Sample Record from IMS R&D Focus (File 445)
2/19/2 DIALOG(R)File 445: IMS R&D Focus (c) 2007 IMS Health & Affiliates. All rights reserved. 02014304 ** Image available ** Drug Name: vatalanib; vatalanib R&D Focus - January 22, 2007 (20070122 )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 Inhibition of Angiogenesis and Retarding of Metastases in Second-line), will evaluate the safety and efficacy of the agent in combination with first- and second-line chemotherapy (Novartis, JAN 2003). These phase III trials of the agent in combination with the FOLFOX4 regimen in patients with colorectal cancer are under way (Novartis, Schering AG, JUN 2003). Enrollment of more than 2000 patients at more than 200 centers has completed and results were expected second quarter 2005 (Schering AG, JAN 2005). Preliminary results from the CONFIRM 1 trial have been reported. Following this preliminary analysis an independent data monitoring board has recommended that the trial continue to allow analysis of overall survival endpoints. Final results from both CONFIRM trials are expected second half 2006 (Novartis, Schering AG, MAR 2005). Preliminary results from the CONFIRM 2 trial have been reported following an interim review by the independent Data Safety Monitoring Board (DSMB), which highlighted there is a low probability that the trial will reach its primary endpoint of improvement in overall survival at final analysis. Data analysis is ongoing and further results from the CONFIRM 2 trial are expected mid 2006; further results from the CONFIRM 1 trial are expected second half 2006 (Schering AG, Novartis, JUL 2005). Phase II trials have been conducted in the USA and Europe for the treatment of colon cancer, and results of phase II trials of the agent in combination with FOLFIRI and FOLFOX4 regimens in colorectal cancer have been reported (Novartis Schering AG, JUN 2003). Lung cancer Bayer Schering has initiated a phase II trial, designated GOAL (Growth Arrest with Oral Anti-angiogenesis in Lung Cancer), to assess the efficacy of vatalanib as a second-line monotherapy for nonsmall cell lung cancer (NSCLC). The trial will be conducted at five different sites in France and Germany and will involve patients with stage IIIB/IV NSCLC who have relapsed or are refractory to first-line treatment (Schering AG, MAR 2005). Preliminary results from a multicenter, phase II trial of vatalanib in the treatment of malignant mesothelioma have been reported; the trial enrolled 47 patients, with a median age of 75 years, at 19 sites across the USA. The primary endpoint of the trial was a three month progression-free survival rate of greater than 55%. Evaluation of the remaining patients is ongoing (Novartis, JUL 2005). Other indications A phase II trial of vatalanib has been initiated in the USA in patients with age-related macular degeneration (AMD) (Novartis, JAN 2006). Results have been reported from a phase I/II trial of vatalanib in patients with myelofibrosis with myeloid metaplasia (Novartis, Schering AG, JUL 2003). A broad phase I/II trial is under way in Europe and the USA to identify potential future indications for further development of vatalinib. These include a number of solid tumors in breast, nonsmall cell lung cancer (NSCLC), ovarian, pancreatic and prostate cancers. Furthermore, Novartis is also investigating the agent for the potential treatment of glioblastoma and hematological malignancies (Novartis, JAN 2005). Results have been reported from a European phase Ib trial in patients with stage IIc to IV epithelial ovarian cancer (Novartis and Schering AG, MAY 2005). Results have been reported from phase I trials of vatalanib in the treatment of recurrent glioblastoma multiforme, renal cell carcinoma and liver metastases (Novartis, Schering AG, JUN 2003). A phase III trial in patients with hematological malignancies was planned to begin during 2003 (Novartis, Schering