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Background: Systemic sclerosis (SSc) is a rare autoimmune disease characterised by fibrosis of the skin and other organs, and there is a significant unmet need for new treatments. Phosphodiesterase (PDE) 4 inhibition is associated with broad anti-inflammatory and antifibrotic effects. BI 1015550 is an oral preferential inhibitor of the PDE4B subtype and a potential treatment for idiopathic pulmonary fibrosis and progressive pulmonary fibrosis 1, 2. In vitro studies have shown that BI 1015550 exerts antifibrotic and anti-inflammatory effects by inhibiting myofibroblast transformation, lung fibroblast proliferation, and proinflammatory cytokine release from peripheral blood mononuclear cells (PBMCs) 1. This suggests that BI 1015550 could be beneficial in SSc by targeting both inflammation and fibrosis. Objectives: The study investigated the effect of BI 1015550 on the expression of fibrosis markers and the proliferation of normal and SSc patient dermal fibroblasts, as well as normal human keratinocytes. The effects of BI 1015550 on proinflammatory mediator release from normal and SSc patient-derived PBMCs and normal macrophages, and IFN response gene expression of normal macrophages, were also investigated. Methods: Normal human and SSc patient-derived dermal fibroblasts, and normal human keratinocytes, were treated with BI 1015550 following cytokine stimulation. The effects of BI 1015550 on cell proliferation were measured using a BrdU assay for normal fibroblasts and keratinocytes, and Ki-67 staining for IL-1β + bFGF-stimulated SSc patient-derived fibroblasts. The effects of BI 1015550 on the expression of fibrosis markers IGFBP3, sICAM-1 and PAI-1, and on the extracellular matrix protein Col1α1, were characterised using ELISA. Antifibrotic effects of BI 1015550 were determined with an in vitro fibrosis model (Scar-in-a-Jar) using SSc patient-derived fibroblasts exposed to TGF-β and PGE2. Effects of BI 1015550 on secretion of TNF-α from LPS-stimulated normal human and SSc patient-derived PBMCs, and from normal human macrophages along with IL-6 secretion, were determined by ELISA. The expression of type 1 and 2 IFN markers from human macrophages was investigated by ELISA and qPCR. Results: BI 1015550 reduced SSc dermal fibroblast proliferation (Figure 1A) and IGFBP3, sICAM-1 and PAI-1 expression (Figure 1B). In a Scar-in-a-Jar assay, BI 1015550 significantly decreased the levels of α-smooth muscle actin in fibroblasts. The effect of BI 1015550 alone was greater compared with mycophenolate mofetil (MMF) alone, a commonly used treatment for SSc. When used in combination with MMF, BI 1015550 exhibited similar or greater effects on proliferation and expression of fibrosis markers, except on soluble ICAM-1. Antiproliferative and antifibrotic effects of BI 1015550 were also observed on normal fibroblasts. In addition, BI 1015550 reduced Col1α1 expression in normal human keratinocytes and TNF-α secretion from PBMCs. BI 1015550 also suppressed TNF-α and IL-6 secretion from human macrophages and attenuated type 1 and 2 IFN responses. Conclusion: BI 1015550 had significant antifibrotic and anti-inflammatory effects on cell types relevant to SSc in vitro, indicating that it could attenuate the underlying disease pathology in SSc. REFERENCES: 1 Herrmann F, et al. Front Pharmacol. 2022; 13:838449. 2 Richeldi L, et al. N Engl J Med. 2022; 386:2178─87. Acknowledgements: This study was supported and funded by Boehringer Ingelheim. The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). The authors did not receive payment for the development of the abstract. Claire Scott, PhD of Nucleus Global provided writing, editorial support and formatting assistance, which was contracted and funded by Boehringer Ingelheim. Boehringer Ingelheim was given the opportunity to review the abstract for medical and scientific accuracy as well as intellectual property considerations. Disclosure of Interests: Daniel Schniertshauer has received financial support from Boehringer Ingelheim paid to his institution for this project, David L Ebenezer owns shares in AbbVie, Bristol Myers Squibb, Pfizer, Novo Nordisk, and is a current employee of Boehringer Ingelheim, Daniela Schloesser is a current employee of Boehringer Ingelheim, Karim Christian El Kasmi is a current employee of Boehringer Ingelheim, Christian Hesslinger is a current employee of Boehringer Ingelheim, Jörg Bergemann has worked as a paid consultant for MSE Pharmaceuticals (Mitochondrial Medicine)/professional development (Biomedicine), and received financial grants from Boehringer Ingelheim.
Schniertshauer et al. (Sat,) studied this question.