P-177 Safety, Tolerability, and Pharmacokinetics of the Intestine-Restricted Oral Pan-Jak Inhibitor TD-1473 After Single and Multiple Oral Doses in Healthy Subjects

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Abstract

Background:

TD-1473 is a novel, intestine-restricted, pan-Janus kinase (JAK) inhibitor being developed for the treatment of inflammatory bowel diseases, including ulcerative colitis. JAK inhibition has demonstrated efficacy for inducing remission in ulcerative colitis 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 locally inhibit JAK in the gastrointestinal tract following oral dosing while minimizing the systemic exposure and associated systemic adverse events. This double-blind, placebo-controlled, dose-escalation study in healthy subjects was conducted to evaluate the safety, tolerability, and pharmacokinetics after single and multiple oral doses of TD-1473.

Methods:

Healthy male and female subjects (n = 8 per cohort) were randomized to receive oral TD-1473 or placebo in a 3:1 ratio, respectively, for each dose cohort in the single ascending dose (SAD, 10–1000 mg) or the 14-day multiple ascending dose (MAD, 10–300 mg) parts of the study. Safety and tolerability were assessed by monitoring treatment-emergent adverse events (TEAEs), electrocardiograms (ECGs), vital signs, and laboratory parameters. Pharmacokinetics were 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 part of the study was 33% (10/30) for subjects receiving TD-1473 and 40% (4/10) for subjects receiving placebo. TEAEs incidence in the MAD part of the study was 58% (14/24) for subjects receiving TD-1473 and 88% (7/8) for subjects receiving 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 hours. Median Tmax values ranged between 0.51 and 2.00 hours. Systemic TD-1473 exposures were low; Cmax and AUC0-24 increased in a near 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 1.36–1.63, 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 and 8662 L/hr and 113500 to 571300 L, respectively. The fraction of the dose excreted as unchanged TD-1473 in urine through 24 hours post-dosing after single and multiple doses of TD-1473 was <0.500%.

Conclusions:

TD-1473 exhibits low systemic concentrations (consistent with intestine restriction) and displays approximately dose-proportional pharmacokinetics following single and multiple oral doses of up to 1000 and 300 mg, respectively. TD-1473 was generally well tolerated in this study. Results are supportive of further development of TD-1473 for the treatment of inflammatory bowel diseases, including ulcerative colitis.

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