Theravance Biopharma Reports Data from TD-1473 Phase 1b Four-Week Study in Oral Late-Breaker Presentation at UEG Week 2018
The Phase 1b exploratory study was designed to evaluate the safety, tolerability, and pharmacokinetics (PK) of TD-1473 over a 28-day treatment period. In addition, 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 UEG Week 2018 include:
Clinical Response Rate:
- Trends were observed for higher rates of clinical response 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.
Endoscopy Improvement: ≥ 1-point reduction in Mayo endoscopic subscore1 (assessed by central reading):
- Trends were observed for higher rates of endoscopy improvement for TD-1473 after four weeks of treatment as compared to placebo. A ≥ 1-point reduction in Mayo endoscopic subscore 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.
Evidence of Mucosal Healing:
- Trends were observed for higher rates of mucosal healing 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.
Rectal Bleeding Improvement: ≥ 1-point reduction in Mayo rectal bleeding subscore1:
- Trends were observed for higher rates of improvement in rectal bleeding for TD-1473 in the 80 mg and 270 mg cohorts after four weeks of treatment as compared to placebo. A ≥ 1-point reduction in Mayo rectal bleeding subscore 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.
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 required for localized JAK inhibition at the site of inflammation in the 80 mg and 270 mg cohorts.
- No evidence of systemic immunosuppression, and no alterations in total leukocytes, neutrophils, or lymphocytes in patients receiving TD-1473, relative to patients receiving placebo.
Safety and Tolerability:
- 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. There were no serious infections, tuberculosis or other opportunistic infections, bowel perforations, or herpes zoster. Additionally, there were no meaningful changes in hepatic, renal or hematologic laboratory parameters. While high-density lipoprotein (HDL) showed dose-dependent increases from baseline (possibly related to reduced inflammation), there was no evidence of elevated low-density lipoprotein (LDL) relative to placebo or baseline.
"It is very promising to see such clinical and biomarker improvements in ulcerative colitis patients over a short duration of therapy as seen in this Phase 1 study. While the small size of this trial did not allow for these results to achieve statistical significance, the observed trends are very encouraging, particularly with minimal systemic exposure of TD-1473 found at all doses," said Julian Panés, M.D., Chief of the Inflammatory Bowel Disease Unit at Hospital Clínic of
TD-1473 is a novel, potent, 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 and myelofibrosis, and have demonstrated therapeutic benefit for patients with 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 an oral, 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 our relentless pursuit of this objective, we strive to apply insight and innovation at each stage of our business, including research, development and commercialization, and utilize both internal capabilities and those of partners around the world. Our research efforts are focused in the areas of inflammation and immunology. Our research goal is to design localized medicines that target diseased tissues, without systemic exposure, in order to maximize patient benefit and minimize risk. These efforts leverage years of experience in developing localized medicines for the lungs to treat respiratory disease. The first potential medicine to emerge from our research focus on immunology and localized treatments is an oral, gut-selective pan-Janus kinase (JAK) inhibitor, currently in development to treat a range of inflammatory intestinal diseases. Our pipeline of internally discovered product candidates will continue to evolve with the goal of creating transformational medicines to address the significant needs of patients.
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