European Respiratory Society Annual Congress. Presented at: of new drugs for respiratory diseases. Barcelona, Spain, September 7-11, 2013 Page 1
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1 PBI-4050, a novel first-in-class anti-fibrotic compound, reduces lung fibrosis in the bleomycin-induced lung fibrosis model: a comparative study with pirfenidone Presented at: Thematic Poster Session: European Respiratory Society Annual Congress Preclinical models for the development of new drugs for respiratory diseases Barcelona, Spain, September 7-11, 2013 Page 1
2 Background The pathobiological mechanisms underlying the development of idiopathic pulmonary fibrosis (IPF) are highly complex. PBI-4050, a novel first-in-class, orally active low molecular weight compound, plays a key role in inflammation/fibrosis regulation by reducing pro-fibrotic cytokines, fibrocyte differentiation, myofibroblast activation and EMT, resulting in improvement of organ function. The aim of this study is to compare the anti-fibrotic activity of PBI-4050, pirfenidone and combination of both compounds in the bleomycin-induced lung fibrosis model. Barcelona, Spain, September 7-11, 2013 Page 2
3 Study Design Mice were randomized according to their bleomycin-induced body weight loss, and treatments with PBI-4050 and pirfenidone or combination of both compounds started on day 7. Only animals that recovered their body weight loss by day 20 were used for data analysis. Barcelona, Spain, September 7-11, 2013 Page 3
4 Toxicity No toxicity was reported with PBI 4050 treatment. Treatment with Pirfenidone induced severe vertigo that was reduced with the PBI pirfenidone combination therapy. PBI-4050 (200 mg/kg) No toxicity observed Pirfenidone (400 mg/kg) vertigo ++++ PBI Pirfenidone vertigo ++ Barcelona, Spain, September 7-11, 2013 Page 4
5 PBI-4050 alone, or in combination with pirfenidone, significantly reduces histological lesions in bleomycininduced lung fibrosis Barcelona, Spain, September 7-11, 2013 Page 5
6 % of lung area affected by bleomycin is reduced by PBI-4050 alone as well as by the combination of PBI-4050 & pirfenidone Barcelona, Spain, September 7-11, 2013 Page 6
7 Significant reduction of the % of leukocyte infiltration in lung determined in Masson s trichrome staining (Morphometric evaluation) Barcelona, Spain, September 7-11, 2013 Page 7
8 Significant reduction of [% leukocyte infiltration] X [% of collagen in leukocyte infiltration] in lung determined in Masson s trichrome staining (Morphometric evaluation) Effect of PBI-4050, pirfenidone and combination therapy on lung collagen in leukocyte infiltrates quantified by histomorphometric analysis. Barcelona, Spain, September 7-11, 2013 Page 8
9 Effect of treatment regimen on lung fibrosis Ashcroft s score (HEP and Masson s Trichrome staining) for PBI-4050 and combination therapy were both significantly reduced compared to bleomycin under ANOVA / Dunnett s analysis. Visual grading of pulmonary fibrosis was also determined according to Ashcroft s score. Briefly, the entire fields of each lung section were read by a blinded examiner, and each field was visually graded from 0 to 8. Criteria for grading lung fibrosis were as follows: Grade 0= normal lung; Grade 1= minimal fibrous thickening of alveolar or bronchiolar walls; Grade 3= moderate thickening of walls without obvious damage to lung architecture; Grad 5= increased fibrosis with definitive damage to lung structure and formation of fibrous bands or small fibrous masses; Grade 7= severe distortion of structure and large fibrous area; Grade 8= total fibrous obliteration of lung fields. Barcelona, Spain, September 7-11, 2013 Page 9
10 Histological lesions in bleomycin (bleo)-induced lung fibrosis reduced by PBI-4050 alone and by PBI pirfenidone combination Photomicrographs of lung tissue from mice treated with PBI-4050 showing the reduction of histological lesions (disrupted lung architecture and thickness of alveolar wall, (trichrome staining, 40X) by PBI-4050 alone and by the combination therapy. Pirfenidone alone has no effect. Barcelona, Spain, September 7-11, 2013 Page 10
