Treprostinil for Idiopathic Pulmonary Fibrosis
27 May, 2022 | DelveInsight
- Treprostinil inhibits fibrosis by acting on the prostanoid receptor subtype EP2, demonstrating the importance of this receptor subtype in the treatment of IPF.
- Treprostinil's potential to inhibit profibrotic cytokine secretion may further increase its anti-fibrotic effects.
Treprostinil is a stable prostacyclin analog with potent vasodilatory and antiproliferative activity. In human lung fibroblasts (HLF), treprostinil inhibits the expression of genes associated with collagen formation and secretion (COL1A1, COL1A2, and COL3A1), collagen biosynthesis (P4HA1), and myofibroblast differentiation (ACTG2). The drug has proved its efficacy in several pulmonology indications. Treprostinil palmitil inhalation powder (TPIP) is a dry powder formulation of treprostinil palmitil, a treprostinil prodrug consisting of treprostinil linked by an ester bond to a 16-carbon chain. Developed entirely in Insmed's laboratories, TPIP is a potentially highly differentiated prostanoid being evaluated for the treatment of patients with pulmonary arterial hypertension (PAH) and other rare and serious pulmonary disorders. Beyond PAH, Insmed continues to explore potential development pathways for TPIP in patients with pulmonary hypertension associated with interstitial lung disease (PH-ILD) and idiopathic pulmonary fibrosis (IPF).
Recently, at the American Thoracic Society (ATS) International Conference 2022, Insmed presented three treprostinil posters at ATS showcasing preclinical data. The first poster showed that treprostinil exerts an anti-fibrotic effect by acting via prostanoid receptor subtype EP2. The anti-fibrotic effects of treprostinil may also be enhanced by its ability to inhibit profibrotic cytokine secretion. The poster was titled “Treprostinil Exerts Anti-Fibrotic Effects via the Prostanoid Receptor Subtype EP2 in Human Lung Fibroblast” (P250) and was presented in Session A60 (Pulmonary Fibrosis: Animal and Cell Culture Models).
The preclinical study results:
The company determined the prostanoid receptor subtypes(s) responsible for treprostinil-induced collagen gene inhibition and examined the effects of treprostinil on profibrotic cytokine secretion, to investigate anti-fibrotic mechanisms of action by treprostinil in HLF stimulated by tumor growth factor (TGF)-β1. EP2 receptor antagonist (PF-04418948) significantly reduced the inhibition of TGF-1 upregulation of COL1A1, COL1A2, and ACTG2 genes by treprostinil, with non-significant reductions in COL3A1 and P4HA1 gene expression; however, DP1 receptor antagonist (BWA868C, RO1138452) and EP1 receptor antagonist (ONO8130) had no effect. Treprostinil decreased the release of eotaxin, IL-8, and CCL-2 in TGF-1-stimulated HLF while increasing the release of IL-6. TGF-1 had no impact on the production of IL-5 or PDGF- ββ.
DelveInsight analysis from the above findings shows that treprostinil inhibits fibrosis by acting on the prostanoid receptor subtype EP2, supporting the subtype's importance in IPF treatment. Treprostinil's capacity to decrease profibrotic cytokine release may also boost its anti-fibrotic actions, but more research into the roles of treprostinil-induced profibrotic cytokines in IPF is needed.
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