D29-04 AGMB-447, an Inhaled Lung-Restricted TGFβR1/ALK5 Inhibitor Intended for the Treatment of Idiopathic Pulmonary Fibrosis, Shows Robust Anti-Fibrotic Activity and Target Engagement in Preclinical Species and Healthy Subjects

Rationale TGFβ signaling plays a central role in the pathogenesis of fibrotic lung diseases, including idiopathic pulmonary fibrosis (IPF). However, the development of systemic inhibitors has been hampered by non-clinical findings of cardiac toxicity limiting clinical dosing to intermittent schedules. AGMB-447 is a novel inhaled small molecule inhibitor of TGFβR1/ALK5, specifically designed for localized action in the lung. Its high pulmonary retention and rapid hydrolysis aim to maximize lung efficacy while minimizing systemic exposure and associated safety risks. Methods The inhibitory potency of AGMB-447 against ALK5 was evaluated in biochemical and cellular (A549-based) assays. Anti-fibrotic activity was assessed by measuring expression of fibrotic biomarkers COL1A, FN1, PAI-1 and ITGB6 in lung tissue, precision-cut lung slices (PCLS) and lung fibroblasts. In vivo efficacy was tested in a 21-day bleomycin-induced mouse lung fibrosis model, with once-daily intratracheal administration of AGMB-447 from day 7 onwards. Target engagement was assessed by quantifying the phospho/total SMAD3 ratio in lung tissue of mice receiving AGMB-447 oropharyngeally, as well as in broncho alveolar lavage (BAL) cells collected from healthy subjects in a Phase 1 study assessing safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple inhaled doses of AGMB-447. Results AGMB-447 is a potent inhibitor of the serine/threonine kinase activity of ALK5 and reduces fibrotic marker expression in TGFβ-stimulated primary human lung fibroblast and PCLS. In vivo, local administration of AGMB-447 to mice significantly decreased fibrosis markers in lung tissue and demonstrated strong anti-fibrotic efficacy in the therapeutic setting of the mouse bleomycin-induced fibrosis model. Preclinical studies of inhaled AGMB-447 support a lung-restricted distribution, with lung-to-plasma exposure ratios exceeding 2000-fold. In mice, five-day dosing of inhaled AGMB-447 reduced the phospho/total SMAD3 ratio in lung tissue, comparable to a high dose of a systemically acting benchmark ALK5 inhibitor. In healthy subjects, inhaled AGMB-447 was generally safe and well tolerated and showed low systemic exposure with high lung levels. Furthermore, a dose- and time-dependent reduction in phospho/total SMAD3 ratio in alveolar cells confirmed local target engagement and suppression of TGFβ signaling in the lung. Conclusion AGMB-447 exhibits a lung-restricted pharmacokinetic profile that overcomes the toxicity limitations of earlier systemic ALK5 inhibitors, while achieving robust inhibition of the lung TGFβ pathway in both preclinical models and humans. Collectively, these strong translational data support the further clinical development of AGMB-447 as a potential treatment for fibrotic lung diseases with high unmet medical need, such as IPF.