Section 3 -

Curing Idiopathic Pulmonary Fibrosis: Beyond Interferon Gamma Kevin O. Leslie Mayo Clinic Arizona

Introduction Idiopathic pulmonary fibrosis (IPF) is a specific form of progressive fibrosing interstitial pneumonia of unknown etiology, occurring most frequently in older men, and confined to the lungs. [1] The prognosis historically for this disorder is dismal, with median survival estimates at less than 3.5 years from diagnosis. No therapy has proven effective in the treatment of IPF but many have been tried over the years. [2] In this presentation, we will explore data from prior experiments in therapy for IPF and review ongoing/proposed clinical trials aimed at improving survival and quality of life in this universally fatal condition. Idiopathic Pulmonary Fibrosis and Usual Interstitial Pneumonia The pathology of IPF is usual interstitial pneumonia (UIP). [3] This progressive fibrosing interstitial pneumonia was originally described by Liebow as the most common or "usual" form of idiopathic interstitial pneumonia occurring in adults. [4] UIP has a distinctive appearance in surgical lung biopsies and resected lung material, with "temporally heterogeneous" structural remodeling including fibrosis, fibroblast foci at the interface between fibrosis and uninvolved lung, and microscopic honeycombing in the classical example. [3] This morphologic pattern of usual interstitial pneumonia can occur as a manifestation of other lung diseases such as rheumatoid arthritis and chronic hypersensitivity pneumonitis, but when UIP is clinically idiopathic, IPF is nearly always the correct diagnosis. Diagnosis of IPF Patients with IPF are typically over 50 at the time of their clinical presentation, although the age distribution at presentation is quite wide. [1] Slowly progressive breathlessness, especially with exertion, is the most common clinical complaint. Nonproductive cough is typically present and can be a difficult component of the disease to manage. Laboratory studies may show mild nonspecific elevation of antinuclear antibodies (ANA), but serologic studies for defined rheumatic disease are by definition absent. Pulmonary function testing reveals restrictive physiology with decreased total lung capacity, forced vital capacity, and diffusing capacity for carbon monoxide (DLco). Oxygen desaturation with exercise is commonly present and the degree of desaturation during the six minute walk test has been shown to have prognostic value for the individual patient. [5] The high resolution CT scan is a major cornerstone in the diagnostic work up and typically shows bibasilar reticular abnormalities, frequently accompanied by subpleural honeycombing. [6] Subpleural disease is variable in distribution along the pleura and some asymmetry from side to side is expected. Increased reticular lines are nearly always present in the upper lung zones when subpleural honeycombing is identified at the bases. A gradient towards the apex occurs with abnormalities accruing from base toward the apex as the disease progresses. Today, a characteristic HRCT in the appropriate clinical and physiologic presentation obviates the need for a surgical lung biopsy in most practice settings, [7, 8, 9] with the caveat that when IPF is a clinical concern, a less than diagnostic HRCT scan will be frequently overridden by usual interstitial pneumonia in the surgical lung biopsy. [7] Past, Present, and Future Therapies for IPF After critically reviewing 3,500 published reports on IPF including physiologic, radiologic, and pathologic findings; pathogenesis, epidemiology, clinical presentation, staging, inheritance or familial occurrence, treatment, and prognosis, a 2000 international consensus statement from the American Thoracic Society concluded that "There is no supportive evidence [for therapy] from well-conducted randomized control trials. The best evidence is from well-conducted cohort studies from case-control studies. Even in these instances the diagnosis of IPF was frequently not well established and the series often included patients with other diseases as potential causes of lung fibrosis". [1] That document went on to say "until adequate studies are conducted that define the best treatment for patients with IPF, this committee suggests the following combined therapy (corticosteroid and either azathioprine or cyclophosphamide) for those patients who have been given adequate information regarding the merits and pitfalls of treatment and who possess features consistent with a more likely favorable outcome". A recent review article also reached this consensus for combined therapy for those patients who cannot enroll in clinical trials. [10] The major milestones in IPF therapy are presented here with analysis and brief discussion. Corticosteroid Therapy for IPF Systemic corticosteroid therapy for patients with IPF began with the notion that inflammatory diseases that result in fibrosis might be controlled or cured with immunosuppression. [1] This notion was not misguided, as pulmonary practice experience and the published literature have clearly documented the effectiveness of anti-inflammatory therapies in a number of inflammatory lung diseases (e.g. eosinophilic pneumonia, rheumatic diseases manifesting in the lung, drug reactions, hypersensitivity reactions). While it is generally agreed that systemic corticosteroids have no proven benefit for patients with IPF, many anecdotal experiences would suggest that some patients who appear to have IPF clinically can rarely derive a benefit from this therapy. Unfortunately, agreed-upon criteria for the pathologic diagnosis of IPF only recently became available from a 2002 international consensus conference based on clinical radiologic and pathologic correlation and