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Year: 2011
Tyrosine kinase inhibitors in the treatment of systemic sclerosis: from animal models to clinical trials Iwamoto, N; Distler, J H W; Distler, O
http://www.ncbi.nlm.nih.gov/pubmed/21042889. Postprint available at: http://www.zora.uzh.ch Posted at the Zurich Open Repository and Archive, University of Zurich. http://www.zora.uzh.ch Originally published at: Iwamoto, N; Distler, J H W; Distler, O (2011). Tyrosine kinase inhibitors in the treatment of systemic sclerosis: from animal models to clinical trials. Current Rheumatology Reports, 13(1):21-7.
Tyrosine kinase inhibitors in the treatment of systemic sclerosis: from animal models to clinical trials Abstract Efficient antifibrotic therapies are not available for patients with systemic sclerosis (SSc). This review summarizes the current preclinical and clinical evidence for imatinib and related tyrosine kinase inhibitors as potential antifibrotic therapies for SSc and other fibrotic diseases. In experimental models of SSc, imatinib, nilotinib, and dasatinib demonstrated strong antifibrotic effects. Imatinib not only prevented fibrosis in the bleomycin-induced model of dermal fibrosis and the tight skin mouse-1 model but also reduced established fibrosis in a modified bleomycin model. Open-label, proof-of-concept trials in SSc showed moderate effects on skin fibrosis, biological measures of skin fibrosis, and lung fibrosis compared with baseline measures. However, whether this reflects the natural course of the disease or is a result of treatment effects is unclear and needs to be analyzed in larger, multicenter, randomized, placebo-controlled trials. Toxicity is expected from cancer trials with frequent mild to moderate adverse events.
Tyrosine Kinase Inhibitors in the Treatment of Systemic Sclerosis: From Animal Models to Clinical Trials
Naoki Iwamoto1, Jörg HW Distler2 and Oliver Distler1
1
Department of Rheumatology, Center of Experimental Rheumatology, University Hospital
Zurich, Switzerland 2
Department of Internal Medicine 3 and Institute for Clinical Immunology, University of
Erlangen-Nuremberg, Germany;
Key words: systemic sclerosis, fibrosis, tyrosine kinase inhibitors, imatinib, transforming growth factor-β, platelet derived growth factor
Correspondence and reprints request to: Oliver Distler, MD, Department of Rheumatology, University Hospital Zurich, Gloriastr. 25, 8091
Zürich,
Switzerland,
Email:
[email protected],
Tel:
++41-44-255-2932
Abstract Efficient anti-fibrotic therapies are not available for patients with systemic sclerosis (SSc). This review summarizes the current preclinical and clinical evidence for imatinib and related tyrosine kinase inhibitors as potential anti-fibrotic therapies in SSc and other fibrotic diseases. In experimental models of SSc, imatinib, nilotinib and dasatinib demonstrated strong antifibrotic effects. Imatinib did not only prevent fibrosis in the bleomycin-induced model of dermal fibrosis and the tight skin mouse 1 model, but also reduced established fibrosis in a modified bleomycin model. Open-labeled proof of concept trials in SSc showed moderate effects on skin fibrosis, biological measures of skin fibrosis, and also lung fibrosis when compared to baselines measures. However, whether this reflects the natural course of the disease or is caused by treatment effects is unclear and needs to be analyzed in larger multicenter randomized placebo-controlled trials. Toxicity as expected from cancer trials with frequent mild to moderate adverse events.
2
Introduction The histopathology in systemic sclerosis (SSc) is characterized by fibrosis of the skin and internal organs and by widespread vasculopathy. Although its etiology still remains unknown, knowledge about the pathogenesis of SSc is rapidly increasing. Activation of profibrotic pathways with overexpression of cytokines such as transforming growth factor-β (TGF-β) and platelet derived growth factor (PDGF) is one of the major steps in the pathogenesis of SSc (1). In recent years, blockade of PDGF and TGF-β signalling pathways emerged as a potential strategy to treat and prevent fibrotic diseases. Imatinib is a tyrosine kinase inhibitor (TKI) that efficiently blocks both PDGFR and TGF-β signalling pathways. In this review, we will summarize the current preclinical and clinical evidence for imatinib and related TKIs as a potential anti-fibrotic therapy in SSc and other fibrotic diseases and its potential limitations.
