P0334 AGMB-129, an investigational ALK5 inhibitor for the treatment of Fibrostenosing Crohn’s Disease (FSCD), shows gastrointestinal (GI) restricted pharmacokinetics (PK) and a favorable safety profile in healthy subjects

Abstract Background AGMB-129 is an oral GI-restricted small molecule inhibitor of Activin Receptor-Like Kinase 5 (ALK5) intended for the treatment of Fibrostenosing Crohn’s Disease (FSCD). AGMB-129 potently blocks signaling of the key pro-fibrotic cytokine Transforming Growth Factor-b (TGFβ) and is designed to avoid clinically relevant systemic exposure via high first-pass metabolism to overcome the severe toxicities reported for prior systemic ALK5 inhibitors. This study evaluated the safety, systemic and ileal PK of single- and multiple-doses AGMB-129 in healthy subjects. Methods This was a randomized, double-blind, placebo-controlled, single and multiple ascending dose study in healthy subjects who received single doses (SD) up to 1200mg or multiple doses (MD) up to 400mg once-daily (QD) for 5 days or 200mg twice-daily (BID) or for 10 days, or placebo. The effect of food on PK of 400 mg SD was evaluated in a cross-over fashion. Results 82 participants (60 male/22 female) completed the study except for 2 subjects on placebo (both due to viral infection). After oral dosing AGMB-129 was rapidly absorbed with a median time to maximum plasma concentration (Tmax) of 0.7-1.5h, followed by a rapid decline in plasma concentration with geometric mean (gMean) concentration dropping <1 ng/mL within 4 to 8h post-dose resulting in low systemic exposure at all doses. The gMean maximum AGMB-129 plasma concentration (Cmax) after 1200mg SD was 63.3 ng/mL. After MD QD dosing, AGMB-129 accumulation based on the area-under-the-curve (AUC) was limited (accumulation ratio <2). After AGMB-129 200 mg BID, the gMean Cmax on Day 7 was 46.4ng/mL, and the gMean AGMB-129 concentration in ileal biopsies at 2h post-dose on Day 10 was 4244 ng/mL. MET-158 (inactive against ALK5) was the main circulating metabolite (gMean AUCMET-158/AUCAGMB-129 > 100). After intake with food, AGMB-129 Tmax was delayed by about 2h, Cmax and AUC increased by 1.3- and 2-fold, respectively, and intersubject variability was reduced compared to fasted intake. AGMB-129 was safe and well tolerated at all dosages. There were no dose-limiting toxicities, deaths, serious adverse events, or clinically-relevant abnormalities in laboratory results, vital signs or ECG parameters. Conclusion After oral dosing, low systemic and high ileal exposure to AGMB-129 was observed. This confirms the GI-restricted profile of AGMB-129 with systemic exposure more than 100-fold lower than previously observed for systemic ALK5 inhibitors [Rodón 2015, Jung 2020]. AGMB-129 was safe and well-tolerated at all dosages and is the first ALK5 inhibitor suitable for continuous daily dosing in humans. The STENOVA Ph2a study of AGMB-129 up to 200 mg BID in symptomatic FSCD is ongoing (NCT05843578). References Rodon J, Carducci M, Sepulveda-Sanchez JM, et al. Pharmacokinetic, pharmacodynamic and biomarker evaluation of transforming growth factor-β receptor I kinase inhibitor, galunisertib, in phase 1 study in patients with advanced cancer. Invest New Drugs (2015) 33:357-370. Jung SY, Hwang S, Clarke JM, et al. Pharmacokinetic characteristics of vactosertib, a new activin receptor-like kinase 5 inhibitor, in patients with advanced solid tumors in a first-in-human phase 1 study. Invest New Drugs (2020) 38:812-820.