Therapeutic Management of Idiopathic Pulmonary Fibrosis: An Evidence-Based Approach

Clin Chest Med 27 (2006) S27 – S35

Therapeutic Management of Idiopathic Pulmonary Fibrosis: An Evidence-Based Approach Steven D. Nathan, MD Lung Transplant and Advanced Lung Disease Program, Inova Heart and Vascular Institute, 3300 Gallows Road, Falls Church, VA 22042, USA

Idiopathic pulmonary fibrosis (IPF), also known as cryptogenic fibrosing alveolitis, is a distinct form of interstitial lung disease of unknown etiology that is limited to the lung; it is associated with the histologic pattern of usual interstitial pneumonia (UIP) [1]. IPF often presents clinically with progressive dyspnea, restrictive lung physiology, including impaired gas exchange, and radiographically with patchy reticular abnormalities that are found mainly at the lung bases. Once diagnosed, IPF carries a bleak prognosis, with 5-year survival rates estimated at 30% – 50% [1]. Optimal management of IPF remains controversial, but it is probable that potential therapies are most likely to be effective early in the course of disease, before the development of irreversible fibrosis. In a consensus statement published in 2000, the American Thoracic Society (ATS) and European Respiratory Society (ERS) suggested combined therapy with corticosteroids and azathioprine or cyclophosphamide for patients with IPF who understand the benefits and risks of treatment and who have features associated with a greater likelihood of treatment success [1]. These features include younger age, symptom duration less than 1 year, and well preserved lung function with limited dyspnea. The limited benefits of these regimens may be outweighed by the risks for treatment-related complications, especially in older patients and those who have significant comorbidities, such as heart disease, diabetes, obesity, or osteoporosis [1].

Dr. Nathan has received speaking honoraria from InterMune. E-mail address: [email protected]

In the regimen suggested in the ATS/ERS consensus statement, prednisone (or equivalent) should be administered orally at a dose of 0.5 mg/kg lean body weight (LBW) daily for 4 weeks, 0.25 mg/kg daily for 8 weeks, and then tapered to 0.125 mg/kg daily or 0.25 mg/kg every other day [1]. The corticosteroid should be administered with azathioprine 2 – 3 mg/kg LBW or cyclophosphamide 2 mg/kg LBW to a maximum dose of 150 mg/d. Either drug may be started at a dose of 25 – 50 mg/d orally and then increased gradually in 25-mg increments every 7 – 14 days until the maximum dose of 150 mg/d is reached. Because objective responses to therapy may require treatment for 3 months or longer, treatment should be continued in the absence of complications or adverse events for at least 6 months. At that time, treatment should be continued if the patient has improved or remains stable, but it should be stopped or changed if the patient’s condition worsens. Indefinite treatment should be considered only in patients who have objective evidence of disease improvement or stabilization. The ATS/ERS guideline statement acknowledges that there is little high-quality evidence to support the safety and efficacy of these and other regimens in the treatment of IPF [1].

Cochrane reviews In two recent reviews, the Cochrane Library, Medline, and EMBASE were used to identify randomized controlled trials (RCTs) and controlled clinical trials (CCTs) of corticosteroids and immuno-

0272-5231/06/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.ccm.2005.08.004

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modulatory agents in the treatment of IPF [2,3]. Richeldi and colleagues identified 15 studies of corticosteroid monotherapy in adults who had IPF, but excluded these studies from a planned meta-analysis because of inadequate methodologies [2]. In most cases, the studies were not RCTs or CCTs that compared corticosteroids to placebo. In several cases, the studies involved comparisons between corticosteroids given alone versus in combination with another drug. The investigators concluded that there is no clinical trial evidence to support the efficacy of corticosteroid monotherapy in patients who have IPF and acknowledged that appropriate clinical trials are not likely to be performed in the future, given advances in the understanding of the pathogenesis of IPF. They suggested that immunomodulators rather than antiinflammatory/immunosuppressive agents might be more promising in treating patients who have IPF. Davies and colleagues conducted a review of RCTs and CCTs in which noncorticosteroid immunosuppressive, antifibrotic, or immunomodulatory agents were compared with placebo or corticosteroids alone in patients with histologic evidence of IPF/UIP or a diagnosis consistent with the ATS/ERS guidelines [3]. Although 59 studies were identified, the overall quality of these studies was poor; consequently, only 3 studies were considered suitable for inclusion in a meta-analysis. Because each of the high quality studies had tested a different agent (azathioprine, colchicine, and interferon gamma-1b [IFN g-1b]), meaningful comparisons were not possible. The investigators concluded there is little high quality information about the efficacy of immunosuppressive, antifibrotic, or immunomodulatory agents in IPF, and thus there is little evidence to support the routine use of these agents in the management of patients who have IPF.

