Theravance Biopharma Reports Data from Phase 1b Study of TD-1473 in Oral Presentation at Digestive Disease Week (DDW) 2019
The Phase 1b exploratory study was designed to evaluate the safety and pharmacokinetics (PK) of TD-1473 over a 28-day treatment period. In addition, although not powered for these observations, the study incorporated biomarker analysis and clinical, endoscopic, and histologic assessments as exploratory endpoints to evaluate biological effect. The trial enrolled 40 patients across four treatment arms: placebo (n=9); TD-1473 20 mg/daily (n=10); TD-1473 80 mg/daily (n=10); and, TD-1473 270 mg/daily (n=11).
Study results presented at DDW 2019 include:
Clinical Response Rate and Mucosal Healing:
- Numerically higher rates of clinical response were observed for TD-1473 after four weeks of treatment as compared to placebo. Clinical response, which was defined as a reduction in total Mayo score of ≥ 3 points and ≥ 30%, with a reduction in rectal bleeding subscore by ≥ 1 point or an absolute rectal bleeding subscore of ≤ 1 point, was achieved by 2 of 10 patients (20%) in the 20 mg cohort, 2 of 10 patients (20%) in the 80 mg cohort, and 6 of 11 patients (55%) in the 270 mg cohort, compared to 1 of 9 patients (11%) in placebo group.
- Numerically higher rates of mucosal healing were observed for TD-1473 after four weeks of treatment as compared to placebo. Mucosal healing, categorized as having an endoscopic subscore ≤ 1, was achieved by 2 of 10 patients (20%) in the 20 mg cohort, 2 of 10 patients (20%) in the 80 mg cohort, and 1 of 11 patients (9%) in the 270 mg cohort, compared to 0 of 9 patients (0%) in placebo group.
Endoscopic and Rectal Bleeding Improvements:
- Numerically higher rates of endoscopy improvement were observed for TD-1473 after four weeks of treatment as compared to placebo. Endoscopic improvement, which was defined as a ≥ 1-point reduction in Mayo endoscopic subscore1 (assessed by central reading), was achieved by 2 of 10 patients (20%) in the 20 mg cohort, 3 of 10 patients (30%) in the 80 mg cohort, and 2 of 11 patients (18%) in the 270 mg cohort, compared to 0 of 9 patients (0%) in placebo group.
- Numerically higher rates of improvement in rectal bleeding were observed for TD-1473 in the 80 mg and 270 mg cohorts after four weeks of treatment as compared to placebo. Rectal bleeding improvement, which was defined as a ≥ 1-point reduction in Mayo rectal bleeding subscore1, was achieved by 3 of 10 patients (30%) in the 20 mg cohort, 7 of 10 patients (70%) in the 80 mg cohort, and 8 of 11 patients (73%) in the 270 mg cohort, compared to 4 of 9 patients (44%) in placebo group.
- Histologic activity was measured using the Robarts Histopathology Index (RHI), a histologic scoring system ranging from 0 (no UC disease activity) to 33 (severe UC disease activity). Patients in the 20 mg and 270 mg cohorts demonstrated average reductions in RHI score from baseline of 4.5 points and 5.3 points, respectively. This compared to an average RHI score reduction of 2.0 points from baseline in the placebo group.
Surrogate Inflammatory Biomarkers:
- Placebo-adjusted reductions in serum C-reactive protein (CRP) were seen in all TD-1473 cohorts, ranging from 57% to 70%.
- Placebo-adjusted reductions in fecal calprotectin (FC) were seen in the 80 mg and 270 mg cohorts, ranging from 26% to 31%.
Evidence of Gut-Selective Activity:
- Minimal systemic exposure to TD-1473 based on evaluation of plasma levels, consistent with data seen in a previously conducted Phase 1 study of healthy volunteers.
- Colonic tissue concentrations of TD-1473 were higher than plasma at respective dose levels and at or above those predicted to be required for localized JAK inhibition at the site of inflammation in the 80 mg and 270 mg cohorts.
- No evidence of systemic immunosuppression, as reflected by no alterations in total leukocytes, neutrophils, or lymphocytes in patients receiving TD-1473, relative to patients receiving placebo.
- TD-1473 was generally well tolerated in the study with no adverse events leading to study drug interruption or discontinuation. There were two serious adverse events (20 mg and 80 mg) which were characterized as hospitalizations for UC exacerbations, deemed by the reporting investigators as not related to study drug. There were no serious infections, tuberculosis or other opportunistic infections, bowel perforations, or herpes zoster. Additionally, there were no meaningful changes in hepatic, renal, lipid, or hematologic laboratory parameters.
"The totality and consistency of these data across a broad range of clinical, histologic and biomarker measures of UC disease activity after just four weeks of treatment is quite encouraging, despite the small number of patients enrolled in the study," said
"Systemically active JAK inhibitors have been shown to be effective in treating inflammatory diseases, but continue to be challenged by dose-limiting side effects that prevent such therapies from being used at the optimal dose.
TD-1473 is a novel, orally administered and gut-selective pan-JAK inhibitor in clinical development with the potential to treat a range of inflammatory intestinal diseases, including ulcerative colitis and Crohn's disease. In contrast to other oral JAK inhibitors under development for inflammatory bowel disease, TD-1473 is specifically designed to act locally at the site of inflammation in the intestinal wall thereby limiting systemic exposure.
About Gut-Selective 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 ulcerative colitis. However, these products are known to have side effects associated with their 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 a gut-selective treatment specifically designed to distribute adequately and predominantly to the tissues of the intestinal tract, treating inflammation in those tissues while minimizing its systemic exposure.
In pursuit of our purpose, we apply insights and innovation at each stage of our business and utilize our internal capabilities and those of partners around the world. We apply organ-selective expertise to biologically compelling targets to discover and develop medicines designed to treat underserved localized diseases and to limit systemic exposure, in order to maximize patient benefit and minimize risk. These efforts leverage years of experience in developing lung-selective medicines to treat respiratory disease, including
We have an economic interest in potential future payments from
For more information, please visit www.theravance.com.
THERAVANCE® and the Cross/Star logo 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 (including the data therefrom), the potential characteristics, benefits and mechanisms of action of the Company's product and product candidates, and the Company's expectations for product candidates through development and potential regulatory approval and commercialization (including their potential as components of combination therapies and their differentiation from other products or potential products). These statements are based on the current estimates and assumptions of the management of
1 Gastroenterology Vol. 148,
View original content to download multimedia:http://www.prnewswire.com/news-releases/theravance-biopharma-reports-data-from-phase-1b-study-of-td-1473-in-oral-presentation-at-digestive-disease-week-ddw-2019-300853312.html