Evidence for PDGF and TGF-β as potential targets for therapy in SSc PDGF family members act via 2 receptor tyrosine kinase receptors, PDGFRα and PDGFRβ. A recent study showed that SSc patients have autoantibodies against PDGFR, which stimulate the production of reactive oxygen species and expression of typeＩcollagen (2). Because these findings could not be reproduced in other studies (3, 4), more work is necessary to identify the role of PDGFR stimulating autoantibodies (5). However, the importance of PDGF/PDGFR in the pathogenesis of SSc is further underlined by their upregulation and activation in skin and bronchoalveolar lavage fluids (5-7). PDGF promotes chemotaxis, stimulates proliferation, enhances myofibroblast differentiation, increases collagen production, and promotes fibroblast adhesion of cultured SSc fibroblasts in vitro. Profibrotic effects of PDGF have also been observed in various animal models, and overexpression of PDGF-A or PDGF-B chains results in fibrosis of various organs (for review see 5). 3
TGF-β is a multifunctional cytokine that regulates growth, differentiation and function of various cell types (8). TGF-β stimulates fibroblasts to produce extracellular matrix proteins (1). TGF-β has been shown to induce myofibroblast differentiation and to increase expression of collagen types I, III, VI, VII, and X, fibronectin and proteoglycans (9, 10). In addition, postnatal induction of TGF-β signaling in mouse fibroblasts of mice induces profound fibrosis of the dermis (11). The intracellular tyrosine kinase c-abl is required for the profibrotic effect of TGF-β, and fibroblasts deficient for c-abl do not increase collagen synthesis upon TGF-b stimulation (12, 13). Thus, PDGF and TGF-β pathways are thought to be molecular key players in the fibrotic and vascular complications of SSc.
Inhibition of tyrosine kinases Tyrosine kinases (TKs) are involved in a wide variety of physiological processes and their pathological activation is important for various disease processes including carcinogenesis, vascular remodeling, and fibrogenesis (14-16). To target pathological TK activity, monoclonal antibodies have been developed against the extracellular domains of receptor TKs, such as the anti-vascular endothelial growth factor (VEGF) receptor antibody bevacizumab and the anti-epithelial growth factor (EGF) receptor antibody cetuximab. In addition to monoclonal antibodies, small molecule tyrosine TKIs, which can enter the cytoplasm to bind the intracellular catalytic domains of both receptor and non-receptor TKs, have been developed for targeting pathological TK activity in various diseases. Imatinib mesylate is the lead substance among the small molecule TKIs. Imatinib mesylate was the first TKI approved by the Food and Drug Administration in 2001 for treatment of chronic myelogenous leukemia (CML) in order to block the Abl kinase activity associated with Bcr-Abl translocation. In addition to c-abl, imatinib blocks the activity of PDGFR, c-kit and c-fms. Imatinib has rather rare serious adverse events in cancer patients, but mild to moderate adverse events are common. Imatinib mediated edema is frequent, 4
affecting more than 50% of patients (17). Often edema is periorbital in presentation with peripheral edema also occurring. Females are at higher risk for this side effect. Other risk factors include age with patients older than 65 years being at higher risk, and the presence of either cardiac or renal disease. There is often improvement of adverse event with dose reduction. Bone marrow suppression sometimes occurs. Other adverse events include nausea, muscle cramps and diarrhea. Dasatinib and nilotinib are second-generation TKIs which were developed for patients with treatment-refractory CML and with intolerance to imatinib (18). As with imatinib, they can be administered orally with a favorable toxicity profile. Nilotinib is structurally related to imatinib with 20-30-fold more potent affinity to BCR-ABL than imatinib. Dasatinib is structurally distinct from imatinib (19). It has activity against many of the mutant forms of Bcr-Abl that are resistant to imatinib, but also targets other TKs including PDGFR and SRC.
