Abstract B57: Safety profile of zoledronic acid in a novel oral formulation
Authors: Leonard Thomas W. , Fox John , McHugh Catherine , Madigan Kieran , Walsh Angela 
Published: June 2012

Background: Orazol™(MER-101) tablets utilize GIPET® to formulate an oral alternative to intravenous zoledronic acid (ZA) IV (Zometa®). Orazol's enteric coating and high bioavailability decreases GI exposure and provides a tablet with an excellent safety profile. Three clinical trials on doses from 10 to 20mg demonstrated that a weekly 20mg tablet delivers systemic ZA doses equivalent to 4mg infusions given every 4 weeks. Therapeutic equivalence of 20mg tablets and the 4mg infusion has been demonstrated in prostate cancer patients with bone metastatic disease based on change from baseline values for biomarkers of bone metabolism, including uNTX and sCTX.

Methods: Safety information from three open label studies is presented here.

MER-101-01 was a pilot single weekly dose, 3-way crossover study in 13 osteoporotic women. Orazol tablets 10mg and 20mg were administered versus a 1mg IV infusion after an overnight fast (and 4 hours fast post-dose). Absorption was determined by LCMS urine assay over 48 hours post-dose.

MER-101-02 was a single-dose, 5-way crossover study in 30 postmenopausal women and examined Orazol 15mg and 20mg tablets versus 1mg IV infusion. Absorption was determined by serum LCMS assay over 36 hours post-dose.

Treatments:(a) Orazol 15mg, overnight fast, breakfast 30 minutes later.(b) Orazol 20mg, overnight fast, breakfast 30 minutes later.(c) Orazol 20mg, FDA standardized breakfast.(d) Orazol 20mg, bedtime, following a 4-hour fast.(e) ZA 1mg IV infusion.

MER-101-03 was a multi-center, 8 week, Phase II study comparing two regimens of Orazol tablets 20mg to the standard dose of ZA 4mg infusion in male bisphosphonate-naive hormone-refractory prostate cancer patients with bone metastases. The cohorts were:Cohort A: ZA 4mg infusion, Day 0 & 28.Cohort B: Orazol tablets 20mg, Days 0, 7, 14, 21, 28, 35, 42 & 49.Cohort C: Orazol tablets 20mg, Days 0, 1, 2, 3, 28, 35, 42 & 49.

Safety assessments included AE monitoring, PE, hematology, urinalysis, and blood chemistry panels.

Results: Orazol tablets yielded a very acceptable safety profile. In MER-101-03, which evaluated Orazol tablets directly against the 4mg infusion, the greatest incidence of AEs occurred in patients on the ZA infusion (75%). Half of the patients in this cohort experienced fever following administration, which lasted up to 72 hours post-dose. The incidence of bone pain was twice that in patients on oral Orazol therapy. There was a consistent decrease in mean diastolic blood pressure, and a greater number of abnormal hematology laboratory results for patients on IV than for Orazol. In analyzing MER-101-01 and MER-101-02 together, which compared Orazol tablets to a 1mg Zometa infusion, AEs were evenly distributed across groups. GI related AEs were similar with the Orazol treatments compared to the ZA infusions.

Conclusions: Based on data collected thus far, Orazol tablets offer a substantial improvement over IV infusion in bisphosphonate therapy for oncological uses. The results of these studies combined with the excellent safety profile of Orazol tablets 20mg administered weekly support further development as a preferred route of ZA administration. Results to date indicate Orazol is an effective and potentially safer alternative to IV ZA, which may substantially improve patients’ quality of life. Orazol offers a new treatment paradigm for patients with metastatic bone cancer.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B57.