Available clinical trials of new agents The limitations of older clinical trials highlight the need for larger, prospective, randomized trials of new agents for IPF. In the past, IPF was considered to be the result of a chronic inflammatory response to an unknown exogenous insult, which led to the development of progressive pulmonary fibrosis [4]. Accordingly, anti-inflammatory strategies were seen as appropriate for arresting or preventing fibrosis. Concepts regarding the pathogenesis of IPF, however, have evolved to focus on alveolar epithelial cells and myofibroblasts. The alveolar epithelium is damaged early in IPF, leading to alteration of the epithelial cell

phenotype [5]. These cells undergo morphologic changes that are accompanied by increased expression of various profibrotic cytokines and growth factors that are implicated in the pathogenesis of IPF. Fibroblastic foci, a key feature of the histologic UIP pattern, contain proliferating fibroblasts with activated phenotypes [5]. Some possess a myofibroblast phenotype with ultrastructural features intermediate between fibroblasts and smooth muscle cells. These myofibroblasts secrete a myriad of products that may contribute to fibrotic lung injury, including contractile proteins, extracellular matrix molecules, profibrotic growth factors, cytokines, and oxidants. Evolving concepts in the pathogenesis of IPF thus suggest that targeting these specific aberrant pathways may offer a more promising approach to the treatment of IPF.

Interferon c-1b IFN g-1b produces multiple antifibrotic effects, including inhibition of fibroblast proliferation, reduction of collagen synthesis, and decreases in myofibroblast numbers [6 – 9], together with immunomodulatory and anti-infective properties [10,11]. IFN g-1b has been shown to reduce fibrosis in animal models, which may be mediated by its ability to reduce expression of or signaling by profibrotic cytokines, such as transforming growth factor-beta (TGF-b) [8,11,12]. These effects may be relevant to the treatment of IPF, because these patients have an excess of profibrotic cytokines combined with a relative deficiency in IFN g-1b [13]. IFN g-1b also has been shown to be an inducer of the angiostatic chemokine CXCL11, and therefore through this and perhaps other mechanisms might have an effect on vascular remodeling, which might play an important role in the genesis of IPF [14]. Clinical interest in IFN g-1b for the treatment of IPF was sparked by a small pilot study conducted in 18 patients who were resistant to treatment with corticosteroids, other immunosuppressive agents, or both [15]. Patients were randomly assigned to receive IFN g-1b (200 mg subcutaneously three times per week) plus daily prednisolone, or prednisolone alone for 12 months. Treatment with IFN g-1b plus prednisolone produced meaningful improvements in several physiologic indices. Total lung capacity (TLC) and the partial pressure of arterial oxygen (PaO2) at rest increased in the group treated with IFN g-1b plus prednisolone, whereas these parameters declined in patients receiving the corticosteroid alone (all P < .001). These results provided the impetus for evaluating IFN g-1b in a large clinical trial (GIPF-001).

management of ipf: an evidence-based approach

GIPF-001 was a double-blind, placebo-controlled trial conducted at 58 centers in the United States, Europe, Canada, and South Africa [16]. A total of 330 patients were assigned randomly to treatment with IFN g-1b (200 mg subcutaneously three times per week) or placebo for 48 weeks. Patients diagnosed with IPF according to the ATS/ERS criteria were eligible if they had clinical symptoms for at least 3 months, a forced vital capacity (FVC) of 50% – 90% of predicted, a carbon monoxide diffusing capacity (DLCO) 25% of predicted, and a PaO2 >55 mm Hg at rest. In addition, patients had to show evidence of worsening disease in the preceding year, as manifest by either a decrease in predicted FVC 10%, worsening features on chest radiograph, or worsening dyspnea. Patients also had to have failed a course of steroid therapy. They were still eligible for enrollment if they continued on prednisone, but only at a dose of 15 mg/d. The primary endpoint was constituted by three criteria; disease progression as defined by (1) a decline in FVC >10%, (2) an increase in the alveolar– arterial oxygen tension difference [P(A-a)O2] >5 mm Hg), and (3) death. The results of the study showed that IFN g-1b did not significantly affect progression-free survival relative to placebo; disease progression or death occurred in 46% of patients in the IFN g-1b group and 52% of patients in the placebo group [17]. Notably, most endpoint events in both groups were attributed to disease progression associated with an