Anti-fibrotic effects of imatinib in vitro We observed that imatinib inhibited the synthesis of collagen 1a1, collagen 1a2, and fibronectin-1 mRNA in SSc fibroblasts by up to 90 % in pharmacologically relevant doses (20•). Similar results were seen on the protein levels. We did not observe any compensatory changes in the expression of matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases. The effects were dose-dependent and were seen in both PDGF- and TGFβ stimulated fibroblasts. Bhattacharyya et al confirmed these findings and could further show that the induction of early growth response protein 1 (Egr-1) by TGF-β is dependent on c-abl, and that inhibition by imatinib abrogates the TGF-β induced activation of Egr-1 (12). Imatinib also restores the reduced levels of the antifibrotic microRNA miR-29 in SSc fibroblasts in a PDGFRβ- and c-abl-dependent manner (21). Furthermore, c-abl is involved in the phosphorylation/activation of Smad1, which results in upregulation of CCN2 (Connective tissue Growth Factor, CTGF), and inhibition of c-abl by imatinib abrogates this signalling 5
loop (22). Finally, c-Abl activates protein kinase C (PKC)-δ, which in turn decreases binding affinity of the antifibrotic transcription factor Fli1 to the type I collagen promoter thereby promoting fibrosis. Imatinib inhibits c-Abl and consequently appears to block activation of PKC-d by TGF-β (Bujor et al, unpublished data and 23). Taken together, these data show that c-abl plays an important role in profibrotic signalling mechanisms of TGF-β, and that imatinib is a potent dual inhibitor of the profibrotic effects of PDFGR and TGF-β/c-abl in vitro.
Tyrosine-kinase inhibitors and in vivo models of SSc The antifibrotic in vitro effects of imatinib could be confirmed in different animal models of SSc. The bleomycin model of dermal fibrosis is an inflammatory model that reflects early disease stages of SSc (24). Treatment of mice with imatinib at doses of 50 mg/kg/day and 150 mg/kg/day had strong anti-fibrotic effects and could almost completely prevent bleomycin induced skin thickening. Similarly, imatinib prevented the differentiation of resting fibroblasts into myofibroblasts and reduced synthesis and accumulation of extracellular matrix in lesional skin. These strong antifibrotic effects occurred without overt toxicity including peripheral edema (20). Treatment with dasatinib and nilotinib revealed the same results without differences between the TKIs (25). Similar results exist for animal models of other organ fibrosis such as pulmonary, renal and liver fibrosis (13, 26-28). Doses of imatinib used in animal studies are higher than in humans because of a faster metabolism of imatinib in mice, but these doses lead to serum levels of imatinib similar to those found in humans with standard doses of 400–800 mg imatinib per day. In the clinical setting, treatment of established fibrosis might be even more relevant than prevention of fibrosis. We therefore tested imatinib in a modified bleomycin model of skin fibrosis, in which treatment with imatinib was started after skin fibrosis was established. Indeed, imatinib reduced also established fibrosis in this model as compared to sham-treated mice (29••). 6
The TSK-1 model is a non-inflammatory model of skin fibrosis that reflects intermediate and later stages of SSc, when the perivascular inflammatory infiltrates are no longer detectable (24). Similar to the bleomycin model, treatment with imatinib was strongly anti-fibrotic and did not only reduce dermal and hypodermal thickening, but also prevented differentiation of resting fibroblasts into myofibroblasts in TSK-1 mice (29). Accordingly, in a rat model of bleomycin-induced lung fibrosis, which shows early inflammatory and later non-inflammatory profibrotic stages, imatinib was effective in both early and late stages (30).