available literature [3] and retrospective review of biopsy material from prior cohorts of IPF reveal significant heterogeneity of diagnosis. This variability has been blamed for a false sense that a subset of patients with IPF will respond to corticosteroids or combined immunosuppressive therapies. Corticosteroids and Azathioprine for IPF The most cited early study of combined corticosteroid and cytotoxic therapy for IPF was a 1991 randomized control trial published by Raghu et al. describing the results of 27 patients randomized to prednisone alone (n= 13) or combined prednisone with azathioprine (n=14). [11] The initial results did not reach statistical significance (p= 0.16). A recent reanalysis (after two patients were discovered to have switched therapy arms from prednisone to combined prednisone with azathioprine, one patient in the azathioprine arm had switched to prednisone, a death was discovered in the prednisone arm at year 6, and age adjustment), showed significant differences in these two therapies (p= 0.02). N-acetyl-cysteine in IPF N-acetyl-cysteine is an antioxidant and is proposed as a useful therapy given evidence that oxidative stress may play a role in pulmonary fibrosis. [12] A recent European clinical trial (Ifigenia) in which combined therapy with prednisone and azathioprine was compared with the same regimen plus N-acetyl-cysteine (n=155) showed statistically less decline in FVC and DLco in the Pred-Aza-Nac arm compared to Pred-Aza alone over the year of study. No difference in survival was detected between the groups however. [13] Prednisone and Cyclophosphamide in IPF While no randomized control trials have been evaluated for this therapy, a study by Collard et al. in 2004 compared two historical groups of patients treated at two different medical centers, one where all patients with IPF received prednisone and cyclophosphamide and the other where patients received no therapy. After matching patients by age and FVC at baseline across the two populations, no difference in survival (p=0.58) was detected between the two groups as compared to expected mortality. [14] Colchicine and IPF Colchicine was used for many years in the therapy of IPF, especially by clinicians at the Mayo Clinic. Colchicine is reported to have anti-fibrotic properties, but several studies have shown no efficacy for colchicine in the treatment of IPF. [15, 16, 17, 18] Interferon Gamma and IPF In 1999 a study appeared in the New England Journal of Medicine by Ziesche et al. describing the results of a randomized clinical trial using human recombinant interferon gamma 1b in 18 patients with IPF (9 in each arm). The control group received low dose prednisone while the treatment arm received combined low-dose prednisone with interferon gamma 1b by subcutaneous injection (200 µg) three times a week. At the end of one year, a significant improvement in pulmonary function was detected for the treatment arm compared to the "placebo arm". [19] Based on these results, a large randomized double-blind placebo controlled clinical trial of interferon gamma 1b was designed and implemented. Three hundred and thirty (330) patients were recruited and the primary end points selected for the 48-week period study were a 10% decrement in forced vital capacity or an upward change in A-a gradient of greater than 15%. Mortality was chosen as a secondary endpoint. At the end of the study no difference was identified between the placebo and treatment arms regarding the primary end points, but an unexpected trend was identified with decreased mortality for the interferon-treated group (p = 0.08). [20] When the patients were examined using baseline FVC of greater than or equal to 55% of predicted, the interferon treated arm showed a statistically significant improved survival compared to FVC matched controls. [21] In April of 2006, a second large randomized placebo-controlled trial (2:1 randomization) closed enrollment with 800 + patients accrued and survival as the primary endpoint (GIPF-007). The results of this second clinical trial of interferon gamma 1b in IPF will be available at the end of 2007. Enrollment criteria for this study required on FVC of greater than 55% of predicted and a DLCo of greater than 35% of predicted (baseline physiologic parameters associated with 100% survival in the treatment arm compared controls in the GIPF-001 trial). A recent publication from the Mayo Clinic examined all of the available clinical trial data on interferon gamma in the treatment of IPF. [22] Their comparison of mortality at different time points revealed that IFN-gamma1b therapy was associated with significantly reduced mortality at 1 year (0.0861; 95% CI, 0.0244 to 0.1478; p = 0.0063), 18 months (0.1682; 95% CI, 0.1065 to 0.2299; p < 0.0001), 650 days (0.1939; 95% CI, 0.1386 to 0.2492; p < 0.0001), and 2 years (0.2652; 95% CI, 0.1652 to 0.3652; p < 0.0001). They concluded that the use of interferon gamma 1b in patients with IPF was associated with reduced mortality. Anti-TNF Alpha and IPF Tumor necrosis factor alpha (TNF alpha) is a pleotropic cytokine thought to be involved with regulation of fibroblast proliferation and collagen expression modulated through TGF-beta and/or PDGF. Enhanced expression of TNF alpha has been shown in both experimental models and patients with IPF. [23, 24, 25, 26] A clinical trial assessing the safety and efficacy of anti-TNF alpha in IPF patients enrolled 87 patients. At the end of 48 weeks, a favorable trend (p=0.05) relative to death or a 10% decrement of FVC was identified in the treatment group compared to controls. (Presented at Chest in abstract form 2005;128:496S) Anti-Endothelin 1 and IPF Endothelin-1 (ET-1) is instrumental in regulating fibroblast proliferation, migration, and