Theravance Biopharma, Inc., recently reported positive data from its Phase 1 clinical trial assessing TD-1473, a new and oral pan-Janus kinase (JAK) inhibitor designed to enter the gastrointestinal tract and target inflammation without significant systemic exposure.
Proinflammatory cytokines play an important role in inflammatory bowel disease (IBD), many of which signal via the JAK/signal transducer and activator of transcription (STAT) pathway.
The study was a placebo-controlled, randomized, single ascending dose (SAD) and multiple ascending dose (MAD) Phase 1 trial (NCT02657122) assessing TD-1473 in healthy subjects. Its primary objective was to evaluate the safety and tolerability of TD-1473 SAD and MAD in participants, and a key secondary objective was to characterize pharmacokinetics related to TD-1473, to help determine the amount of drug that enters systemic circulation following oral dosing. The drug is being developed to treat IBDs, including ulcerative colitis.
Results showed that treatment with TD-1473 is safe and well-tolerated as a single dose (up to 1000 mg), and as a daily dose (up to 300 mg) given for 14 days, without causing serious adverse reactions.
In terms of systemic circulation, the results demonstrated that TD-1473 exposures were low relative to that seen for tofacitinib, a JAK inhibitor recently tested in Phase 3 trials as a potential ulcerative colitis treatment. Compared to the plasma exposure of tofacitinib at twice daily doses of 10 mg, the plasma exposures of TD-1473 at daily doses of 30 mg and 100 mg were about 75-fold and 15-fold lower, respectively, Theravance reported in a news release.
Additionally, vital sign and ECG assessments after TD-1473 administration did not show any clinically relevant changes from baseline, and no clinically significant changes in chemistry or hematology parameters were reported in those dosed with TD-1473 compared to placebo.
Trial participants also showed high stool concentrations of TD-1473, similar to concentrations related with efficacy in preclinical models of ulcerative colitis. Preclinical trial results also showed penetration of TD-1473 into the intestinal membrane, as well as into the intestinal wall.
Overall, TD-1473 program results support the company’s view that a therapeutically relevant level of TD-1473 can be delivered to and penetrate the colon wall, with minimal release into systemic circulation. Theravance plans to begin a Phase 1b study of TD-1473 in patients with ulcerative colitis later this year.
“We are encouraged by the data from this initial clinical trial of TD-1473, as they provide validation for our strategy of targeting JAK inhibition to the affected tissues within the GI [gastrointestinal] tract in order to achieve desired therapeutic results with a favorable safety and tolerability profile,” Brett Haumann, chief medical officer at Theravance Biopharma said in the release. “We look forward to initiating the planned Phase 1b trial in patients as the next step in our efforts to develop a treatment for ulcerative colitis and other inflammatory intestinal diseases. We believe TD-1473 has the potential to provide significant improvements over current and emerging therapeutic options.”
Data from preclinical studies assessing TD-1473 and tofacitinib showed that both drugs reduced the scores of disease activity, however, when considering doses offering comparable efficacy, the systemic exposure of TD-1473 was lower than the systemic exposure of tofacitinib, and TD-1473 did not decrease the counts of systemic immune cells.
Based on this data, the company believes that TD-1473 might be a breakthrough therapeutic approach for the treatment of ulcerative colitis without the risk associated with systemically active treatment options now in common use. In addition, the potential for a beneficial safety profile may allow TD-1473, if approved, to be offered to patients in early disease stages.