Clinical efficacy of imatinib in organ fibrosis associated with hematological disorders The first clinical evidence for anti-fibrotic effects of imatinib came from patients with CML and concomitant bone marrow fibrosis. Two clinical studies suggested that treatment of patients with CML with imatinib might lead to a regression of bone marrow fibrosis within three months of therapy (31, 32). Interestingly, the anti-fibrotic effect did not correlate with the cytogenetic response and thus, mechanisms independent from the suppression of Philadelphia chromosome-positive cancer cells might have caused regression of bone marrow fibrosis (32). Similarly to bone marrow fibrosis, two studies with a total of 33 patients suffering from sclerotic chronic graft versus host disease (cGvHD) revealed promising results. Imatinib was used for treatment-resistant and severe sclerotic cGvHD in these studies. Strong clinical responses were seen in 50% and 79% of patients respectively, with some patients showing a complete disappearance of fibrosis. Imatinib had to be stopped in 7/33 patients due to drug intolerance (33•, 34•). These results were supported by a retrospective analysis on the prophylactic impact of imatinib on chronic graft versus host disease after allogeneic stem cell transplantation in 96 patients with Philadelphia chromosome-positive leukemia. Both the incidence and severity of cGvHD were reduced by administration of imatinib after stem cell transplantation as compared to patients without imatinib treatment (35). A smaller study on patients with severe lung fibrosis showed limited efficacy in pulmonary cGvHD (36). Overall, 7
the clinical studies with imatinib in bone marrow fibrosis and cGvHD are encouraging. However, because of their uncontrolled and in part retrospective nature, the encouraging results still have to be interpreted with caution and need to be confirmed in larger, controlled and prospective studies.
Clinical efficacy of imatinib in SSc Several case reports and smaller case series demonstrated beneficial effects of imatinib in patients with treatment refractory SSc (37-40). Imatinib was also an efficient therapy in two patients with gadolinium-induced nephrogenic systemic fibrosis (41). We reported the successful treatment of pulmonary fibrosis with imatinib in a patient with anti-U1-antibodypositive mixed connective tissue disease (42). Before initiation of imatinib, the patient deteriorated despite treatment with corticosteroids and immunosuppressives. However, during a 20-week trial with 400 mg/day imatinib, the patient progressively improved. The New York Heart Association (NYHA) class changed from NYHA IV to NYHA II. The 6 minute walking distance increased by 50m and the carbon monoxide transfer factor increased from 26% predicted to 45 % predicted. The arterial oxygen pressure increased from 64 mm Hg to 70 mm Hg at rest and from 50 mmHg to 62 mm Hg after exertion. Ground-glass opacities decreased during treatment, whereas the reticular changes remained constant. However, no changes in forced vital capacity and total lung capacity were seen. The patient tolerated the treatment well and did not experience adverse events apart from mild edema. In general, case reports have to be interpreted with caution, as there might be a publication bias of negative cases. Thus, larger, prospective and partially controlled clinical trials are currently ongoing. Many of them have finished recruitment and results have been presented in abstract form at congresses. The following is a summary of these abstracts. It needs to be emphasized that definite interpretation of these studies is only possible after the final analysis is published in full paper form. 8