11 Histological lesions in bleomycin (bleo)-induced lung fibrosis reduced by PBI-4050 alone and by PBI pirfenidone combination Photomicrographs of lung tissue from mice treated with PBI-4050 showing the reduction of histological lesions (disrupted lung architecture and thickness of alveolar wall, (trichrome staining, 100X) by PBI-4050 and the combination therapy. Pirfenidone alone has no effect. Barcelona, Spain, September 7-11, 2013 Page 11
12 Effect of treatment regimen on inflammatory/ pro-fibrotic cytokines mrna expression in lung Bleomycin induced a significant increase in mrna expression of all key mediators in the lung. PBI-4050 and PBI Pirfenidone combination therapy significantly decreased: TGF- 1 (slide 13), CTGF (slide 14), IL-23p19 (slide 15) and IL-6 (slide 16) expression in lung, Pirfenidone alone had no significant effect on CTGF and IL-23p19. Barcelona, Spain, September 7-11, 2013 Page 12
13 Effect of treatment regimen on inflammatory/pro-fibrotic cytokines mrna expression in lung TGF- 1 Effect of PBI-4050, pirfenidone and combination therapy on TGF- 1 expression in bleomycininduced lung fibrosis. Barcelona, Spain, September 7-11, 2013 Page 13
14 Effect of treatment regimen on inflammatory/pro-fibrotic cytokines mrna expression in lung (Cont d) CTGF Effect of PBI-4050, pirfenidone and combination therapy on CTGF expression in bleomycin-induced lung fibrosis. Barcelona, Spain, September 7-11, 2013 Page 14
15 Effect of treatment regimen on inflammatory/ pro-fibrotic cytokines mrna expression in lung (Cont d) IL-23p19 Effect of PBI-4050, pirfenidone and combination therapy on IL-23p19 expression in bleomycin-induced lung fibrosis. Barcelona, Spain, September 7-11, 2013 Page 15
16 Effect of treatment regimen on inflammatory/pro-fibrotic cytokines mrna expression in lung (Cont d) IL-6 Effect of PBI-4050, pirfenidone and combination therapy on IL-6 expression in bleomycin-induced lung fibrosis. Barcelona, Spain, September 7-11, 2013 Page 16
17 Effect of treatment regimen on fibrotic markers mrna expression in lung IPF is characterized by exaggerated fibroblast proliferation and accumulation of collagens and fibronectin. All treatments induced a significant reduction of collagen I (slide 18) and fibronectin 1 (slide 19) expression to the control level (no bleomycin). Barcelona, Spain, September 7-11, 2013 Page 17
18 Effect of treatment regimen on fibrotic markers mrna expression in lung Collagen I Effect of PBI-4050, pirfenidone and combination therapy on collagen I expression in bleomycin-induced lung fibrosis. Barcelona, Spain, September 7-11, 2013 Page 18
19 Effect of treatment regimen on fibrotic markers mrna expression in lung (Cont d) Fibronectin 1 Effect of PBI-4050, pirfenidone and combination therapy on fibronectin 1 expression in bleomycin-induced lung fibrosis. Barcelona, Spain, September 7-11, 2013 Page 19
20 Effect of treatment regimen on remodeling markers mrna expression in lung Bleomycin induced a significant increase in mrna expression of SPARC and MMP-2. PBI-4050 and combination therapy reduced SPARC expression while pirfenidone had no effect (slide 21). MMP-2 mrna expression was significantly reduced in the combination therapy (slide 22). Barcelona, Spain, September 7-11, 2013 Page 20
21 Effect of treatment regimen on remodeling markers mrna expression in lung SPARC Effect of PBI-4050, pirfenidone and combination therapy on SPARC expression in bleomycin-induced lung fibrosis. Barcelona, Spain, September 7-11, 2013 Page 21
22 Effect of treatment regimen on remodeling markers mrna expression in lung (Cont d) MMP-2 Effect of PBI-4050, pirfenidone and combination therapy on MMP-2 expression in bleomycin-induced lung fibrosis. Barcelona, Spain, September 7-11, 2013 Page 22
23 Conclusion Our results show that PBI-4050 and combination of PBI-4050 and pirfenidone: Reduce inflammatory/profibrotic cytokines (TGF- 1, CTGF, IL-23p19 and IL-6) mrna expression Reduce fibrotic markers (collagen I and fibronectin 1) mrna expression Reduce remodeling markers (SPARC and MMP-2) mrna expression Reduce histological lesions PBI-4050 may be an efficacious treatment in IPF. The combination therapy with pirfenidone provides superior outcomes. Barcelona, Spain, September 7-11, 2013 Page 23
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