Idiopathic Pulmonary Fibrosis: Treatment Strategies

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Abstract: Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive condi- tion of unknown etiology. Both the tomographic patterns and the pathologic.
Send Orders for Reprints to [email protected] Clinical Anti-Inflammatory & Anti-Allergy Drugs, 2014, 1, 87-94

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Idiopathic Pulmonary Fibrosis: Treatment Strategies Brenda E. Varelaa,* and Gabriela C. Tabajb a

Hospital Alemán. Buenos Aires. Argentina; bHospital del Tórax Dr. Antonio A. Cetrángolo. Buenos Aires. Argentina

Abstract: Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive condition of unknown etiology. Both the tomographic patterns and the pathologic anatomy correspond to usual interstitial pneumonia (UIP). Unfortunately, this is an irreversible disease with a variable clinical course that involves different phenotypes. Some patients are stable for a long time, while others present frequent acute exacerbations, or suffer a rapid decline and die. Not long ago, most treatment options for IPF patients focused on inflammation and lung fibrosis, relying on antiinflammatories and immunosuppressants. However, results observed for steroid, azathioprine, and Nacetylcysteine therapies proved ineffective and were associated with increased mortality. During the last 3 years, our understanding of the underlying mechanisms of IPF pathogenesis has evolved remarkably. There is new evidence about the treatment of this disease. New trials have been published and are breaking new ground in the management of IPF patients. There are also numerous ongoing clinical trials studying potential targets related to IPF treatment.

Keywords: Idiopathic pulmonary fibrosis, clinical trials, treatment. 1. INTRODUCTION According to its definition, idiopathic pulmonary fibrosis (IPF) is a form of chronic, fibrosing, progressive interstitial pneumonia of unknown etiology with a higher prevalence in men over 60 years of age and smokers or former smokers [1]. IPF has a poor prognosis and is marked by progressive worsening of dyspnea and lung function [2]. Since IPF is associated with UIP’s histopathologic and/or radiologic patterns, it is mandatory to rule out other known causes of interstitial lung disease (ILD), such as connective tissue disease, drug toxicity or household and occupational exposure. IPF should be suspected in all adult patients with unexplained chronic dyspnea on exertion. Bibasal inspiratory crackles, cough, and finger clubbing are common signs of this disease. Incidence is higher among older people, occurring typically in the sixth and seventh decades [3, 4]. *Address correspondence to this author at the Av Pueyrredón 1640, Box: C1118AAT, Ciudad de Buenos Aires, Argentina; Tel/Fax: +54-011- 4827-7000; E-mail: [email protected] 2212-7046/14 $58.00+.00

The natural course of the disease is progressive and the median survival time from diagnosis is 3.5 years [5]. Currently, IPF research focuses on the molecular genetics of pathologic events likely to occur at the epithelial-mesenchymal interface of the alveolus [6-11]. On the basis of information obtained from IPF patients’ samples and in vitro investigations, researchers believe that IPF may be mediated by the prolonged survival of myofibroblasts activated by an unknown lesion, the shortened survival of lung epithelial cells, or both [12]. Even though some risk factors have been identified for this disease, such as environmental, exposures, genetic determinants, smoking [13], pollutants, gastroesophageal reflux [14, 15], and occupational [16] viral infections [17] and old age [18], IPF’s origin and onset are not fully understood. Some authors suggest the onset involves the perpetuation of alveolar epithelium microinjuries that lead to dysregulation of cellular homoeostasis in the alveolar epithelial– mesenchymal unit, the reactivation of developmental signaling pathways © 2014 Bentham Science Publishers

