Theravance Biopharma Reports Encouraging Data from First Cohort of Patients in Phase 1b Clinical Trial of TD-1473 in Ulcerative Colitis
The Phase 1b exploratory study is designed to evaluate the safety, tolerability, and pharmacokinetics (PK) of TD-1473 over a 28-day treatment period. In addition, the study incorporates biomarker analysis and clinical, endoscopic, and histologic assessments to evaluate biological effect. The first cohort of patients included 10 patients receiving 80 mg of TD-1473 once daily for 28 days and three receiving matched placebo.
Data from the first cohort of patients demonstrated encouraging evidence of localized biological activity for TD-1473 and included the following:
- Minimal systemic exposure of TD-1473 based on evaluation of plasma levels, consistent with data seen in a previously conducted Phase 1 study of healthy volunteers
- No evidence of systemic immunosuppression or infections, including no occurrences of zoster reactivation. In addition, no alterations in total leukocytes, neutrophils, or lymphocytes in patients receiving TD-1473, relative to patients receiving placebo
- 7 of 10 patients receiving TD-1473 experienced ≥ 1-point reduction in Mayo rectal bleeding subscore1, compared to 1 of 3 patients receiving placebo
- 3 of 10 patients receiving TD-1473 experienced ≥ 1-point reduction in Mayo endoscopic subscore1 (assessed by central reading), compared to none of the patients receiving placebo
- 2 of 10 patients receiving TD-1473 showed evidence of mucosal healing, based on Mayo endoscopic subscore1, compared to none of the patients receiving placebo
- 2 of 10 patients receiving TD-1473 achieved clinical response by total
Mayo Score1, compared to none of the patients receiving placebo
- 4 of 10 patients receiving TD-1473 achieved clinical response by partial Mayo score1, compared to 1 of 3 patients receiving placebo
- Reductions in serum C-reactive protein (CRP) and fecal calprotectin (FC), two surrogate biomarkers for ulcerative colitis, in patients receiving TD-1473
- Reduction in levels of phosphorylated signal transducer and activator of transcription 1 (pSTAT1), indicative of diminished cytokine activity, in tissue biopsies from patients receiving TD-1473
"In a small Phase 1b trial not statistically powered to demonstrate efficacy, it is remarkable to see compelling directional change in local biological effect for patients receiving TD-1473, particularly a change in rectal bleeding and endoscopic subscores. Further, these effects were measured after just four weeks of treatment, a timeframe shorter than the typical induction endpoint in ulcerative colitis trials," said
In the first cohort, there were no moderate or serious adverse events related to TD-1473, and the only adverse events reported in patients dosed with TD-1473 were considered mild in severity, with none leading to study discontinuation. Furthermore, evaluations of chemistry and hematologic parameters typically affected by systemically active JAK inhibitors, including natural killer cells and lipid levels, showed no alterations relative to placebo.
"These data provide encouraging initial evidence of TD-1473's clinical activity in our first cohort of ulcerative colitis patients. In addition to seeing improvements in measurements of disease activity within four weeks of treatment, we have seen minimal systemic exposure and a favorable tolerability profile that is consistent with the desired target product profile," said
Top-line results from the entire Phase 1b study will be available following completion of the two remaining cohorts, with an objective of evaluating both a higher and lower dose of TD-1473 in ulcerative colitis patients. On the basis of the encouraging data generated in the first cohort of patients, the Company plans to progress TD-1473 into a larger induction and maintenance study in 2018.
About the Phase 1b Study
The ongoing Phase 1b trial of TD-1473 is a multi-center, randomized, double-blind, multi-dose, placebo-controlled study in 40 patients with moderate to severe active ulcerative colitis. Three doses of TD-1473 (80, 20, and 270 mg) are being evaluated versus placebo. The primary objectives of the study are to evaluate the safety and tolerability of TD-1473 administered for 28 days, as well as to assess the compound's plasma exposure following administration. Secondary objectives of the study include the evaluation of the effect of TD-1473 on ulcerative colitis disease activity through biomarker analysis and clinical, endoscopic, and histologic assessments.
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 and myelofibrosis, 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.
Our pipeline of internally discovered product candidates includes potential best-in-class medicines to address the unmet needs of patients being treated for serious conditions primarily in the acute care setting. VIBATIV® (telavancin), our first commercial product, is a once-daily dual-mechanism antibiotic approved in the U.S.,
In addition, we have an economic interest in future payments that may be made by
For more information, please visit www.theravance.com.
THERAVANCE®, the Cross/Star logo and VIBATIV® are registered trademarks of the
This press release contains certain "forward-looking" statements as that term is defined in the Private Securities Litigation Reform Act of 1995 regarding, among other things, statements relating to goals, plans, objectives, expectations and future events. Theravance Biopharma intends such forward-looking statements to be covered by the safe harbor provisions for forward-looking statements contained in Section 21E of the Securities Exchange Act of 1934 and the Private Securities Litigation Reform Act of 1995. Examples of such statements include statements relating to: the company's strategies, plans and objectives, the company's regulatory strategies and timing of clinical studies, the potential benefits and mechanisms of action of the company's product and product candidates, the company's expectations for product candidates through development, potential regulatory approval and commercialization (including their potential as components of combination therapies) and the company's expectations for product sales. These statements are based on the current estimates and assumptions of the management of
1 Gastroenterology Vol. 148,
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