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Pan-JAK inhibitor for UC shows signs of targeted action in early study
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Theravance Biopharma’s oral, intestinally-restricted pan-Janus kinase inhibitor has shown signs of localized target engagement in an ongoing phase 1b trial of patients with moderate-to-severe active ulcerative colitis, the company announced.
TD-1473 is “an internally-discovered JAK inhibitor that has demonstrated a high affinity for each of the JAK family of enzymes,” and unlike other oral JAK inhibitors being developed for inflammatory bowel disease, it is “designed to act directly at the site of inflammation in the intestinal wall with minimal systemic exposure,” according to a press release.
“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 4 weeks of treatment, a timeframe shorter than the typical induction endpoint in ulcerative colitis trials,” William Sandborn, MD, chief of the division of gastroenterology of University of California, San Diego Health, said in the press release. “These early signals of efficacy with limited levels of systemic exposure position TD-1473 as a promising potential treatment for ulcerative colitis.”
In this ongoing multicenter, double-blind trial evaluating the safety, tolerability and pharmacokinetics of TD-1473 over 28 days, Sandborn and colleagues randomly assigned 40 patients with moderate-to-severe active UC to receive one of three doses of the study drug or placebo. They also assessed biomarkers and clinical, endoscopic and histologic endpoints.
Data from the first 10 patients who received 80 mg of study drug for 28 days, as well as three who received placebo, showed “encouraging evidence of localized biological activity” in those who received the study drug.
Plasma levels showed minimal systemic exposure of the study drug consistent with data from a previous phase 1 study in health volunteers. Further, the investigators found no evidence of systemic immunosuppression or infections, and no changes in total leukocytes, neutrophils or lymphocytes vs. placebo. Patients who received the study drug also showed improvements in rectal bleeding, endoscopic and clinical features, and inflammatory biomarkers.
No moderate or serious adverse events related to the study drug occurred, and of the mild adverse events that occurred, none caused patients to discontinue treatment. Additionally, “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,” according to the press release.
“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 4 weeks of treatment, we have seen minimal systemic exposure and a favorable tolerability profile that is consistent with the desired target product profile,” Brett Haumann, MD, chief medical officer of Theravance Biopharma, said in the press release. “The body of evidence from the first cohort of this study suggest both that TD-1473 was restricted to, and biologically active at, the target disease location within the intestinal tract with minimal absorption into the systemic circulation and that active intestinal inflammation does not lead to increased systemic exposure of TD-1473.”
While the evaluation of a higher and lower dose of the study drug remain to be completed in this study, the company plans to proceed with a larger induction and maintenance study next year based on these preliminary findings.
Disclosures: Sandborn reports a consulting relationship with Theravance. Haumann is employed by Theravance.