Mucosal p-STAT1/3 correlates with histologic disease activity in Crohn's disease and is responsive to filgotinib.

The validity and relevance of histologic disease activity in Crohn's disease (CD) is unclear, owing to disconnects with endoscopic pathology. Here, we explore relationships between endoscopic, histologic, and molecular activity. This post hoc analysis of the Phase 2 FITZROY trial (NCT02048618) assessed baseline and week 10 (W10) inflammation across matched ileal and colonic segments in CD patients receiving filgotinib 200 mg (n = 42) vs placebo (n = 18). Macroscopic and microscopic disease were assessed by Simple Endoscopic Score for CD ulceration subscore (uSES-CD) and Global Histologic Activity Score activity subscore (aGHAS), respectively. Molecular activity was quantified by phosphorylated signal transducer and activator of transcription (pSTAT)1 and pSTAT3 in epithelium and nonepithelium. Segments were classified as "low" or "high" activity; correlations and concordance were calculated. Logistic regression identified W10 outcome predictors. Overall, 300 segments in 60 patients were assessed. Baseline uSES-CD and aGHAS correlations were 0.72 and 0.53 in colon and ileum, respectively. pSTAT levels had poor-to-moderate concordance with uSES-CD (κ range, 0.11-0.49) but moderate-to-good concordance with aGHAS (0.43-0.77). With filgotinib vs placebo, uSES-CD and aGHAS decreased in significantly more segments with high baseline uSES-CD and aGHAS, and significantly more segments with high baseline pSTAT improved at W10. pSTAT1 was more sensitive to change than uSES-CD and aGHAS. Low baseline pSTAT3 in colon nonepithelium predicted W10 low uSES-CD (P = .044). There was better concordance between histologic and molecular disease activity associated with higher sensitivity to change vs endoscopic severity in ileocolonic CD. Our results suggest histologic activity be included in the assessment of CD inflammatory burden.

Pharmacokinetics, Safety, and Tolerability of Selonsertib, an Apoptosis Signal-Regulating Kinase 1 (ASK1) Inhibitor, Following First-in-Human Single and Multiple Ascending Doses in Healthy Subjects.

BACKGROUND: Selonsertib is a first-in-class inhibitor of apoptosis signal-regulating kinase 1 (ASK1) with therapeutic potential for fibrotic diseases. This phase I study evaluated the safety, tolerability, pharmacokinetics (PK), and food effect of selonsertib in healthy subjects. METHODS: This was a double-blinded, randomized, placebo-controlled dose-escalation study. Healthy subjects received 1, 3, 10, 30, or 100 mg of selonsertib or placebo as single or multiple doses once daily for 14 days in the fasted state, or 30 mg or placebo single dose in the fed state. Blood and urine (single-dose cohorts only) samples for selonsertib PK were collected and safety was assessed throughout the study. Ex vivo pharmacodynamic (PD) assessment was performed in blood from a separate cohort of healthy donors using an auranofin-stimulated C-X-C motif chemokine ligand 1 (CXCL1) assay. RESULTS: Overall, 107 subjects (83 active, 24 placebo) were enrolled and randomized to 11 cohorts. Selonsertib was generally well tolerated; adverse events were generally mild to moderate. Selonsertib was rapidly absorbed with dose-proportional PK of both parent and inactive metabolite GS-607509. There was no food effect on selonsertib PK. Renal excretion was a minor pathway of selonsertib elimination. Selonsertib half maximal effective concentration (EC50) in human whole blood was determined to be 56 ng/mL. CONCLUSIONS: Selonsertib exhibited a favorable PK profile amenable to once-daily dosing without regard to food. PD data suggest pharmacologically relevant exposures were achieved in the dose range evaluated. Study results support further clinical development of selonsertib.