Novel JAK inhibitor acts locally in the gut for ulcerative colitis treatment
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A gut-selective Janis kinase inhibitor called TD-1473 showed a trend toward reduced ulcerative colitis disease activity in a translational medicine program.
William J. Sandborn, MD, from the division of gastroenterology at the University of California, San Diego, told Healio Gastroenterology and Liver Disease that unlike other JAK inhibitors such as Xeljanz (tofacitinib, Pfizer), TD-1473 (Theravance) does not work systemically, but rather only in the location it is delivered, in this case, the gut, allowing it to be effective by administering higher doses without increasing adverse events.
“It’s to change the toxicity profile, potentially allowing more intensive dosing,” he said. “JAK inhibitors for IBD are generally more effective as you go up in dose, but you also go up in side effects.”
Sandborn said the translational study took the drug from molecule testing in the lab, to pre-clinical experiments in mouse models of colitis, and into human testing using healthy volunteers. From there, researchers evaluated the drug in a phase 1b study of patients with moderately to severely active UC.
Patients received once-daily oral TD-1473 20 mg, 80 mg or 270 mg or placebo for 28 days. Investigators assessed plasma and colonic tissue concentrations of the drug, as well as safety and efficacy endpoints.
“It had about 10 patients per arm, and what you can see is that the higher two doses led to substantial tissue concentrations of the drug and very little drug spilling into the bloodstream,” Sandborn said. “It was only a 4-week study, but we did see some benefit to clinical measures. If you can see anything at 4 weeks, you’re doing pretty well.”
Sandborn said they observed a benefit to rectal bleeding during the study. The drug was also well-tolerated from a safety perspective.
Theravance is in a partnership with Janssen to move the drug into phase 2 trials, which are currently recruiting patients with UC and Crohn’s disease. Sandborn said, however, that recruiting has slowed because of the COVID-19 pandemic.
“We’re anxious to see much larger patient numbers and for longer induction trials more typical of what we would usually do,” Sandborn said. – by Alex Young
Disclosures: Sandborn reports receiving research grants from Atlantic Healthcare Limited, Amgen, Genentech, Gilead Sciences, AbbVie, Janssen, Takeda, Lilly, Celgene/Receptos,Pfizer, Prometheus Laboratories (now Prometheus Biosciences); consulting fees from AbbVie, Allergan, Amgen, Arena Pharmaceuticals, Avexegen Therapeutics, BeiGene, Boehringer Ingelheim, Celgene, Celltrion, Conatus, Cosmo, Escalier Biosciences, Ferring, Forbion, Genentech, Gilead Sciences, Gossamer Bio, Incyte, Janssen, Kyowa Kirin Pharmaceutical Research, Landos Biopharma, Lilly, Oppilan Pharma, Otsuka, Pfizer, Progenity, Prometheus Biosciences (merger of Precision IBD and Prometheus Laboratories), Reistone, Ritter Pharmaceuticals, Robarts Clinical Trials (owned by Health Academic Research Trust, HART), Series Therapeutics, Shire, Sienna Biopharmaceuticals, Sigmoid Biotechnologies, Sterna Biologicals, Sublimity Therapeutics, Takeda, Theravance Biopharma, Tigenix, Tillotts Pharma, UCB Pharma, Ventyx Biosciences, Vimalan Biosciences, Vivelix Pharmaceuticals; and stock or stock options from BeiGene, Escalier Biosciences, Gossamer Bio, Oppilan Pharma, Prometheus Biosciences (merger of Precision IBD and Prometheus Laboratories), Progenity, Ritter Pharmaceuticals, Ventyx Biosciences, Vimalan Biosciences. Spouse: Opthotech - consultant, stock options; Progenity - consultant, stock; Oppilan Pharma - employee, stock options; Escalier Biosciences - employee, stock options; Prometheus Biosciences (merger of Precision IBD and Prometheus Laboratories) - employee, stock options; Ventyx Biosciences – employee, stock options; Vimalan Biosciences – employee, stock options. Please see the full study for all other authors relevant financial disclosures.
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