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increase in P(A-a)O2. Although the administration of IFN g-1b did not result in significant physiologic improvement in FVC, P(A-a)O2, or DLCO, the investigators observed a trend toward enhanced overall survival (P = .08) among patients receiving IFN g-1b (Fig. 1). Overall, 10% of patients in the IFN g-1b group died during the study, compared with 17% of those in the placebo group. Moreover, in the treatment-adherent cohort (defined as those patients who received 80% of scheduled doses of the assigned treatment), IFN g-1b was associated with a significant (66%) reduction in risk for death relative to placebo (5% versus 14%, P = .02). Improved survival with IFN g-1b thus may occur in the absence of any improvement in lung function. Exploratory analysis of the GIPF-001 endpoints found that 43% of deaths occurred before disease progression [17]. During treatment, a decrease in predicted FVC 10% was associated with a 2.4-fold increase in risk for death relative to improvement or a stable FVC. In contrast, an increase in P(A-a)O2 5 mm Hg, the most commonly reached endpoint event in the study, was not associated with a higher mortality risk. These findings indicate that a decrease in predicted FVC 10% is a valid measure of disease progression, but mortality is still the most inclusive endpoint for IPF clinical trials. The molecular effects of IFN g-1b in patients who have IPF were evaluated in a subsequent randomized, double-blind, placebo-controlled study (GIPF-002)

Fig. 1. Kaplan-Meier estimate of overall survival among patients treated with IFN g-1b or placebo in GIPF-001. (From Raghu G, Brown KK, Bradford WZ, et al. A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. N Engl J Med 2004;350(2):130; with permission.)

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[18]. Thirty-two patients with IPF with FVCs of 50% – 90% of predicted and worsening disease were assigned randomly to IFN g-1b or placebo for 26 weeks. Treatment with IFN g-1b did not significantly affect the primary endpoint markers of mRNA for TGF-b and connective tissue growth factor (CTGF) in transbronchial biopsy specimens. IFN g-1b showed a trend for increasing the mRNA for IFN-inducible T-cell-a chemoattractant (ITAC)/CXCL11 (a chemokine with immunomodulatory, antiangiogenic, and antimicrobial properties; P = .063), and for reducing mRNA for elastin (P = .054). IFN g-1b also significantly increased ITAC/CXCL11 in bronchoalveolar lavage (BAL) fluid (P = .016) and plasma (P < .001), and reduced several profibrotic biomarkers in BAL fluid, including platelet-derived growth factor (PDGF) A (P = .033) and epithelial neutrophil-activating protein-78 (ENA-78)/CXCL5 (P = .054). Therefore, the results from this study suggest that IFN g-1b may affect IPF by way of multiple molecular mechanisms involving increased expression of angiostatic/immunomodulatory molecules and decreased expression of profibrotic/angiogenic molecules. A recent meta-analysis of IFN g-1b therapy for IPF suggests that this form of therapy significantly reduces mortality. This meta-analysis included three studies of IFN g-1b therapy in IPF involving 390 patients with comparisons of mortality at 6-month time intervals calculated for up to 2 years [19]. The investigators concluded that the data supporting the use of IFN g-1b for IPF are more compelling than those for any other therapy. Meta-analyses, however, should be regarded as ‘‘hypothesis-generating,’’ and broad acceptance of IFN g-1b as a therapy for IPF should depend on the results of further randomized controlled studies. Such a study is currently well underway in the form of a large, phase III, multicenter study designed to further evaluate the potential survival benefit seen with IFN g-1b. Known as the International Study of Survival Outcomes in Idiopathic Pulmonary Fibrosis With IFN g-1b (INSPIRE), this ongoing study randomly assigns patients who have IPF (up to 800) in a 2:1 ratio to treatment with IFN g-1b or placebo for a minimum of 2 years [20,21]. Patients with a diagnosis of IPF within the preceding 3 years are eligible if they have an FVC of 55% – 90% of predicted, a DLCO of 35% – 90% of predicted, and evidence of disease progression within the past year. Overall survival will be evaluated as the primary endpoint. Additional efficacy variables include changes from baseline in the 6-minute walk test, dyspnea, FVC, DLCO, total days of hospitalization, and survival-adjusted quality of life. Because of the large

