POS0620 BI 685509: A POTENT ACTIVATOR OF SOLUBLE GUANYLATE CYCLASE (SGC) AS A NOVEL TREATMENT OF VASCULOPATHY AND FIBROSIS IN SYSTEMIC SCLEROSIS (SSc)

Background SSc is an autoimmune disease characterized by vasculopathy and tissue fibrosis. Oxidative stress is prominent in affected organs and is hypothesized to contribute to inflammatory and fibrotic damage. sGC is a heterodimeric enzyme that binds nitric oxide (NO) to a prosthetic heme group and catalyzes the production of cGMP. Released cGMP acts as a second messenger to regulate processes including tissue remodeling and immune/inflammatory response [1]. Pharmacologic modulation of sGC with a class of compounds called sGC stimulators have been shown to exert anti-fibrotic and anti-inflammatory effects in models of SSc [2]. In a phase II study in SSc, patients treated with the sGC stimulator Riociguat showed a trend towards clinical efficacy [3]. The action of sGC stimulators is dependent on NO-sGC complexes bearing a reduced heme molecule. In environments of oxidative stress, as seen in SSc, altered redox balance may limit efficacy of sGC stimulators due to heme oxidation and the formation of a pool of NO-insensitive sGC. A second class of sGC compounds, called sGC activators, are heme-independent and can act as a substitute for the heme-NO complex and in turn activate the sGC enzyme. Thus, sGC activators may show enhanced activity vs. sGC stimulators in conditions of compromised redox balance. Objectives To evaluate the efficacy of the potent sGC activator BI 685509 in cellular and in vivo models of SSc pathobiology. Methods Human dermal microvascular endothelial cells (HDMVEC) were cultured in normoxic or 1% O 2 conditions in the presence of BI 685509 ranging in doses from 0.04 to 10 µM. After 48 hrs, culture supernatant was collected and the concentration of TGFβ2 was determined. Human platelet rich plasma (PRP) was isolated and activated for 5 minutes with ADP in the presence of BI 685509 or Riociguat at doses of 0.1, 1 or 10 µM. Following activation, supernatants were collected and the level of CXCL4 was measured. For the bleomycin indued skin and lung fibrosis studies, adult female C57Bl/6 mice were used. Mice received intradermal injections of bleomycin every other day for six weeks or a single intratracheal injection. Mice were treated with BI 685509, Riociguat or Nintedanib daily beginning at day 21 (dermal) or 14 (lung) after initiation of bleomycin injection. At 6 (dermal) or 4 (lung) weeks post treatment initiation, skin or lung samples were analyzed via histologic analysis for various cellular and biochemical markers of tissue fibrosis. Results In HDMVEC, hypoxia induced production of the tissue remodeling factor TGFβ2 was significantly inhibited upon treatment with BI 685509 (10 µM). In the mouse model of bleomycin induced skin and lung fibrosis, activation of sGC via BI 685509 treatment at 1 mg/kg resulted in significant amelioration of skin thickness and lung fibrosis that was equivalent to mice treated with the standard of care Nintedanib (60 mg/kg) or the sGC stimulator Riociguat (1 mg/kg). Lastly, to mimic a NO deficient environment seen in SSc, human PRP was utilized. Induction of the SSc relevant chemokine CXCL4 was effectively inhibited in activated PRP treated with the sGC activator BI 685509 whereas minimal inhibition was observed in samples treated with the sGC stimulator Riociguat. Inhibition of CXCL4 production in activated human platelet rich plasma treated with the sGC activator BI 685509 Figure 1. Conclusion Collectively, these results point to the use of the sGC activator BI 685509 as a novel treatment for SSc and suggests potential superior effects vs. sGC stimulators like Riociguat in this autoimmune disease. References [1]Stasch JP, et al Circulation 2011;123:2263-2273 [2]Dees C, et al Ann Rheum Dis 2015;74:1621-1625 [3]Khana D., et al Ann Rheum Dis 2020;79:618-625 Acknowledgements: NIL. Disclosure of Interests Gerald Nabozny Employee of: Boehringer Ingelheim Pharmaceuticals Inc., Chao-Ting Wang Employee of: Boehringer Ingelheim Pharmaceuticals Inc., Leeanne Daley Employee of: Boehringer Ingelheim Pharmaceuticals Inc., David Ebenezer Employee of: Boehringer Ingelheim Pharmaceuticals Inc., Denis Delic Employee of: Boehringer Ingelheim, Tom Bretschneider Employee of: Boehringer Ingelheim, Thuong Trinh-Minh: None declared, Cuong Tran-Manh: None declared, Joerg Distler: None declared, Julia Kaufman Employee of: Boehringer Ingelheim Pharmaceuticals Inc.