CLINICAL REVIEW / PEER REVIEWED

Pharmacologic Treatments for Idiopathic Pulmonary Fibrosis

Clinician Reviews. 2018 April;28(4):16-21

References

1. Kim DS, Collard HR, King TE Jr. Classification and natural history of the idiopathic interstitial pneumonias. Proc Am Thorac Soc. 2006;3(4):285-292.
2. Frankel SK, Schwarz MI. Update in idiopathic pulmonary fibrosis. Curr Opin Pulm Med. 2009;15(5):463-469.
3. Olson AL, Swigris JJ, Lezotte DC, et al. Mortality from pulmonary fibrosis increased in the United States from 1992 to 2003. Am J Respir Crit Care Med. 2007;176(3):277-284.
4. Chapman JT. Interstitial lung disease. Cleveland Clinic. August 2010. www.clevelandclinicmeded.com/medical pubs/diseasemanagement/pulmonary/interstitial-lung-disease. Accessed March 12, 2018.
5. Cleveland Clinic. Nonspecific interstitial pneumonia. January 16, 2015. https://my.clevelandclinic.org/health/articles/nonspecific-interstitial-pneumonia. Accessed March 12, 2018.
6. Skandhan AKP, Weerakkody Y. Non-specific interstitial pneumonia. Radiopaedia. https://radiopaedia.org/articles/non-specific-interstitial-pneumonia-1. Accessed March 12, 2018.
7. Tatco V, Weerakkody Y. Lymphocytic interstitial pneumonitis. Radiopaedia. https://radiopaedia.org/articles/lymphocytic-interstitial-pneumonitis-1. Accessed March 12, 2018.
8. King TE Jr, Flaherty KR, Hollingsworth H. Cryptogenic organizing pneumonia. UpToDate. www.uptodate.com/contents/cryptogenic-organizing-pneumonia#H12. Accessed March 12, 2018.
9. Patel NM, Lederer DJ, Borczuk AC, Kawut SM. Pulmonary hypertension in idiopathic pulmonary fibrosis. Chest. 2007; 132(3):998-1006.
10. Lee J. Overview of idiopathic interstitial pneumonias. April 2016. www.merckmanuals.com/professional/pulmonary-disorders/interstitial-lung-diseases/overview-of-idiopathic-interstitial-pneumonias. Accessed March 12, 2018.
11. Lynch DA, Sverzellati N, Travis WD, et al. Diagnostic criteria for idiopathic pulmonary fibrosis: a Fleischner Society White Paper. Lancet Respir Med. 2018;6(2):138-153.
12. Martinez FJ, Flaherty K. Pulmonary function testing in idiopathic interstitial pneumonias. Proc Am Thorac Soc. 2006; 3(4):315-321.
13. 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. Am J Respir Crit Care Med. 2015; 192(2):e3-e19.
14. Chowdhury BA; FDA. Two FDA drug approvals for idiopathic pulmonary fibrosis (IPF). October 15, 2014. https://blogs.fda.gov/fdavoice/index.php/2014/10/two-fda-drug-approvals-for-idiopathic-pulmonary-fibrosis-ipf/. Accessed March 12, 2018.
15. Nakayama S, Mukae H, Sakamoto N, et al. Pirfenidone inhibits the expression of HSP47 in TGF-beta1-stimulated human lung fibroblasts. Life Sci. 2008; 82(3-4):210-217.
16. Noble PW, Albera C, Bradford WZ, et al; CAPACITY Study Group. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomized trials. Lancet. 2011;377: 1760-1769.
17. 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. N Engl J Med. 2014;370(22): 2083-2092.
18. Esbriet [package insert]. South San Francisco, CA: Genentech, Inc; 2016.
19. Hostettler KE, Zhong J, Papakonstantinou E, et al. Anti-fibrotic effects of nintedanib in lung fibroblasts derived from patients with idiopathic pulmonary fibrosis. Respir Res. 2014;15(1):157.
20. Richeldi L, du Bois RM, Raghu G, et al; INPULSIS Trial Investigators. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2071-2082.
21. OFEV [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2018.

