Jeffrey J Swigris Assistant Professor of Medicine, Interstitial Lung Disease Program,
National Jewish Medical and Research Center, Denver , Kevin K Brown, MD Vice Chair, Department of Medicine, and Director, Interstitial Lung Disease Program,
National Jewish Medical and Research Center, Denver
Results of Recent Trials
Given our current understanding of IPF—that inflammation, or at least its treatment, likely does not play a central role34—a more targeted approach to therapy is warranted. As currently viewed, there are multiple legitimate sites for intervention, including transforming growth factor-beta (TGF-beta), glutathione, and endothelin, among others (see Table 2).35 The results of a number of recent trials are summarized below. In the US, interferon-beta (IFNbeta) 1a is approved for the treatment of multiple sclerosis. Although negative, a 167-subject trial of IFN-beta for IPF that included 34 sites in the US and Canada was the first to demonstrate that large, multicenter, placebocontrolled trials in IPF were feasible.36 Early basic scientific investigation, followed by the results of a small controlled trial suggesting that IFN-gamma might be a useful therapy for patients with IPF, led to a number of large-scale, placebo-controlled trials.37,38 Unfortunately the sum result of these studies has been negative. In the first 330-subject study, while IFN-gamma had no effect on the primary end-point,37 hypothesis-generating results from a post hoc analysis led to a larger (800-patient) phase III trial with mortality as the primary end-point; this trial was stopped early because of lack of efficacy.39 Pirfenidone is a small pyridine molecule with antifibrotic effects. Although inhibition of some TGF-beta-mediated activity is likely,40 its exact mechanism of action is unknown. A recent multicenter, placebo-controlled trial of pirfenidone in Japan found a trend toward statistical significance in the primary end-point— change in the lowest SpO2 during a 6MWT—favoring pirfenidone. Also, from baseline to nine months, mean values for vital capacity fell by less in the pirfenidone group (30cc decline versus 130cc decline in the placebo group; p=0.036). In a pre-specified subset of all patients who were able to complete the 6MWT without desaturating below 80%, the SpO2 fell by less in the pirfenidone group. These results provided the impetus for further studies of pirfenidone, whose results are eagerly awaited.
An imbalance between oxidation products and antioxidants may play a role in IPF.41 Glutathione, in its reduced form, mitigates oxidant-induced cellular injury; furthermore, glutathione levels are decreased in the epithelial lining fluid of patients with IPF.42 In follow-up to promising pilot studies, European investigators performed a prospective, randomized, placebo-controlled, multicenter trial comparing the effect of the antioxidant N-acetyl cysteine (NAC) with that of placebo in patients taking prednisone and azathioprine.43 NAC was well-tolerated and, after 12 months of therapy, lung function declined in both groups; however, the group taking NAC had a significantly higher FVC (by 0.18 liters) and DLCO (by 0.75mmol/min/kPa). Because the study lacked a true placebo arm, caution must be exercised in interpreting these results. TGF-beta comprises an entire family of peptides with similar biologic function; however, only TGF-beta 1 is consistently upregulated at sites of lung fibrosis.44 As the most potent stimulator of fibroblast collagen production,44 it appears to play a pivotal role in IPF pathogenesis. It is present in the healthy lung, but increases in message and protein are found in several pathological states, including IPF.45 A phase I, multicenter, open-label, singledose study of a humanized, monoclonal anti-TGF-beta 1, 2, and 3 antibody for the treatment of IPF is currently under way.
Many of the pro-fibrotic activities attributed to TGF-beta are mediated through connective tissue growth factor (CTGF).44 Expression of CTGF is increased in patients with IPF,46 and downregulation of CTGF may offer clinical benefit in those with fibrotic disease.38 Results from a phase I study showed that a single infusion of either 1 or 3mg of anti-CTGF per kg bodyweight was safe and welltolerated, and led to plasma levels of anti-CTGF that remained above predicted minimum effective concentrations (based on animal models) for at least five days.47 Further studies of anti-CTGF therapy are awaited. In the family of endothelins (ET), ET-1 drives several pro-fibrotic activities.48–50 Bronchoalveolar lavage (BAL) and plasma levels of ET-1 are increased in IPF.51,52 Based on this, a double-blind, randomized, placebo-controlled, multicenter trial was undertaken to assess the safety and efficacy of the non-selective ET-1 receptor antagonist bosentan in patients with IPF. Although the study failed to meet the primary end-point, results from a post hoc analysis have led to the currently enrolling follow-up study of selected IPF patients. Tumor necrosis factor (TNF)- alpha stimulates fibroblast proliferation and collagen gene upregulation via a TGF-beta and/or platelet-derived growth factor (PDGF) pathway. A phase II, 48-week, double-blind, placebo-controlled trial of the TNF-alpha antagonist etanercept for the treatment of IPF has been completed; the primary end-point was not met, but post hoc analyses revealed trends toward significantly lesser declines in absolute and ppFVC and absolute and ppDLCO in the group receiving etanercept (results presented at the 2005 meeting of the American College of Chest Physicians). These results will likely fuel further investigation of this drug. Imatinib mesylate is an oral tyrosine kinase inhibitor—a designer molecule developed to treat chronic myelogenous leukemia (CML). In CML, imatinib inhibits the aberrant bcr-abl tyrosine kinase, but it is also known to inhibit the receptor tyrosine kinases for PDGF.53 PDGF has significant pro-fibrotic effects; thus, inhibiting its signaling pathway may be antifibrotic. Results from a phase II, randomized, double-blind, placebo-controlled trial of the efficacy and safety of imatinib mesylate for the treatment of IPF are eagerly awaited.
Prostacyclin is a potent vasorelaxant and may have antifibrotic effects. An inhaled prostacyclin analog (iloprost) was recently approved by the US Food and Drug Administration (FDA) to treat idiopathic PAH in patients with profoundly symptomatic disease. In patients with PAH due to lung fibrosis, inhaled prostacyclin is attractive because it limits the systemic vasodilatory/ hypotensive effects often seen with intravenous preparations, and, because of its extreme pulmonary selectivity, it may maintain ventilation/perfusion matching to a greater degree than oral or intravenous pulmonary antihypertensive preparations. A phase II, multicenter, double-blind, placebocontrolled safety and efficacy trial of iloprost for the treatment of IPF-related PAH is currently under way. There is a strong and growing commitment in the US to conducting rigorously developed clinical trials via multi-institutional collaborations. The National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) recently committed over $30 million to support the IPFnet—a network of collaborating institutions charged with conducting large trials of individual and combination therapies in the hope of identifying an effective treatment for IPF.
Coronary Artery Adventitia
Conclusion Despite aggressive efforts, IPF remains a debilitating and deadly disease. Currently, no medical therapies have been proved to prolong survival or improve quality of life. However, recent discoveries have improved our understanding of many facets of this disease. As knowledge accumulates, the list of potential therapeutic targets and agents directed against them grows. Several carefully designed, multicenter trials have been performed, with more trials on the horizon. Hopefully, these efforts will carry us closer to solving the pathobiologic riddle that is IPF.