AG, JUL 2003). Vatalanib is also under preclinical evaluation for the treatment of multiple myeloma (Novartis, DEC 2001). Schering AG, reported phase III, JUN 2003. Novartis confirmed phase III ongoing, colorectal cancer, phase I ongoing, solid tumors, JAN 2006. Novartis and Schering AG (now Bayer Schering) entered into a collaborative agreement regarding the development of vatalanib in 1995 (Novartis, JAN 2005). Novartis and Schering AG have modified an original agreement, under which Schering AG gained exclusive marketing rights to vatalanib in Europe and Novartis had exclusive rights in North America. Under the new agreement, Schering AG and Novartis will co-market vatalanib in Europe, North America and Japan for oncology indications. Schering AG has exclusive marketing rights to the product in Latin America, Africa and Australia and Novartis has exclusive rights in Asia, excluding Japan. Financial details of the agreement were not disclosed (Schering AG, JAN 2005). Schering AG has granted Novartis exclusive worldwide rights to develop vatalanib for ophthalmic indications including wet age-related macular degeneration. In return, Schering AG is to receive an upfront fee, milestone payments and royalties. Additional terms of the agreement were not disclosed (Schering AG, JAN 2005). Novartis anticipates a regulatory filing for vatalanib for the treatment of colorectal cancer during 2007 (Novartis, JAN 2006). Novartis and Schering AG plan to file for approval with the US FDA and the EMEA first half 2007 (Novartis, Schering AG, MAR 2005). The companies had planned to file for regulatory approval second half 2005 (Schering AG, JAN 2005). Novartis expected to file for regulatory approval during 2005 for the treatment of cancer (Novartis, JAN 2005). Results from the CONFIRM trials were expected second quarter 2005 (Schering AG, JAN 2005). Final results from both CONFIRM trials are expected second half 2006 (Novartis, Schering AG, MAR 2005). A phase III trial in patients with hematological malignancies was planned to begin during 2003 (Novartis, Schering AG, JUL 2003). Latest prediction Analyst, Deutsche Bank, reporting on Novartis, predicts a regulatory filing for PTK 787 (vatalanib) early 2007 for the treatment of solid tumors; estimates sales of US$29 million in 2007, US$100 million in 2008, US$100 in 2009 and US$100 million in 2010 (Deutsche Bank, SEP 2005). >Bear Stearns Analyst, Bear Stearns, reporting on Novartis, predicts an NDA filing for PTK 787 (vatalanib) second half 2005; estimates sales of US$40 million for 2006, US$166 million for 2008, and US$303 million for 2010 (Bear Stearns, FEB 2005). CDC IXIS Analyst, CDC IXIS, reporting on Novartis, predicts a regulatory filing for vatalanib (PTK 787) fourth quarter 2005 and estimates sales of US$70 million in 2007 and peak sales of US$1.5 billion (CDC IXIS, MAR 2004). Citigroup Smith Barney Analyst, Citigroup Smith Barney, reporting on Novartis, estimates sales of US$1105 million in 2006 and US$45 million in 2010 (Citigroup Smith Barney, JAN 2004). Delta Lloyd Securities Analyst, Delta Lloyd Securities, predicts a launch in 2006 and estimates peak sales of EUR250 million (Delta Lloyd Securities, MAY 2003). Deutsche Bank Analyst, Deutsche Bank, reporting on Novartis, predicts a regulatory filing for PTK 787 (vatalanib) for the treatment of colorectal cancer in 2005 and a launch late 2006/2007; estimates sales of US$30 million in 2006 and US$400 million in 2008 (Deutsche Bank, NOV 2004). Lehman Brothers Analyst, Lehman Brothers, predicts a launch in the USA in 2005 with estimated sales of US$470 million in 2005 and peak sales of US$1.3 billion in 2012, and a launch in the rest of the world in 2005 with estimated sales of US$100 million in 2005 and peak sales of US$700 million in 2012 (Lehman Brothers, JUN 2003). Morgan Stanley Analyst, Morgan Stanley, reporting on Novartis, estimates sales