Late Breaking Abstract - GTX-11 – a new drug with anti-fibrotic effects in lung fibroblasts and in an ex vivo model

<bold>Background:</bold> Fibrotic interstitial lung diseases (ILDs) can be progressive and new treatments are urgently needed. GTX-11 is an orally available small molecule in development by GAT Therapeutics. By modulating TGF-β pathway, it reduces fibrosis progression and endothelial dysfunction in lung fibrosis disease models. We aimed to confirm the therapeutic potential of GTX-11 in precision cut lung slices (PCLS) and in primary human normal lung fibroblasts (hNLFs). <bold>Methods:</bold> hNLFs were cultured for 48h with TGF-β1, GTX-11 active metabolite (GTX-11m), nintedanib, pirfenidone or combination treatments. Fibrotic PCLS were generated from human lung tissue pre-exposed to TGF-β1 for 72h to induce fibrotic changes; and were then treated with GTX-11m for an additional 72h. <bold>Results:</bold> In hNLFs, GTX-11m strongly downregulated Smad2/3 phosphorylation as well as gene and protein expression of extracellular matrix (ECM) components after TGF-β1 stimulation: ACTA2, TNC, MMP2, and FN1 (p<0.05). In hNLFs, GTX-11m anti-fibrotic effects equaled or surpassed that of nintedanib and pirfenidone. In PCLS, GTX-11m effectively reduced ECM marker gene expression compared to TGF-β1 alone: COL3A1, VIM, CTGF and MMP7 (p<0.05). Moreover, GTX-11m induced FoxF1 and restored the expression of fibroblast to myofibroblast transition markers CDH11 and N-cadherin in hNLFs and PCLS. <bold>Conclusions:</bold> GTX-11m beneficial effects in hNLFs and PCLS, i.e. reduction in Smads activation and decrease of fibrotic signatures, validate previous results in bleomycin-induced pulmonary fibrosis model and in ILD lung fibroblasts. In sum, GTX-11 holds great promise as a therapeutic drug for fibrotic ILD and is entering Phase I clinical trials 2024.