Background: TD-1473 is a novel, intestine-restricted, pan-Janus kinase (JAK) inhibitor being developed for the treatment of inflammatory bowel diseases (IBD), including ulcerative colitis (UC). JAK inhibition has demonstrated efficacy for inducing remission in UC patients using a systemically active oral agent (tofacitinib), but its use is associated with a risk of serious systemic adverse effects. TD-1473 was designed to inhibit JAK in the gastrointestinal tract following oral dosing while minimizing systemic exposure and associated adverse events. This double-blind, placebo-controlled, dose-escalation study in healthy subjects was conducted to evaluate the safety, tolerability, and PK after single and multiple oral doses of TD-1473.
Methods: Healthy male and female subjects (n=8 per cohort) were randomized to receive TD-1473 or placebo (3:1 ratio) for each cohort in the single ascending dose (SAD, 10 to 1000mg) or the 14-day multiple ascending dose (MAD, 10 to 300mg) parts of the study. Safety and tolerability were assessed by monitoring treatment-emergent adverse events (TEAEs), electrocardiograms (ECGs), vital signs, and laboratory parameters. PK was assessed in plasma and urine.
Results: No moderate, severe, or serious TEAEs were reported in subjects administered TD-1473; no TEAEs led to study discontinuation. TEAEs incidence in the SAD was 33% (10/30) for TD-1473 and 40% (4/10) for placebo. TEAEs incidence in the MAD was 58% (14/24) for TD-1473 and 88% (7/8) for placebo. No clinically meaningful treatment-related effects on vital signs, clinical laboratory, or ECG parameters were observed.
TD-1473 was eliminated in a multiphasic manner with mean terminal elimination half-life values ranging from 4.40 to 43.88 hrs. Median Tmax values ranged between 0.51 to 2.00 hrs. Systemic TD-1473 exposures were low; Cmax and AUC0–24 increased in a dose-proportional manner with minimal accumulation as assessed on Day 14 (Cmax and AUC0–24 accumulation ratios from Day 1 to Day 14 ranged from 0.52 to 2.27 and 1.36 to 1.63, respectively). Steady-state was achieved after 7 to 9 days of dosing. Mean steady-state apparent clearance (CL/F) and volume of distribution (V/F) ranged between 5519 to 8662 L/hr and 113500 to 571300 L, respectively. The fraction of the dose excreted as unchanged TD-1473 in urine through 24 hours after single and multiple doses of TD-1473 was <0.500%.
Conclusions: TD-1473 exhibits low systemic concentrations (consistent with intestine restriction) with dose-proportional PK following single (up to 1000mg) and multiple doses (up to 300 mg). TD-1473 was generally well tolerated in this study. Results are supportive of further development of TD-1473 for the treatment of IBD, including UC.