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Novel fibrosis therapeutics: walking down the TGF-beta pathway

16:09 EDT 20 Aug 2017 | SugarCone Biotech

Recent weeks brought startling news of clinical trial successes in the treatment of Idiopathic Pulmonary Fibrosis (IPF). The clinical and commercial consequences have been heavily reviewed elsewhere (eg. GLPG and FGEN). This short commentary will focus on the underpinning science, with particular reference to the TGF-beta (TGFb) pathway and the role of that pathway in fibrotic disease. First a quick primer on the recent advances in IPF drug development. Fibrogen pulled off a successful and surprising 48 week Phase 2 trial of pamrevlumab, an old antibody targeting CTGF, while Galapogos followed with very compelling early Phase 2a data of GLPG1690, an autotaxin inhibitor, including the apparent reversal in decline of lung function that is the hallmark of IPF (nb. small sample size, short analysis period (12 weeks). These two new drugs are poised to contribute to the next wave of IPF therapeutics, joining pirfenidone (Esbriettm, Roche) and nintedanib (Ofevtm, Boehringer Ingelheim), approved for the treatment of IPF in 2014. Of note, pirfenidone and nintedanib are considered moderately efficacious, slowing but not reversing the rate of decline in lung function, and only modestly improving life expectancy, if at all. Therefore, if pamrevlumab or GLPG1690 can differentiate by either reversing lung damage or increasing life expectancy, they would be expected to overtake the earlier drugs. What’s interesting is that the mechanism of each of these drugs intersects with the activity of TGFb, a dominant cytokine that normally controls wound healing and other tissue repair activities. When dysregulated, TGFb becomes pathogenic, supporting disease processes spanning oncology and fibrosis. We can visualize the initiation and progression of fibrosis as a series of steps controlled, at least in part, by the continuous activity of TGFb signaling through the TGFb-receptors. Indeed, pirfenidone’s mechanism of action includes inhibition of TGFb-receptor signaling, among other activities (both pirfenidone and nintedanib are tyrosine kinase ...

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