The Oral Serine Protease Inhibitor WX-671 – First Experience in Patients with Advanced Head and Neck Carcinoma

Tumor stroma as targets for cancer therapy

“…In preclinical studies, inhibition of uPA/uPAR with antibodies or small interfering RNA (siRNA) has caused a significant restraint in tumor cell growth and invasion (Kargiotis et al, 2008; Duriseti et al, 2010). WILEX AG develops two small synthetic molecules specifically against uPA, the intravenous drug WX-UK1 and its oral pro-drug WX-671/Mesupron, which can generate pharmacologically active WX-UK1 by reductively converting the hydroxyamidino function to the amidino function (Meyer et al, 2008). Data from a number of early clinical monotherapy and combination therapy studies show that these drugs are safe and well tolerated without serious adverse events (Goldstein, 2008; Meyer et al, 2008).…”

“…WILEX AG develops two small synthetic molecules specifically against uPA, the intravenous drug WX-UK1 and its oral pro-drug WX-671/Mesupron, which can generate pharmacologically active WX-UK1 by reductively converting the hydroxyamidino function to the amidino function (Meyer et al, 2008). Data from a number of early clinical monotherapy and combination therapy studies show that these drugs are safe and well tolerated without serious adverse events (Goldstein, 2008; Meyer et al, 2008). A combination of WX-UK1 with capecitabine has exhibited therapeutic benefit, including prolonged stable disease and partial responses (Schmitt et al, 2011).…”

Phase II randomised proof-of-concept study of the urokinase inhibitor upamostat (WX-671) in combination with gemcitabine compared with gemcitabine alone in patients with non-resectable, locally advanced pancreatic cancer

“…Locally advanced pancreatic cancer patients were centrally randomised in a 1 : 1 : 1 ratio to receive either gemcitabine (1000 mg m −2 IV over 30 min weekly for 7 weeks in the first 8 weeks, followed by weekly gemcitabine for 3 weeks of a 4-week cycle; arm A), or combination therapy with the same dose and schedule of gemcitabine and a daily oral dose of either 200 mg (arm B) or 400 mg (arm C) upamostat. Dose selection for this study was based on previous preclinical data, on phase I data of WX-UK1 and upamostat in healthy volunteers and on clinical data obtained from two studies in head and neck patients receiving upamostat before surgery (Wilex AG, data on file; Meyer et al , 2008). In order to assess a potential dose-response relationship two dose levels of 200 and 400 mg upamostat daily were selected.…”

“…Upamostat (WX-671) is the oral pro-drug of the active metabolite WX-UK1, a novel uPA inhibitor (Setyono-Han et al , 2005); pharmacokinetic data on WX-UK1 and upamostat were collected in a total of 8 previous studies (WILEX AG, data on file). In head and neck cancer patients receiving upamostat in the 2 weeks before their scheduled surgery, WX-UK1 tissue levels exceeded the inhibition constant of WX-UK1 by 1.5–2-fold and were comparable for daily administration of both 200 and 400 mg upamostat (Meyer et al , 2008). In a trial of 149 patients with advanced pancreatic cancer, pre-treatment serum uPA levels were elevated in about 40% of patients and elevated serum uPA was associated with a shorter survival compared with patients with normal uPA levels (Ali et al , 2004).…”

New Antithrombotic Drugs

“…174,175 A phase 1 study in 19 patients with advanced head and neck cancer revealed a dose-dependent increase in plasma levels of WX-671, and WX-671 was found in tissue samples collected after tumor resection, 176 suggesting that amounts of drug suffi cient to inhibit u-PA are concentrated in the tumor. 176 In a phase 2 study, 95 patients with locally advanced, metastatic pancreatic cancer received either Mesupron (at doses corresponding to 200 or 400 mg of WX-UK1) or placebo in conjunction with weekly gemcitabine. Mesupron was well tolerated, and compared with placebo, overall survival increased from 10.2 months to 13.5 months.…”