of US$49 million in 2005 and peak sales of US$1.5 billion (Morgan Stanley, NOV 2003). Analyst, Morgan Stanley, reporting on Schering AG, estimates sales of EUR100 million in 2006 and peak sales of EUR2 billion (Morgan Stanley, JAN 2004). Analyst, Morgan Stanley, reporting on Schering AG, estimates sales of EUR100 million in 2006 and EUR300 million in 2009 (Morgan Stanley, OCT 2003). Analyst, Morgan Stanley, reporting on Schering AG, estimates sales for PTK 787 (vatalanib) of EUR50 million in 2006 and EUR300 million in 2010 (Morgan Stanley, NOV 2004). Prudential Finance Analyst, Prudential Financial, predicts a launch post-2006 in Europe and the USA (Prudential Financial, JUN 2003). Sarasin Analyst, Sarasin, reporting on Novartis, predicts a launch for vatalanib (PTK 787) in 2006 (Sarasin, MAR 2004). UBS Analyst, UBS, reporting on Novartis, estimates sales of US$150 million in 2006 and US$210 million in 2007 (UBS, JAN 2004). WestLB Equity Markets Analyst, WestLB Equity Markets, reporting on Novartis, predicts a regulatory filing in 2005 (WestLB Equity Markets, NOV 2003).COMPANY INFORMATION: Originator: Bayer Schering; (Germany); Bayer; co-developer; NA Licensee/Licensor: Novartis; (Switzerland); NA; co-developer; NA Patent Assignee: Novartis DRUG INFORMATION: CAS Registry Number: 212141-54-3, vatalanib, CGP 79787; 212142-18-2, succinate (1:1), CGP 79787D, PTK 787, ZK 222584 Laboratory Code: PTK/ZK; PTK 787; ZK 222584; CGP 79787D; CGP 79787; PTK 7871 Pharmacological Action: VEGF antagonist; angiogenesis inhibitor; tyrosine kinase inhibitor; proteinase inhibitor; signal transduction inhibitor Substance Origin: chemical synthesis Therapeutic Class Code: L1X9 (All Other Antineoplastics); S1P (Ocular Antineovascularization Products) Clinical Indications: cancer; solid tumor; gastrointestinal cancer; colorectal cancer; neurological cancer; glioblastoma; genitourinary cancer; ovarian cancer; renal cancer; liver cancer; metastasis; lung cancer; NSCLC; mesothelioma; AMD Chemical Name: N-(4-chlorophenyl)-4-(4-pyridinylmethyl)-1-phthalazinamine Nomenclature: pINN; USAN Molecular Code: 7104340000 LATEST INFORMATION: 27 February 2006: On 19 January 2006 Novartis reported that it has initiated a phase II trial of vatalanib in the USA in patients with age-related macular degeneration (AMD). The agent is a vascular endothelial growth factor receptor (VEGF-R) inhibitor that is also being evaluated in phase III trials in colorectal cancer patients and in phase I trials in patients with solid tumors. A regulatory filing for the treatment of colorectal cancer is planned for 2007. CURRENT DEVELOPMENT STATUS: Highest Phase: Phase III (50) Development Phase/ Country/Indication: Phase III--Worldwide--colorectal cancer Phase II--France--NSCLC Phase II--Germany-- NSCLC Phase II--USA--AMD Phase II--USA--mesothelioma Phase I--USA-- solid tumor Phase I--Europe--solid tumor Phase I--Europe--ovarian cancer Abstract: DEC 2006: Bayer acquires Schering AG as a wholly-owned subsidiary to form Bayer Schering. JUL 2005: Phase II, USA (AMD). MAR 2005: Phase II, France, Germany (NSCLC). JAN 2005: Phase I/II, USA, Europe (solid tumor, including breast, ovarian, prostate, pancreatic cancer and NSCLC). Agreement between Schering AG and Novartis modified. JUL 2003: Phase II, USA (malignant mesothelioma). JAN 2003: Phase III, USA, Europe (colorectal cancer). DEC 2001: Preclinical, USA (multiple myeloma). APR 2001: Phase II, USA, Europe. APR 2000: Phase I, USA, Europe. OCT 1999: Phase I, Switzerland. 1995: Agreement between Schering AG and Novartis. FEB 1997: Priority product patent application filed in Switzerland, by Novartis. COMMERCIAL SUMMARY:
