment options and critical appraisal of nintedanib. Drug Des Devel Ther. 2015;9:6407-6419. doi: 10.2147/DDDT.S76648.
3.        Tzouvelekis A, Bonella F, Spagnolo P. Update on therapeutic management of idiopathic pulmonary fibrosis. Ther Clin Risk Manag. 2015;11:359-370. doi: 10.2147/TCRM.S69716.
4.        Kim DS, Park JH, Park BK, Lee JS, Nicholson AG, Colby T. Acute exacerbation of idiopathic
pulmonary fibrosis: frequency and clinical features. Eur Respir J. 2006;27(1):143-150. doi: 10.1183/
09031936.06.00114004.
5.        Song JW, Hong SB, Lim CM, Koh Y, Kim DS. Acute exacerbation of idiopathic pulmonary fibrosis: incidence, risk factors and outcome. Eur Respir J. 2011;37(2):356-363. doi: 10.1183/09031936.00159709.
6.        Raghu G, Rochwerg B, Zhang Y, et al; American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, Latin American Thoracic Association. An official ATS/ERS/JRS/ALAT clinical practice guideline: treatment of idiopathic pulmonary fibrosis. an update of the 2011 clinical practice guideline [erratum in Am J Respir Crit Care Med. 2015;192(5):644]. Am J Respir Crit Care Med. 2015;192(2):e3-e19. doi: 10.1164/rccm.201506-1063ST.
7.        Noble PW, Albera C, Bradford WZ, et al; CAPACITY Study Group. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet. 2011;377(9779):1760-1769. doi: 10.1016/S0140-6736(11)60405-4.
8.        King TE Jr, Bradford WZ, Castro-Bernardini S, et al; ASCEND Study Group. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis [erratum in N Engl J Med. 2014;371(12):1172]. N Engl J Med. 2014;370(22):2083-2092. doi: 10.1056/NEJMoa1402582.
9.        Nathan SD, Albera C, Bradford WZ, et al. Effect of continued treatment with pirfenidone following clinically meaningful declines in forced vital capacity: analysis of data from three phase 3 trials in patients with idiopathic pulmonary fibrosis. Thorax. 2016;71(5):429-435. doi: 10.1136/thoraxjnl-2015-207011.
10.      Nathan SD, Albera C, Bradford WZ, et al. Effect of pirfenidone on mortality: pooled analyses and meta-analyses of clinical trials in idiopathic pulmonary fibrosis. Lancet Respir Med. 2017;5(11):33-41. doi: 10.1016/S2213-2600(16)30326-5.
11.      Lancaster L, Albera C, Bradford WZ, et al. Safety of pirfenidone in patients with idiopathic pulmonary fibrosis: integrated analysis of cumulative data from 5 clinical trials. BMJ Open Respir Res. 2016;3(1):e000105. doi: 10.1136/bmjresp-2015-000105.
12.      Anderson A, Shifren A, Nathan SD. A safety evaluation of pirfenidone for the treatment of idiopathic pulmonary fibrosis. Expert Opin Drug Saf. 2016;15(7):975-982. doi: 10.1080/14740338.2016.1187129.
13.      Jiang C, Huang H, Liu J, Wang Y, Lu Z, Xu Z. Adverse events of pirfenidone for the treatment of pulmonary fibrosis: a meta-analysis of randomized controlled trials. PLoS One. 2012;7(10):e47024. doi: 10.1371/journal.pone.0047024.
14.      Richeldi L, Costabel U, Selman M, et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med. 2011;365(12):1079-1087. doi: 10.1056/NEJMoa1103690.
15.      Richeldi L, du Bois RM, Raghu G, et al; INPULSIS Trial Investigators. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis [erratum in N Engl J Med. 2015;373(8):782]. N Engl J Med. 2014;370(22):2071-2082. doi: 10.1056/NEJMoa1402584.
16.      Wuyts WA, Kolb M, Stowasser S, Stansen W, Huggins JT, Raghu G. First data on efficacy and safety of nintedanib in patients with idiopathic pulmonary fibrosis and forced vital capacity of ≤50% of predicted value. Lung. 2016;194(5):739-743. doi: 10.1007/s00408-016-9912-1.
17.      Kolb M, Richeldi L, Behr J, et al. Nintedanib in patients with idiopathic pulmonary fibrosis and preserved lung volume. Thorax. 2017;72(4):340-346. doi: 10.1136/thoraxjnl-2016-208710.
18.      Loveman E, Copley VR, Scott DA, Colquitt JL, Clegg AJ, O’Reilly KM. Comparing new treatments for idiopathic pulmonary fibrosis—a network meta-analysis. BMC Pulm Med. 2015;15:37. doi: 10.1186/s12890-015-0034-y.
19.      Eight studies found for nintedanib plus pirfenidone (search results). ClinicalTrials.gov website.  https://www.clinicaltrials.gov/ct2/results?term=nintedanib+plus+pirfenidone&Search=Search. Accessed May 15, 2017.
20.      King CS, Nathan SD. POINT: should all patients with idiopathic pulmonary fibrosis, even those with more than moderate impairment, be treated with nintedanib or pirfenidone? Yes. Chest. 2016;150(2):273-275. doi: 10.1016/j.chest.2016.04.034.
21.      Kolb M, Richeldi L, Kimura T, Stowasser S, Hallmann C, du Bois RM. Effect of baseline FVC on decline in lung function with nintedanib in patients with IPF: results from the INPULSIS trials. Am J Respir Crit Care Med. 2015;191:A1021.
22.      Albera C, Bradford WZ, Costabel U, et al. Pirfenidone is efficacious in patients with idiopathic pulmonary fibrosis (IPF) and mild restrictive disease. Am J Respir Crit Care Med. 2015;191:A1018.
23.      Meyer KC, Modi D. New treatments for idiopathic pulmonary fibrosis. Clin Pulm Med. 2016;23(6):241-251. doi: 10.1097/CPM.0000000000000166.
 
PDF
 
Copyright AJMC 2006-2017 Clinical Care Targeted Communications Group, LLC. All Rights Reserved.
x
Welcome the the new and improved AJMC.com, the premier managed market network. Tell us about yourself so that we can serve you better.
Sign Up
×

Sign In

Not a member? Sign up now!