Phase I & II with MESUPRON®
MESUPRON® is a serine protease inhibitor targeting the uPA (urokinase Plasminogen Activator) system and was moved into clinical development targeting tumour indications where long-term chronic treatment is necessary. The studies were partly supported by a USD 5.0 million award from the Department of Defence’s Breast Cancer Research Program.
As MESUPRON® was shown to be safe and well-tolerated and demonstrated good inhibition of tumour growth and metastasis in pre-clinical studies, MESUPRON® was moved into clinical development.
MESUPRON® has successfully completed two European Phase I studies in healthy volunteers. In a “first-into-man” Phase I single-dose study, MESUPRON® was safe and well tolerated at all dose levels tested and, in addition, showed good oral bioavailability, i.e. absorption by the gut, and efficient conversion to the active drug WX-UK1 in the body. A placebo controlled, double-blind study tested safety, tolerability, and pharmacokinetics of multiple rising doses of MESUPRON® in healthy volunteers. The study has been successfully completed.
A European Phase Ib study in patients with head and neck tumours demonstrated in 2007 that once daily oral doses of MESUPRON® delivers adequate concentrations of active WX-UK1 in tumour tissues in patients.
Phase II trial in pancreatic cancer
WILEX published impressive final trial results of the Phase II trial in the pancreatic cancer indication in June 2010.
Recruitment of 95 patients with locally advanced, inoperable, non-metastatic pancreatic cancer was completed in July 2008. The randomised, open label, three-arm Phase II trial investigates the anti-metastatic effect of MESUPRON® in combination with the chemotherapeutic agent Gemcitabine (Gemzar®, Eli Lilly and Company, Indianapolis, IN, USA). Patients were administered either Gemcitabine alone or in combination with a daily oral dose of 200 mg or 400 mg MESUPRON® respectively until progression. The therapy has proven to be safe and well tolerated. The trial examined different parameters, including progression-free survival and the time taken for the first metastases to occur.
Positive final data of the study was presented in June 2010 at ASCO (American Society of Clinical Oncology). Gemcitabine alone demonstrated a tumour response rate of 15.4%. Co-administration of 200 mg MESUPRON® led to an increase to 21.4% and to 35.5% with 400 mg MESUPRON®.
Progression free survival (PFS) improved by 66%. In the group receiving Gemcitabine alone 16.2% of patients did not progress at 12 months as determined by computer tomography. Co-administration of 200 mg MESUPRON® improved PFS to 22.5% and to 26.9% with 400 mg MESUPRON®.
One year survival increased by 49%. With Gemcitabine alone it was 33.9%. This increased to 40.7% with 200 mg MESUPRON® and to 50.6% with 400 mg MESUPRON®. The median survival of the patients improved by 26% from 9.9 months with Gemcitabine to 12.5 months in combination with 400 mg MESUPRON®.
Phase II trial in breast cancer
WILEX published data from its Phase II trial in patients with metastatic, HER2 receptor negative breast cancer in June 2012.
The uPA inhibitor MESUPRON® (INN: Upamostat) was given in combination with the chemotherapeutic agent Capecitabine (Xeloda®, Hoffmann La Roche AG, Switzerland).
The double blind randomised Phase II trial evaluated the efficacy and safety of MESUPRON® 200 mg oral once daily in combination with Capecitabine compared to Capecitabine alone (control group). 132 patients were enrolled in 20 centres in five countries (Belgium, Brazil, Germany, Israel, USA).
The primary objective of the study was to evaluate the efficacy of the combination of MESUPRON® and Capecitabine compared to Capecitabine alone by assessment of progression free survival (PFS). The study also evaluated the objective response rate, overall survival and safety as well as pharmacokinetics. Efficacy was evaluated by RECIST (Response Evaluation Criteria in Solid Tumours) by independent central read using computed tomography and bone scans.
In the total study population (intent to treat; ITT) MESUPRON® led to an increase of median progression free survival from 7.5 months in the control group to 8.3 months in the combination therapy. Capecitabine alone demonstrated an objective tumour response rate of 9%. Co-administration of 200 mg MESUPRON® almost doubled the response rate to 17%. Overall survival data have not matured yet as over 60% of patients were still alive at the time of analysis. The combination therapy of MESUPRON® and Capecitabine was safe and well tolerated. Pharmacokinetic analysis demonstrated no drug-drug interactions between MESUPRON® and Capecitabine.
To test whether MESUPRON® also shows efficacy in a more homogeneous patient population two subgroups were evaluated which had sufficient numbers of patients to allow separate analysis: In the subgroup of patients who were Caucasian (n=109) median PFS improved from 7.5 months in the control group to 9.1 months in patients treated with MESUPRON®. In the subgroup of patients (n=95) who received adjuvant chemotherapy following the primary diagnosis of breast cancer, PFS improved from 4.3 months in the Capecitabine alone group to 8.3 months in the MESUPRON® combination group. (back to top)