Spiera and colleagues reported results of a phase IIa, open-label study on 30 patients with diffuse SSc (dSSc) (43). Dose of imatinib was 400 mg daily and treatment duration was 12 months. In the 24 patients completing the 12 months treatment period, the modified Rodnan Skin Score (mRSS) improved significantly by 6.6±4.7 points from baseline. This study included a wide range of disease duration, but the effects were also seen in patients with short disease duration < 18 months. Significant improvements compared to baseline were additionally observed in the visual analog scales for global, shortness of breath and pain as well as in the SF-36 mental component. Other health related quality of life measures remained stable. Physician global assessment also improved. Blinded dermatopathologic analysis demonstrated a significant decrease in skin thickness and improvement in skin morphology with decreased thickness of collagen bundles and increased interstitial space. Adverse events were common, but 98% were grade 1 or 2 and mostly included edema, nausea, myalgias and creatinine kinase elevations. There were two serious adverse events at least possibly related to imatinib. Saggar and colleagues reported an open labeled phase I/IIa study to assess the efficacy and safety of imatinib in 20 patients with SSc–associated interstitial lung disease (44). Eight of 20 patients completed 12 months of treatment with imatinib (up to 600 mg/day), and four patients were still continuing in the study. Use of imatinib was associated with stabilization of FCV% (estimated rate/year =1.39) and with significant improvement of DLCO (estimated rate/year =4.77) and mRSS (estimated rate/year =4.34). There were three serious AE (severe myopathy, diastolic dysfunction, and hypothyroidism) and 10 patients developed lower extremity and/or facial edema. Majority of adverse events were managed with decrease in imatinib dose, but seven patient discontinued treatments due to adverse events. Another trial of imatinib in patients with active dSSc has recently been reported by Pope et al (45). Of the 10 patients enrolled into the study (nine imatinib and one placebo), only four patients completed six months of treatment with 400mg imatinib daily. Another five 9
patients discontinued treatment due to adverse events including fluid retention, weakness and nausea. Efficacy is difficult to interpret due to the short treatment duration and the low number of patients in this study. However, in an intention-to-treat analysis, no effects on skin score, health assessment questionnaire, C-reactive protein, erythrocyte sedimentation rate, physician and patient global were observed. In our multi-center, open-label, proof of concept study, patients with early dSSc of less than 18 months disease duration were treated with 600 mg imatinib per day for six months, followed by a six months observation period (46). This study followed good clinical practice guidelines including external monitoring. Of the 27 patients enrolled, 16 completed six months of treatment with imatinib and 13 patients were followed up another six months. Six patients (22%) discontinued due to adverse events. There were five patients with serious adverse events which included generalized edema, erosive gastritis, anemia, peripheral and facial edema, upper respiratory tract infection, neutropenia and neutropenic infection, nausea and vomiting. While the mRSS increased by 9.9% after six months, there was a 21% decrease of the mRSS after 12 months compared to baseline. Similar results were seen for global physician/patient health assessment. Biomarker analysis demonstrated a reduction of mRNA levels of collagen1a1 and fibronectin.
Clinical efficacy of imatinib in idiopathic lung fibrosis A randomized placebo-controlled double-blind trial with imatinib has been finished in patients with mild to moderate idiopathic lung fibrosis (47•). Over 96 weeks, patients received placebo or imatinib at 600 mg per day. The primary end point defined as time to disease progression (10% decline in percent predicted FVC from baseline) or time to death was not different between imatinib and placebo. There was also no difference in change in FVC, diffusing capacity of carbon monoxide, resting PaO2 and number of death at 96 weeks. Adverse events possibly, probably, or definitely related to study drug occurred in 56 patients 10
on imatinib and 37 patients on placebo. Adverse events that occurred significantly more often in patients with imatinib included – as expected – periorbital edema, nausea, diarrhea/cramping, rash and anemia. Most importantly, number of serious adverse events did not differ between imatinib and placebo. Tissue and other biomarker analysis were not done in this trial. Taken together, these data indicate a good tolerability of imatinib in patients with IPF, but indicate no affect on survival and clinical outcome measures such as lung function in patients with idiopathic lung fibrosis.