study population or n and the duration of follow-up required, study results will not be available for several years. N-acetylcysteine Excessive oxidant stress may contribute to the parenchymal injury and interstitial fibrosis seen in patients who have IPF [22,23]. Moreover, levels of glutathione, the major antioxidant in the lung, are reduced at the alveolar epithelial surface in patients who have IPF [24]. N-acetylcysteine (NAC) is a precursor of glutathione and also scavenges reactive oxygen species, including hydrogen peroxide, hydroxyl radical, and hypochlorous acid [25]. In a proof-of-concept study, 18 patients, 10 of whom met diagnostic criteria for IPF, were treated with highdose NAC (600 mg three times per day) for 12 weeks in addition to existing immunosuppressive therapy [26]. N-acetylcysteine significantly increased total glutathione in BAL fluid (P < .05) and epithelial lining fluid (P < .005) [26]. Nine patients (50%) reported subjective improvement in dyspnea. Pulmonary function, expressed as the sum of changes in vital capacity, DLCO, and post-exercise PaO2, improved significantly (P < .01), but the actual changes in individual parameters were minimal. These findings suggest that NAC may be beneficial in patients who have IPF. On the basis of these results, NAC was evaluated subsequently in the Idiopathic Pulmonary Fibrosis International Group Exploring NAC I Annual (IFIGENIA) trial, a randomized, double-blind, controlled study conducted in seven European countries [27]. In IFIGENIA, 184 patients who have IPF diagnosed according to the ATS/ERS criteria were randomly assigned to receive NAC 600 mg three times daily or placebo for 1 year in addition to conventional immunosuppressive therapy with prednisone and azathioprine. Eligible patients were 18 – 75 years of age with disease of at least 3 months duration, dyspnea score 2 (out of a maximal 20), FVC <80% of predicted (or TLC <90% of predicted), and DLCO <80% of predicted. The changes in VC and DLCO at 6 and 12 months were evaluated as primary efficacy endpoints. NAC administered in conjunction with immunosuppressive therapy was associated with a significantly lower rate of decline in FVC and DLCO at 6 and 12 months as compared with placebo plus immunosuppressive therapy [27]. At 12 months, the absolute differences between treatment groups for FVC and DLCO were 9% of predicted (P = .02) and 24% of predicted (P = .002), respectively. Despite the effects on pulmonary function, NAC did not improve sur-

management of ipf: an evidence-based approach

vival significantly. Seven of 80 patients (8.8%) in the NAC group and 8 of 75 patients (10.7%) in the placebo group died during the study. Moreover, NAC did not affect various secondary efficacy endpoints, including dyspnea score and health status, and it remains unclear whether the physiologic benefits observed in the study represent a true therapeutic effect or an attenuation of a potentially negative effect of prednisone/azathioprine on pulmonary function. Further studies with appropriate controls are necessary to confirm these findings and to clarify the role of NAC in the treatment of patients who have IPF.

Other clinical trials in idiopathic pulmonary fibrosis Several other promising agents are currently undergoing clinical evaluation in IPF (Table 1). The results of several randomized clinical trials should become available over the next several years.

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cause progressive pulmonary fibrosis in transgenic mice [30], and ET-1 is found at elevated levels in BAL fluid from patients who have IPF [28]. These observations suggest that blocking ET-1 may be a viable treatment approach for IPF. Bosentan is an endothelin ETA and ETB receptor antagonist that is approved for the treatment of pulmonary arterial hypertension. In rats with bleomycin-induced lung fibrosis, bosentan reduced fibrosis on morphometric analysis in one study [31], but failed to affect collagen deposition in another study [32]. Bosentan currently is being evaluated in a randomized, double-blind, placebocontrolled, multicenter study of patients who have IPF diagnosed within the past 3 years according to the ATS/ERS criteria [33]. Eligible patients require a 6-minute walk distance of >150 meters and <500 meters, an FVC 50% of predicted, a DLCO 30% of predicted, and a PaO2 55 mm Hg. The efficacy of bosentan will be evaluated based on the change from baseline in 6-minute walk distance.