conversion to the myofibroblastic phenotype. [27] ET-1 increases collagen synthesis and decreases collagen breakdown. ET-1 also plays a primary role in smooth muscle/ endothelial cell regulation through ETa and ETb receptors. [28] A phase II study has been completed and results are pending. Pirfenidone and IPF Pirfenidone (5-methyl-1-phenyl-2-(1H)-pyridone) has proven anti-fibrotic activity both in vitro and in vivo. [29, 30, 31] This agent has been shown to inhibit TNF alpha at the translational level [31] and inhibits TGF-b- induced collagen synthesis in fibroblasts derived from patients with IPF. Pirfenidone also inhibits mitogenic effects of profibrotic cytokines on lung fibroblasts. [29, 30, 32, 33] Three clinical trials of pirfenidone in IPF [34-36] have been completed and have shown this agent to be safe and reasonably well tolerated (oral) in patients with IPF. The most recent of these [35] was a 2:1 randomization with 107 patients. Reduced numbers of acute exacerbation episodes in the treatment arm forced premature closure of the study and the primary endpoints were not met. Some interesting trends were noted between the perfenidone and placebo arms with a statistically significant (p=0.003) smaller decline in FVC over the period of study for the perfenidone treated group. A larger randomized, placebo-controlled trial is currently underway and enrolling patients (PIPF-001). Imatinib Mesylate and IPF Imatinib mesylate is an anticancer drug targeting the c-Abl gene, thought to initiate the destructive and abnormal growth of tissue. Imatinib mesylate also is known to inhibit the profibrotic growth factors to TGF-b and PDGF [37] and has been shown to reduce fibrosis in a mouse experimental model of bleomycin-induced pulmonary fibrosis. [38] A phase II randomized, double-blind placebo-controlled trial has enrolled 100 patients, is currently closed, and the results are under analysis. FG-3019 and IPF FG-3019 is a human monoclonal antibody directed against connective tissue growth factor (CTGF). CTGF and TGFb are felt to play critical roles in the accrual of fibrosis and FG 3019 has been shown to reduce scarring and excess deposition of extracellular matrix following injury in preclinical models. [39] A phase I clinical trial has shown that FG-3019 is well-tolerated and safe for IPF patients. A phase II trial is in the planning stages. [40] Lung Transplant and IPF Lung transplant is a viable therapeutic option for some patients with IPF. New allocation guidelines favor IPF patients and lungs are more available than ever for the treatment of IPF patients. Recent studies have shown that IPF is the most common indication (17%) for adult lung transplantation following COPD/emphysema (39%). 79% survival at one year, 63% survival at two years and 39% survival at five years have been reported. [41] Single lung transplant may be more effective than bilateral lung transplants. [42] Drugs Aimed at Treating Pulmonary Hypertension in IPF Recent data suggest that a subset of patients with IPF develop significant pulmonary hypertension during the course of their disease and there is growing expert consensus that this comorbidity may play a significant role in overall (and possibly sudden unexpected) mortality. [43, 44] Survival for patients stratified by mean arterial pressure (MAP) show significant median survival differences as MAP increases (MAP of 0-35mm/hg = 4.8 yrs, MAP of 35-50 mm/hg = 4.1 yrs, MAP greater than 50mm/hg = 7mos). [45] National Institutes of Health-Sponsored Idiopathic Pulmonary Fibrosis Clinical Research Network Ongoing multi-institutional grant to study novel combined therapies in IPF. No data. Future Drug Therapies Being Considered for Trials: Statins: Lovastatin induces a poptosis in normal and fibrotic lung fibroblasts in vitro, reduces granulation tissue formation and induces fibroblast apoptosis in vivo in rodent wound chamber models. [46] Angiotensin converting enzyme inhibitors: Angiotensin II stimulates expression of TGF-beta gene and proteins expression and induces proliferation of human lung fibroblasts, increasing extracellular matrix production. Blockade of ACE inhibitors has been shown to abrogate fibrosis in experimental models. No human efficacy has been demonstrated. [46] Lipoxygenase: Lipoxygenase increases pro-inflammatory leukotrienes which are likely to play a role in IPF. Leukotrienes may promote fibrosis by influencing fibroblast migration, proliferation, and extracellular matrix protein synthesis. Mice deficient in leukotrienes show attenuated fibrosis following bleomycin administration. [46] Stem cell transplant: Evidence has shown that tissue specific stem cells can differentiate into multiple cell lineages. Mesenchymal stem cells have been shown to home-in on lung tissue after bleomycin injury and help reduce fibrosis in this model. Research avenues hope to be able to reconstitute damaged tissue in the lungs of IPF patients. [47] Anticoagulants: Coagulation events are consistently involved in cell injury and repair and increased procoagulant activity has been shown to be elevated in BAL fluid from IPF patients. [48] A recent clinical study evaluated the effects of anticoagulant therapy, combined with corticosteroids, for acute exacerbations of IPF. The authors demonstrated a significant difference between survival curves of the non-anticoagulant control group and the experimental group, with a 2.9 hazard ratio (p=0.04). They postulated that combined therapy with low molecular weight heparin and prednisolone during the acute exacerbation was responsible for decreased plasma D-dimer levels in the treated survivors and that anticoagualant therapy has a beneficial effect on survival in patients with IPF. 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