Early data from a Phase 1b clinical trial show that the investigational therapy TD-1473 for patients with ulcerative colitis (UC) has demonstrated targeted action and effectiveness, according to the therapy’s developer and study sponsor, Theravance Biopharma.
Preliminary data are from four weeks of treatment. The ongoing study (NCT02818686), which currently is recruiting participants, is for patients with moderate to severe active UC.
TD-1473 is an orally administered, highly specific inhibitor of the Janus kinase (JAK) family of enzymes, which plays a key role in inflammation. Most importantly, TD-1473’s activity is restricted to the intestinal tract, which prevents the risk of systemic exposure and unwanted side effects.
The study was designed to evaluate the treatment’s safety, tolerability, and pharmacokinetics (a therapy’s behavior in the body) in UC patients during a 28-day period. Additional endpoints include assessing TD-1473’s biologic effects by analyzing disease biomarkers and performing a thorough evaluation of clinical and endoscopic parameters.
In the exploratory study, 10 patients from the first cohort received 80 mg of TD-1473 once a day for 28 days, while a control group of three patients received a placebo.
Preliminary results from the first cohort revealed that TD-1473 induced a localized response (restricted to the intestine) with minimal systemic exposure. These results are similar to those observed in a Phase 1 study with healthy volunteers.
Treatment with TD-1473 was not associated with impairment to patients’ immune systems (immunosuppression), as they showed no differences in infections and the number of several key immune cells including leukocytes, neutrophils, and lymphocytes compared with placebo controls.
Some patients who received TD-1473 experienced improvements in several disease parameters, including a reduction in rectal bleeding and biomarkers for ulcerative colitis, such as serum C-reactive protein (CRP) and fecal calprotectin (FC), when compared with controls. Researchers also detected lower cytokine activity in tissue samples from treated patients and an overall improvement in intestinal mucosal healing.
Treatment with TD-1473 resulted in no moderate or serious adverse events. Researchers observed only mild side effects, with none requiring study discontinuation.
The trial aims to recruit patients for two additional cohorts to evaluate TD-1473’s effectiveness in three doses – 80 mg, 20 mg, and 270 mg – versus placebo-matched controls.
“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,” William Sandborn, MD, chief of the University of California at San Diego’s Gastroenterology Division, said in a press release. “These early signals of efficacy with limited levels of systemic exposure position TD-1473 as a promising potential treatment for ulcerative colitis.”
Brett Haumann, MD, Theravance Biopharma’s chief medical officer, also was upbeat, saying, “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.”
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