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(e.g. transforming growth factor: TGF [19], wingless-type like (Wnt) [20] sonic hedgehog (SHH) [21], , and Notch) [22], induced cell dysfunction and death, scar tissue formation, and, therefore, distortion of lung homoeostasis and pulmonary structures [23]. Other authors hypothesize IPF originates from long term recurring stretch injury to the peripheral and basal lung in individuals with a genetic predisposition [12]. Diagnosing IPF is complex. Physicians have to systematically rule out every exposure-related cause, as well as any autoimmune or systemic-disease-related cause. Physicians must do their best to avoid “labeling” patients as IPF patients, but why? Until recently, after an IPF diagnosis, treatment options were very limited: the triple therapy with N-acetylcysteine, azathioprine and steroids was not effective and was associated with higher mortality rate. [24]. Pulmonologists were urged to provide information about disease prognosis, and prescribed proton-pump inhibitors, oxygen therapy and, eventually, referred patients for lung transplantation evaluation or palliative care. However, recently, new evidence about IPF treatment has been found: promising results of INPULSIS [25] and ASCEND [26] trials have been published breaking new ground in the management of these patients. In the last years, we have witnessed a paradigm shift in IPF pathogenesis. Previously, some authors supported the inflammatory theory whereby fibrosis was a consequence of some sort of inflammation, and, therefore, patients received high doses of steroids and immunosuppressive therapy. However, the current paradigm focuses on the malfunctioning of alveolar epithelial cells, which, in response to chronic injury, react abnormally with an excessive proliferation of fibrous tissue and extracellular matrix remodeling (ECM), causing fibrosis [27-29].

preventing disease progression rather than improving lung function in this otherwise devastating and fatal disease [32]. 1.2. Nintedanib The intracellular inhibitor Nintedanib (formerly BIBF 1120) targets multiple tyrosine kinases including VEGF, FGF, and PDGF [33]. It was originally indicated to inhibit angiogenesis in oncologic tehrapies. Later, it showed antifibrotic activity in vitro (in human lung fibroblasts), and in vivo (in mice models of bleomycin-induced pulmonary fibrosis [34, 35]). TOMORROW (To imprOve pulMOnaRy fibROsis With BIBF1120), a phase II, randomized, double-blind, placebo-controlled trial, randomized 432 IPF patients either to placebo or one of four escalating doses of nintedanib during 52 weeks [36]. Change in forced vital capacity (FVC) was the primary endpoint. Treatment with nintedanib (150 mg BID) was associated with a reduction in the annual decline rate of FVC, fewer exacerbations of IPF and the preservation of health-related quality of life. : INPULSIS-1 and INPULSIS-2 studies were developed after TOMORROW results. These phase III doubleblind, randomized studies assessed the efficacy and safety of a treatment administered to IPF patients during 52 weeks using 150 mg of nintedanib twice a day vs placebo. Both studies were performed simultaneously and had the same primary endpoint in common: the annual rate of decline in FVC. Main secondary points were time elapsed until first acute exacerbation and change from baseline according to St. George's Respiratory Questionnaire total score.

1.1. New Evidence

205 sites participated in the INPULSIS trials. Said sites were located across 24 countries in America, Asia, Europe, and Oceania (Australia). INPULSIS-1 and INPULSIS-2 enrolled 515 patients and 551, respectively, adding to a total of 1066 randomized patients. Inclusion criteria included: >40 years of age, diagnosis of idiopathic pulmonary fibrosis in the last 5 years, diffusing capacity of the lungs for carbon monoxide (DLCO) of 30-79% of predicted normal and FVC of 50% of predicted normal.

So far, IPF’s characteristic scarring has resisted all the compounds currently under study in clinical trials. A paradigm shift has allowed assessing treatment success in IPF patients from a different perspective. Thus, treatment goals are aimed at

The 1066 subjects were randomized either to nintedanib or placebo in a 3:2 ratio. In INPULSIS-1, for nintedanib, the adjusted annual rate of change in FVC was 114.7 ml, as compared to 239.9 ml

IPF pathogenesis involves several cellular signaling pathways mediated by tyrosine kinases, such as vascular endothelial growing factor (VEGF), fibroblastic growing factor (FGF) and platelet derived growth factor (PDGF) [30, 31].

Idiopathic Pulmonary Fibrosis: Treatment Strategies

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with placebo (i.e. there was a 125.3 ml difference; P