The Drug Profile Record (cont'd)

COMMERCIAL SUMMARY:
Vatalanib is an inhibitor of the vascular endothelial growth factor receptor (VEGF-R) tyrosine kinases. Two international phase III trials of vatalanib, designated CONFIRM 1 and 2, in the first and second-line treatment of colorectal cancer are under way. Novartis and Bayer Schering (formerly Schering AG) are co-developing vatalanib as an oral angiogenesis inhibitor for the potential treatment of cancer and age-related macular degeneration (AMD). In July 2007, Novartis initiated a phase II trial in patients with AMD. A phase II trial of vatalanib as a second-line monotherapy for nonsmall cell lung cancer (NSCLC) is ongoing in France and Germany and a phase II trial of vatalanib in the treatment of malignant mesothelioma has completed. A phase I/II trial of vatalanib in patients with myelofibrosis with myeloid metaplasia has completed, and a broad phase I/II trial to identify potential future indications, including NSCLC, breast, ovarian, pancreatic and prostate cancers, for further development is being conducted in the USA. In February 1997, Novartis filed a priority product patent application in Switzerland. Schering AG and Novartis established their vatalanib collaboration in 1995. In January 2005, the original agreement was modified; under the terms of the amended agreement, the companies will co-market vatalanib in Europe, North America and Japan for oncology indications. In a separate agreement between the companies, also signed January 2005, Schering AG (now Bayer Schering) granted Novartis exclusive worldwide rights to develop vatalanib for ophthalmic indications including wet AMD. Colorectal cancer Phase III trials of vatalanib in the treatment of colorectal cancer have been initiated worldwide. The two trials, CONFIRM 1 (Colorectal Oral Novel Therapy for the Inhibition of Angiogenesis and Retarding of Metastases in First-line) and CONFIRM 2 (Colorectal Oral Novel Therapy for the

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SCIENTIFIC SUMMARY:
Vatalanib, 1-5 mcM, inhibited proliferation of multiple myeloma cells by 50%. Vatalanib is an inhibitor of the VEGF-R tyrosine kinases and inhibits angiogenesis and tumor cell growth in animal cell models. In a CWR 22 androgen-dependent prostate tumor model, a daily dose of 50 mg/kg po vatalanib inhibited tumor growth and in combination with cyproterone (50 mg/kg sc) resulted in no visible tumors. In a DU 145 androgen-independent prostate tumor model, treatment with vatalanib at 50-100 mg/kg po resulted in disease stabilization. Tumor growth resumed upon cessation of therapy and was arrested after restarting treatment (91st AACR, Abs 299, APR 2000). Vatalanib, at 1-5 mcM, inhibited proliferation of multiple myeloma (MM) cells by 50%, this effect being dose-dependent in several cell lines and in MM patient cells that were both sensitive and resistant to conventional therapies. In addition, the agent blocked secretion of IL-6 by 75%, that is triggered by in vitro binding of MM cells to bone marrow stromal cells (BMSCs). Furthermore, vatalanib inhibited proliferation of MM cells adherent to BMSCs (43rd ASH, Abs 699, DEC 2001). In phase I studies, vatalanib was rapidly absorbed with a Cmax 5-32 mcM, and a half-life of 4-6 h. Vatalanib was well tolerated and no sign of hematological, renal, or liver toxicity was observed even after chronic administration. In 32% of patients, stable disease was maintained (Novartis, OCT 1999). In a phase I trial of vatalanib in combination with temozolomide (200 mg/m2 daily every five days) in patients with recurrent glioblastoma multiforme, oral vatalanib was well tolerated at doses of 500, 1000, 1250 and 1500 mg/day (39th ASCO, Abs 412, JUN 2003). In a phase I trial in patients with metastatic renal cell carcinoma, vatalanib was well tolerated with only mild to moderate adverse effects; the MTD was not reached at doses up to 1500 mg/day. Among 42 evaluable patients, 19% had measurable responses; 60% had stable disease. The median time to progression was 5.3 months and overall survival at one year was 66.7% (39th ASCO, Abs 1548, JUN 2003). In a phase I trial in patients with liver metastases vatalanib was well tolerated at doses up to 1200 mg/day, and induced stable disease in 12 of 23 evaluable patients; median duration of stable disease was 4.3 months (39th ASCO, Abs 1142, JUN 2003). Ovarian cancer In an open-label multicenter phase Ib trial, vatalanib was administered in combination with paclitaxel and carboplatin in patients with stage IIc to IV epithelial ovarian cancer. Treatment consisted of paclitaxel as a 3 h infusion on day 1 of each

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PATENT SUMMARY:
Product: WO 98/35958 1998, priority CH 315 1997, designating 93 states. One equivalent identified.