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Treatment Updates in Idiopathic Pulmonary Fibrosis and Considerations in Transplant

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Christine Hui, PharmD, BCPS
UCSF Medical Center
San Francisco, CA, USA

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal lung disease that is characterized by irreversible loss of lung function [1,2,3]. IPF remains the most common interstitial lung disease referred for lung transplantation and the second most common disease for which lung transplantation is performed [4,5]. Two medications, pirfenidone (Esbriet) and nintedanib (Ofev), appear to slow disease progression in IPF and were recently approved for use in the United States by the Food and Drug Administration (FDA) [2,3,6,7]. The approval of these medications signifies a turning point in the management of IPF as pharmacologic options are now available.

Pirfenidone exerts anti-fibrotic and anti-inflammatory by inhibiting the synthesis of transforming growth factor-β and tumor necrosis factor-α [6, 8]. Two of three phase 3 studies of pirfenidone in IPF demonstrated a reduction in disease progression, as measured by the decline in forced vital capacity (FVC). These studies included a trial conducted in Japan and two multinational studies, CAPACITY 004 and 006. Of the three studies, CAPACITY 006 did not show a reduction in the decline in FVC when compared to placebo. This prompted the fourth trial, ASCEND, which was designed to clarify the previous results [2,3].

The ASCEND study compared pirfenidone to placebo. The primary endpoint was the change in the percentage of the predicted FVC (%FVC) at week 52. Two secondary endpoints were the change in 6-minute walk distance and progression-free survival at week 52. Treatment with pirfenidone resulted in a significant difference in the predicted %FVC (P<0.001). The pirfenidone group had a 47.9% relative reduction in the proportion of patients who had a decline of 10 percentage points or more in %FVC predicted or who had died, as compared with the placebo group. There was a significant difference in the 6-minute walk test with pirfenidone (P=0.04) and a reduction in the relative risk of death or disease progression by 43%. These findings led to the FDA granting pirfenidone fast track, priority review, orphan product, and breakthrough designations [2,3].

Nintedanib is an intracellular inhibitor that targets multiple tyrosine kinases implicated in fibrogenesis. Two phase 3 trials (INPULSIS-1 and INPULSIS-2) were conducted to evaluate its safety and efficacy. The INPULSIS studies compared nintedanib to placebo for 52 weeks. The primary end point was the annual rate of decline in FVC. Secondary endpoints included time to first acute exacerbation and the change from baseline in total score on the St. George's Respiratory Questionnaire (SGRQ). Nintedanib significantly reduced the decline in FVC compared with placebo in INPULSIS-1 (difference of 125.3 mL, 95% CI 77.7-172.8 mL, P<0.001) and INPULSIS-2 (difference of 93.7 mL, 95% CI 44.8-142.7 mL, P<0.001). In INPULSIS-2, there was a significant increase in the time to first acute exacerbation with nintedanib as compared with placebo (HR, 0.38; 95% 0.19 to 0.77; P=0.005) and a smaller increase in the total SGRQ score (difference -2.69; 95% CI, -4.95 to -0.43; P=0.02), corresponding with less deterioration in health-related quality of life [3,7]. Based on these results, the FDA also granted nintedanib fast track, priority review, orphan product, and breakthrough designations.

Fibrosis after lung transplantation can lead to chronic lung allograft dysfunction (CLAD), which is the leading cause of allograft failure, morbidity and mortality. Due to their mechanisms of action and anti-fibrotic properties, pirfenidone and nintedanib may be viable options in the treatment of CLAD as it has a final common pathway leading to organ fibrosis [8]. Furthermore there is evidence in animal models that pirfenidone, used in combination with calcineurin inhibitors, results in down-regulation of profibrotic genes [8,9]. Current case reports in lung transplant recipients show conflicting experience with use of pirfenidone in CLAD. One report showed radiographic evidence of improvement, as well as a decrease in the decline of FVC with use of pirfenidone [9]. However, another report showed improvement on physical exam and computed tomography scan, but no symptomatic improvement in the patient [10].

IPF is a progressive and fatal lung disease. Until recently, treatment options were limited to lung transplantation and supportive care. With the recent approval of pirfenidone and nintedanib as treatment options for IPF, the need for lung transplantation may slowly decline. However, more experience with the use of these new agents is needed to further evaluate their long-term impact on patients with IPF. Additionally, more studies are needed to consider whether pirfenidone and nintedanib have a role for lung transplant recipients suffering with CLAD. ■

Disclosure Statement: The author has no conflicts of interest to disclose.

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8. Dosanjh A. Pirfenidone: a novel potential therapeutic agent in the management of chronic allograft rejection. Transplant Proc 2007;39:2153-2156.
9. Ihle F, von Wulffen W, Neurohr C. Pirfenidone: a potential therapy for progressive lung allograft dysfunction? J Heart Lung Transplant 2013; 32:574-575.
10. Vos R, Verleden SE, Ruttens D, et al. Pirfenidone: a potential new therapy for restrictive allograft syndrome? Am J Transplant 2013; 11:3035-3040.

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