The Company is developing TD-1473 as an investigational compound with the potential to treat a range of inflammatory intestinal diseases.
TD-1473 is an internally-discovered JAK inhibitor that has demonstrated a high affinity for each of the JAK family of enzymes (JAK1, JAK2, JAK3 and TYK2). Through the inhibition of these enzymes, TD-1473 interferes with the JAK/STAT signaling pathway and, in turn, modulates the activity of a wide range of pro-inflammatory cytokines.
Importantly, TD-1473 is a GI-targeted treatment specifically designed to distribute adequately and exclusively to the tissues of the GI tract and to minimize systemic exposure.
The Phase 1 trial is a randomized, double-blind, placebo-controlled, single ascending dose (SAD) and multiple ascending dose (MAD) study in healthy subjects. The primary objective of the study will be evaluation of the safety and tolerability of single ascending doses and multiple ascending doses of TD-1473 in healthy subjects.
A key secondary objective of the trial will be the characterization of pharmacokinetics related to TD-1473, which will help determine the amount of TD-1473 that enters systemic circulation following oral administration.
Theravance Biopharma senior vice president, research and development Mathai Mammen said: "In the past month we have advanced two novel, potentially best-in-class programs from our internal discovery and research engine into Phase 1 clinical trials. This is a true testament to the talent and dedication of our research team as we work to identify and develop the Company’s next wave of impactful medicines.
"We are excited about the therapeutic potential of TD-1473, and in particular about our targeted approach which seeks to maximize the therapeutic potential of JAK inhibition in the affected areas of the gastrointestinal tract, while minimizing the safety and tolerability concerns associated with systemic JAK blockade. Our ability to create a pan-JAK inhibitor that is targeted specifically to the GI tract may enable us to offer patients with ulcerative colitis and other inflammatory intestinal diseases a treatment option that significantly improves upon currently available therapeutics."
Findings from a preclinical study in models of colitis evaluating TD-1473 and tofacitinib demonstrated that both compounds significantly reduced colitis manifestations. However, at doses providing similar reductions in colitis manifestations, the systemic exposure of TD-1473 was much lower than that of tofacitinib. This suggests that TD-1473 may be able to provide an effective treatment for colitis with reduced potential for systemically-mediated adverse events.
Tofacitinib is a pan-JAK inhibitor approved for second-line treatment of adults with moderate to severe rheumatoid arthritis with ongoing clinical studies to evaluate its effectiveness in treating ulcerative colitis.
About Gastrointestinal (GI)-Targeted Pan-Janus (JAK) Kinase Inhibition
JAK inhibitors function by inhibiting the activity of one or more of the Janus kinase family of enzymes (JAK1, JAK2, JAK3, TYK2) that play a key role in cytokine signaling. Inhibiting these JAK enzymes interferes with the JAK/STAT signaling pathway and, in turn, modulates the activity of a wide range of pro-inflammatory cytokines.
JAK inhibitors are currently approved for the treatment of rheumatoid arthritis and are also being evaluated as potential therapies for ulcerative colitis. However, these non-targeted products are known to have side effects based on their systemic exposure.
Theravance Biopharma is focused on utilizing targeted JAK inhibitors for potential treatment of inflammatory intestinal diseases including ulcerative colitis, which affects roughly 700,000 patients in the United States.
While currently available treatments for ulcerative colitis have systemic safety liabilities and limited efficacy, Theravance Biopharma believes that the company’s targeted approach to JAK inhibition has the potential to treat the inflammation in the tissues of the GI tract while minimizing the risk of systemic side effects.