Pirfenidone Bosentan Endothelin-1 (ET-1) is a vasoactive peptide that is secreted by airway epithelial, smooth muscle cells and by vascular endothelial cells [28]. ET-1 stimulates fibroblast proliferation and collagen synthesis, promotes phenotypic conversion of fibroblasts into myofibroblasts, and induces expression of TGF-b [28,29]. Overexpression of ET-1 has been shown to

Table 1 New agents for treatment of idiopathic pulmonary fibrosis Drug IFN g-1b

Mechanism

Antifibrotic and immunomodulatory cytokine N-acetylcysteine Antioxidant Pirfenidone Antifibrotic agent Bosentan Endothelin ETA/ETB receptor antagonist Etanercept TNF-a blocker Imatinib mesylate c-Abl and PDGF receptor tyrosine kinase inhibitor Inhaled iloprost Therapy for IPF-related PAH FG-3019 Anti-CTGF monoclonal antibody

Status Phase III ongoing

Completed Phase III planned Phase II ongoing Phase II ongoing Phase II ongoing

Phase II study Phase II planned

Pirfenidone inhibits TGF-b – induced collagen synthesis in lung fibroblasts and blocks the mitogenic effects of other profibrotic growth factors and cytokines [6]. In the bleomycin-induced lung fibrosis model, pirfenidone inhibited collagen production, reduced expression of TGF-b and PDGF, and lowered the number of inflammatory cells in BAL fluid [34,35]. In an open-label study, pirfenidone was administered to 54 patients who had IPF, most of whom had failed conventional immunosuppressive therapy [36]. The dose of pirfenidone was increased slowly to a maximum daily dose of 1800 mg. Immunosuppressive therapy was stopped and corticosteroids tapered over an 8-week period. Overall, most patients (83%) were able to discontinue prednisone within 2 months of entry. After 6 months, FVC and DLCO stabilized or improved in 29 and 25 patients, respectively. Repeat pulmonary function testing was not available for many patients, however, and six patients died by the 6-month assessment. Similar results were reported in a smaller open-label study [37]. In a recently reported double-blind trial conducted in Japan, 107 patients with IPF were assigned randomly to pirfenidone or placebo [38]. After 6 months of treatment, pirfenidone showed a trend for improving the primary efficacy endpoint, which was the lowest oxygen saturation (SpO2) measured by pulse oximetry during a 6-minute exercise test (P = .07). In addition, pirfenidone reduced the number of episodes of acute exacerbation of IPF (P = .003)

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and improved the FVC (P = .037) relative to placebo. A phase III study of pirfenidone is planned. Etanercept Tumor necrosis factor-alpha (TNF-a) is a pleiotropic cytokine that may stimulate fibroblast proliferation and collagen synthesis by way of TGF-b or PDGF pathways [6]. Overexpression of TNF-a led to spontaneous development of lung fibrosis in transgenic mice [39], but paradoxically protected against fibrosis induced by bleomycin or TGF-b [40]. The risk for developing IPF seems doubled in persons with a G to A polymorphism at position 308 of the promoter region of the TNF-a gene [41]. These findings suggest that blocking TNF-a may be useful in IPF. Etanercept is a recombinant fusion protein that blocks TNF-a and is approved for the treatment of rheumatoid arthritis, psoriatic arthritis, psoriasis, and ankylosing spondylitis. In an open-label pilot study, etanercept was administered at a dose of 25 mg twice weekly to nine patients with IPF and worsening disease despite conventional therapy [42]. After treatment for an average of 19 months, etanercept in combination with prednisone 10 mg/d improved or stabilized pulmonary function and gas exchange in most patients. Overall, FVC declined by an average of 1%, but DLCO and P(A-a)O2 improved by an average of 9% and 17%, respectively. Two patients died during the trial. These findings suggest that etanercept may reduce or prevent further loss of lung function in patients who have IPF. Etanercept currently is being evaluated in a randomized, doubleblind, placebo-controlled phase II study of patients who have IPF with disease progression despite conventional treatment [43,44]. For this study, eligibility is defined by worsening dyspnea in conjunction with worsening oxygenation, worsening chest radiograph, or lack of improvement in FVC or DLCO. Entry criteria include an FVC 45% of predicted, a DLCO 25%, and a PaO2 55 mm Hg. The study is designed to evaluate the safety and efficacy of etanercept in IPF, with quality of life and pharmacokinetics measured as secondary endpoints. This study has now been completed with preliminary results expected in the near future. Imatinib mesylate Another approach to IPF involves blocking intracellular signaling pathways activated by profibrotic growth factors. Imatinib mesylate is an inhibitor of the c-Abl tyrosine kinase that is constitutively activated in patients who have Philadelphia chromosome-