Are animal models useful to predict clinical responses in molecular-targeted therapies? While definite conclusions on the antifibrotic effects in human SSc are difficult to draw at this time, it is clear that the effects of imatinib are less strong than in the animal models. One explanation might be increased levels of circulating α-1 acid glycoprotein (AGP) in fibrosis patients. Widmer et al reported high levels of AGP in patients with CML resulting in threefold reduction of serum concentrations of imatinib through plasma binding. This accounted for half of the observed imatinib resistance (48). In addition, failure of imatinib treatment to prevent lung fibrosis in a mouse model of bleomycin lung fibrosis was caused by AGP. Furthermore, in human patients with idiopathic pulmonary fibrosis half of patients had circulating levels of AGP high enough to lower imatinib serum levels below that needed to inhibit PDGFR in vitro (49). Another reason for the stronger antifibrotic effects in animals might be a lower activation status of TKI targets in humans. We recently examined the expression of activated TKI targets, p(phospho)-PDGFR and p-c-Abl, in skin sections of the bleomycin induced skin fibrosis model and human SSc. In bleomycin-induced mice, expression of p-PDGFR and p-cAbl was significantly higher than in control animals and much higher than in human SSc. Moreover, the pattern of expression was different. In skin sections of SSc patients, the
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expression of p-c-abl and p-PDGFR was largely limited to vascular structures, while their expression in the bleomycin model was ubiquitous including dermal fibroblasts (50). Thus, animal models of SSc are of key importance in the evaluation, whether molecular targets for therapy contribute to the development of fibrosis and whether their inhibition abrogates fibrosis. These animal experiments cannot be omitted in the development of molecular-targeted therapies. However, the results from the animal models have to be interpreted in the right context and analysis of a similar activation status of targets in humans and animals helps to predict the magnitude of responses to therapeutic inhibition in humans.
Conclusion Taken the clinical studies together, the following statements can be made at this time regarding efficacy and safety of imatinib in SSc and other fibrotic diseases (1) Conclusions for all studies except the trial in idiopathic lung fibrosis are limited by the uncontrolled study design and interpretations have to be made with great caution. (2) Efficacy signals coming from clinical studies differ between the various fibrotic conditions: Overall encouraging results in bone marrow fibrosis and cGvHD, moderate results in SSc and a negative result from idiopathic lung fibrosis. This indicates that the fibrotic conditions might differ in part in their pathophysiology and might therefore respond differentially to molecular target therapies. (3) In SSc, positive signals were obtained for clinical measures of skin fibrosis, biological measures of skin fibrosis, and also lung fibrosis when compared to baselines measures. However, it is unclear, whether this does not simply reflect the natural course of the disease. (4) Effects seen in the preclinical animal models are stronger than in the human disease. Possible explanations include among others a stronger activation of 12
imatinib targets in the animal models than in humans, and the presence of inhibitors such as circulating α-1 acid glycoprotein in humans. (5) Biomarker and biosample analysis is preliminary or not existing in all studies. In particular tissue sample analysis obtained from the clinical studies should be a focus of further activities in this field. These analyses should be able to answer whether target inhibition was successful or limited by disease-related factors and whether successful target inhibition was accompanied by inhibition of extracellular matrix synthesis. If inhibition of extracellular matrix synthesis was successful despite mild clinical effects, this would raise questions about the sensitivity of clinical outcome measures currently used and might have important impact on future clinical study design. (6) Results for safety and tolerability are remarkably consistent between most of the studies: Adverse effects are frequent and most often include edema, nausea, myopathy, diarrhea/cramping, rash and anemia. However, many adverse events are mild to moderate and can be managed with dose-reduction. Still, taken all studies in SSc together, about 28% of the patients discontinued treatment because of adverse events in 6-12 months clinical trials. This might indicate that chronically ill rheumatic patients with a systemic disease are more sensitive to moderate side effects than cancer patients. It might also indicate that rheumatologists are less experienced in handling these adverse events. Notably, serious adverse events were not different between imatinib and placebo in the only randomized controlled trial in patients with idiopathic lung fibrosis. (7) Definite answers can only be drawn from double-blinded, prospective, randomized placebo-controlled trials. These studies should be initiated in those fibrotic conditions with positive signals in the open-labeled clinical trials. If the
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tissue analysis reveals positive effects on extracellular matrix synthesis, SSc should be among those conditions to be tested in placebo-controlled trials.
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