Theravance doses first patient in phase 1b trial of TD-1473 in moderate to severe ulcerative colitis

TD-1473 is a novel, potent, orally administered and intestinally restricted pan-Janus kinase (JAK) inhibitor in clinical development, with the potential to treat a range of inflammatory intestinal diseases.

Importantly, TD-1473 is specifically designed to act directly at the site of inflammation in the intestinal wall with minimal systemic exposure.

The Phase 1b trial is a multi-center, randomized, double-blind, multi-dose, placebo-controlled study in 40 patients with moderate to severe ulcerative colitis. Patients will be randomized to receive one of three doses of TD-1473 or placebo for 28 days in sequential fashion.

The primary objectives of the study will include evaluation of the safety and tolerability of TD-1473 administered for 28 days, as well as assessment of the compound's plasma exposure following administration.

A key secondary objective of the trial will be the evaluation of the effect of TD-1473 on levels of a range of key ulcerative colitis biomarkers, including C-reactive protein (CRP) and fecal calprotectin (FC).

Additionally, investigators will evaluate a number of exploratory objectives, including changes in partial Mayo score and improvement in disease activity through endoscopic and histologic assessments. The Company expects data from the Phase 1b trial to be available in mid-2017.

Theravance Biopharma recently announced positive results from a Phase 1 clinical trial of TD-1473 in healthy volunteers demonstrating the compound to be generally well tolerated as a single dose (up to 1000 mg) and as a daily dose (up to 300 mg) given for 14 days. There were no serious adverse events and the only adverse events reported in subjects dosed with TD-1473 were considered mild in severity and short in duration, with none leading to study discontinuation.

Furthermore, findings from the Phase 1 trial related to systemic exposure and stool concentrations of TD-1473 support the Company's perspective that a therapeutically relevant level of TD-1473 can be delivered to and penetrate the colon wall with minimal release into the systemic circulation.

Brett Haumann, MD, Chief Medical Officer at Theravance Biopharma, said: "The start of our Phase 1b clinical trial is the latest development milestone for our TD-1473 program, which we believe represents a potentially transformative approach to treating inflammatory intestinal diseases. The totality of the data generated in the program to date provides support for our strategy of targeting JAK inhibition to affected tissues within the intestinal tract in order to achieve desired therapeutic results with a favorable safety and tolerability profile. 

"In addition to safety and tolerability objectives, this Phase 1b study includes exploratory endpoints aimed at assessing potential efficacy measures in ulcerative colitis patients. By providing initial insight into the impact of TD-1473 on such outcomes as clinical response and mucosal healing, this trial will help guide future studies of this unique, intestinally restricted pan-JAK inhibitor."

About Intestinally Restricted 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 diseases, such as rheumatoid arthritis, myelofibrosis and psoriasis, and have demonstrated therapeutic benefit for patients with ulcerative colitis. However, these products are known to have side effects associated with systemic exposure.

TD-1473 is an internally-discovered JAK inhibitor that has demonstrated a high affinity for each of the JAK family of enzymes. Importantly, TD-1473 is an intestinally restricted treatment specifically designed to distribute adequately and predominantly to the tissues of the intestinal tract, treating inflammation in those tissues while minimizing systemic exposure.

Theravance Biopharma is focused on utilizing targeted JAK inhibitors for potential treatment of a range of inflammatory intestinal diseases including ulcerative colitis, which affects roughly 700,000 patients in the United States.