positive chronic myelogenous leukemia. In such patients, imatinib induces marked regression of bone marrow fibrosis [45]. Imatinib also inhibits the tyrosine kinase associated with the PDGF receptor. Upregulation of PDGF seems to play an important role in causing radiation-induced and bleomycininduced lung fibrosis in experimental models [46,47]. In these models, imatinib inhibits the development of lung fibrosis. In addition, TGF-b stimulates fibroblasts by activating c-Abl, and imatinib inhibits this effect independently of any inhibition of signaling through the PDGF receptor [48]. The efficacy of imatinib in the treatment of IPF currently is being explored in a randomized, double-blind, placebocontrolled phase II trial [44,49]. Approximately one hundred and twenty patients who have worsening IPF on conventional therapy as manifest by a >10% decrease in predicted FVC, worsening chest radiograph, or increasing dyspnea at rest or exertion will be treated with imatinib 600 mg daily or placebo for up to 2 years. The primary endpoint will be IPF progression defined by a >10% decline in FVC or death.

Pulmonary hypertension therapies The development of pulmonary hypertension (PH) is a recognized consequence of advanced IPF with an estimated prevalence in the range of 37% – 85% [50 – 52]. The presence of PH also has been shown to impact on survival [52]. With five FDA-approved agents for the treatment of PH, it is not surprising that some of these agents are being evaluated as potential therapies for PH secondary to other conditions. Mention has been made already of bosentan, which is being studied primarily for its potential antifibrotic properties, but the added possible benefit of this agent is that it might abrogate the development of secondary PH in patients who have IPF. There has been a small series attesting to the potential usefulness of inhaled iloprost as a potential therapy for patients who have IPF [53]. This agent is now being studied through the ACTIVE (Aerosolized iloprost: a Clinical Trial in IPF to Improve Ventilation and Exercise) study as a potential therapy for IPF. This is a randomized, double-blind, placebo-controlled phase II study of patients who have mild to moderate IPF and abnormal pulmonary arterial pressures. Six-minute walk test parameters constitute the primary endpoints of this study. There has also been a small series looking at the usefulness of sildenafil as a potential therapy for IPF. It seems that this agent has a favorable impact on ventilation/perfusion matching with an improvement in oxygenation noted [54]. Sildenafil is

management of ipf: an evidence-based approach

now also being evaluated in a small pilot study of patients who have IPF and associated PH.

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likely require some form of multimodality therapy targeted at different pathways and sequela of this devastating condition.

FG-3019 Connective tissue growth factor (CTGF) stimulates fibroblast proliferation and migration and increases production of collagen and fibronectin. Expression of CTGF is increased in proliferating type II alveolar epithelial cells and activated fibroblasts from patients who have IPF [55]. FG-3019 is a human anti-CTGF monoclonal antibody. In animal models, FG-3019 reduced excess deposition of collagen and fibronectin, and inhibited scarring associated with CTGF [56]. The feasibility of administering FG-3019 was evaluated in a phase I study of patients with IPF diagnosed according to the ATS/ERS criteria [56]. FG-3019 was administered at doses of 1 and 3 mg/kg by intravenous infusion over 2 hours to six and nine patients, respectively. At the higher dose, mean plasma levels of FG-3019 remained above the minimum effective concentration predicted from animal studies for 13 days. Dose-limiting toxicities were not reported. Further clinical studies are needed to explore the efficacy of this agent.

Summary Conventional treatment of IPF with corticosteroids and immunosuppressive agents has unproven benefit and significant side effects. As the understanding about the pathogenesis of IPF has increased, it has led to identification of new therapeutic approaches. Profibrotic growth factors and cytokines seem to be important intermediaries in driving disease progression, and consequently, modulating their activity seems to be an attractive approach. Several agents with antifibrotic, immunomodulatory, or antioxidant properties are now being evaluated in randomized, controlled trials of patients who have IPF. IFN g-1b has shown evidence that it may prolong survival in patients who have IPF, particularly among those with more preserved lung function [16]. N-acetylcysteine stabilized the decline in lung function as compared with placebo, although it did not prolong survival [27]. Other agents including bosentan, pirfenidone, etanercept, imatinib, inhaled iloprost, and FG-3019 currently are being evaluated in randomized, controlled studies. These studies will provide the clinical evidence necessary for identifying optimal treatment strategies. Ultimately this will

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