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 21 day cycle at a dose of 175 mg/m2. Carboplatin, as a 30 min iv infusion, was administered immediately after paclitaxel, and vatalanib was given once-daily from day three to day 21 of each chemotherapy cycle. Results showed that the combination had an acceptable safety profile, with no dose-limiting toxicities or vatalanib-related side effects. Vatalanib had no impact on the systemic exposure of carboplatin, and preliminary data showed that paclitaxel exposure was not affected by the maximum dose of 1250 mg/day vatalanib (41st ASCO, Abs 5042, MAY 2005). Colorectal cancer In a phase I/II trial of vatalanib in combination with irinotecan/fluorouracil/leucovorin (FOLFIRI) in the treatment of metastatic colorectal cancer, results from 11 evaluable patients showed that four (36%) had a partial response, and four (36%) achieved stable disease. The combination of vatalanib and FOLFORI was well tolerated (39th ASCO, Abs 1144, JUN 2003). In a phase I/II trial of vatalanib in combination with oxaliplatin/fluorouracil/leucovorin (FOLFOX4) in patients with metastatic colorectal cancer, results showed that of 21 evaluable patients, nine (43%) had partial responses, eight (38%) had stable disease and four (19%) had progressive disease. The combination of vatalanib and FOLFOX4 was well tolerated (39th ASCO, Abs 1098, JUN 2003). In the phase III CONFIRM 1 trial, previously untreated patients received vatalanib in combination with the FOLFOX-4 regimen (oxaliplatin/5FU/LV) or FOLFOX-4 alone. Progression-free survival, as assessed by radiology review, was not significantly improved in patients receiving vatalanib/FOLFOX-4, compared with those receiving FOLFOX-4 alone. However, analysis of progression-free survival as assessed by the trial investigators, did achieve statistical significance. The side effect profile was consistent with those for other antiangiogenic therapies, with adverse events including hypertension and thromboembolic events (Novartis, Schering AG, MAR 2005). Preliminary results from the phase III CONFIRM 2 trial of vatalanib in the second-line treatment of metastatic colorectal cancer showed that the secondary endpoint of progression free survival was improved in favor of the vatalanib treatment arm. The greatest effect was observed in a subgroup of patients with high lactate dehydrogenase levels (Schering AG, Novartis, JUL 2005). Myelofibrosis In a phase I/II trial in six patients with myelofibrosis with myeloid metaplasia, treatment with oral vatalanib (500 mg bid) resulted in significant reduction in spleen size in two patients (33%). Adverse effects associated with vatalanib were neutropenia (1 patient) and thrombocytopenia (1 patient) (94th AACR, Abs 5356, JUL 2003). Lung cancer In a phase II trial of single agent vatalanib in the treatment of malignant mesothelioma, which enrolled 47 patients with a median age of 75 years, results from the first 33 patients showed that the three month progression-free survival rate was 44.9%, with a median duration of progression-free survival of 2.66 months. An overall survival at three months of 76.3% and a median duration of survival of 5.2 months was observed. Partial responses were experienced by 6.1% of patients and 57.6% of patients had stable disease; disease progression occurred in 21.2% of patients. Patients were administered single, daily oral doses of 1250 mg vatalanib for a median duration of two cycles; the toxicity of the agent in 32 of the patients was modest, with grade 4 neutropenia and transaminase elevation experienced by 3% and 6% of patients, respectively. Grade 3 toxicities included nausea, vomiting, dyspnea and transaminase elevation (11th WCLC, Abs 403, JUL 2005). Other indications In a phase I/II trial of vatalanib in combination with FOLFOX4, results showed that of 28 evaluable patients, one had a complete response, 14 had partial responses, nine had stable disease and four had progressive disease (94th AACR, Abs 5356, JUL 2003).
PATENT SUMMARY:
Product: WO 98/35958 1998, priority CH 315 1997, designating 93 states. One equivalent identified.
File 445 Sample Record