Abstract
A need exists for effective and safe oral therapeutic options for moderate to severe ulcerative colitis (UC). TD-1473 is an orally administered and gut-selective pan-Janus kinase (JAK) inhibitor that was well tolerated by healthy volunteers when administered up to 300mg once daily for 14 days with very low systemic exposure.
To assess the safety, tolerability, and pharmacokinetics (PK) of TD-1473 in subjects with moderately-to-severely active UC.
In this double-blind placebo-controlled multicenter phase 1b study, 40 subjects were enrolled and administered placebo (n=9), 20mg (n=10), 80mg (n=10), or 270mg (n=11) TD-1473 once daily for 28 days after meeting eligibility criteria (including Mayo rectal bleeding subscore of ≥ 1, stool frequency subscore of ≥ 1, and endoscopic subscore of ≥ 2). Safety, PK, clinical outcomes, and biomarkers were evaluated.
The mean age was 44 years with 65% of subjects being male and a median disease duration of 3.1 years. The baseline mean total Mayo Score ranged from 8.2 (80mg) to 9.6 (20mg), with an overall mean of 8.9. All subjects completed dosing, except for one subject at 20mg who stopped taking TD-1473 at Day 5 due to lack of efficacy. Two serious treatment-emergent adverse events consisted of hospitalization for UC exacerbation (20mg and 80mg). No cases of serious or opportunistic infection or signals for adverse abnormalities in hematologic or chemistry laboratory parameters were observed. Plasma exposures were low and consistent with those observed previously in healthy subjects. Colonic tissue concentrations of TD-1473 were higher than plasma and in the range needed for JAK inhibition. There were trends for higher rates of mucosal healing and improvement by ≥ 1 point in rectal bleeding and endoscopy, relative to placebo (Table). C-reactive protein (CRP) decreased relative to placebo at all dose levels. Fecal calprotectin decreased in subjects treated with 80mg and 270mg. High variability was observed for CRP and fecal calprotectin at all dose levels.Discussion/
TD-1473 was well tolerated over 4 weeks with evidence of gut selectivity, low systemic exposure, and signals for clinical and biomarker activity in subjects with moderately-to-severely active UC.
Key Efficacy, Biomarker and PK Results in Subjects with Moderately-to-Severely Active UC after 28 Days of Treatment with TD-1473 or Placebo