NEW PHARMACOLOGIC OPTIONS

Pirfenidone

In 2008, a study was conducted in Japan to determine the mechanism of action of pirfenidone.¹⁵ Through in vitro studies of healthy adult lung fibroblasts with added pro-fibrotic factor and transforming growth factor (TGF-ß 1), the researchers found that pirfenidone was effective at decreasing the production of a collagen-binding protein called HSP47. This protein is ubiquitous in fibrotic tissue. The study also showed that pirfenidone decreased the production of collagen type 1, which, when uninhibited, increases fibrosis.¹⁵

CAPACITY trials. In the CAPACITY trials, two phase 3 multinational studies conducted from 2006 to 2008, patients were given either pirfenidone or placebo.¹⁶ In the first study arm, patients were assigned to pirfenidone 2,403 mg/d (n = 174), pirfenidone 1,197 mg/d (n = 87), or placebo (n = 174). In the second study arm, 171 patients received pirfenidone 2,403 mg/d and 173 patients received placebo. Endpoints were measured at baseline and up to week 72.

The first study arm found that the mean rate of decline of FVC—the primary endpoint—was 4.4% less in the treatment group than in the placebo group (p = 0.001), and there was a 36% decrease in risk for death or disease progression in the treatment group (HR, 0.64; p, 0.023). (Endpoints were defined as: time to confirmed > 10% decline in percentage predicted FVC, > 15% decline in percentage predicted DL_CO, or death.) The researchers found no clinically significant change in the six-minute walk test—a secondary endpoint of the study.¹⁶

The second study arm, however, found no statistically significant change in FVC between the treatment and placebo groups (with a 0.6% smaller decrease in FVC in the pirfenidone group), nor did they see a difference in progression-free survival. However, there was a significant change in the six-minute walk test between the treatment and placebo groups (p = 0.0009). Throughout the study, the most common adverse effects included nausea (36%), rash (32%), and dyspepsia (19%).¹⁶

ASCEND trial. The 2014 Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis (ASCEND) trial was a phase 3, multinational, randomized, double-blind, placebo-controlled study of the use of pirfenidone 2,403 mg/d.¹⁷ The study was conducted from 2012 to 2013. Of the total number of patients (N = 522), half received pirfenidone and half received placebo. After 52 weeks of treatment (the end of the study), the researchers found a smaller decline in FVC—the primary endpoint—in the treatment group compared to placebo (mean decline, 235 mL vs 428 mL, respectively [p < 0.001]). Regarding the six-minute walk test, the investigators found that 25.9% of the treatment group exhibited a decrease of ≥ 50 meters, compared to 35.7% of the placebo group (p = 0.04). (Progression-free survival was defined as a confirmed ≥ 10% decrease in predicted FVC, a confirmed decrease of 50 meters in the six-minute walk test, or death.)

The pirfenidone group in the ASCEND trial showed a 43% reduced risk for death or disease progression (HR, 0.57; p, < 0.001).^16,17 All-cause mortality was lower in the pirfenidone group (4%) than in the placebo group (7.2%), but this was not statistically significant. Deaths from IPF in the pirfenidone group totaled three patients (1.1%) versus seven patients (2.5%) in the placebo group; this was also not statistically significant. The most common adverse effects seen during the study were nausea (36%), rash (28.1%), and headache (25.9%).¹⁷

Recommendations for use. Liver function testing should be performed at baseline, monthly for six months, and every three months afterward, as elevations in liver enzymes have been observed.¹⁸ Pirfenidone is a CYP1A2 substrate; moderate-to-strong CYP1A2 inhibitors should therefore be discontinued prior to initiation, as they are likely to decrease exposure and efficacy of pirfenidone. There are currently no black box warnings.¹⁸

Continue to: Nintedanib

Pharmacologic Treatments for Idiopathic Pulmonary Fibrosis

References

NEW PHARMACOLOGIC OPTIONS

Pirfenidone

Pages

Recommended Reading