Biotechnology company Exelixis Incyesterday said that its six-year collaboration with GlaxoSmithKline to discover and develop oncology compounds has ended with GSK having decided againnst exercising its option to license the compounds, developed under this collaboration.
According to Exelixis, GSK informed it that it would not to license XL184, XL281, XL228, XL820, and XL844, leaving Exelixis free to develop, commercialise, and / or license all of the compounds, subject to payment of a 3-per cent royalty to GSK on the net sales of any product incorporating XL184.
As a result of the conclusion of the collaboration, Exelixis said its exclusivity obligations will be limited to the compounds selected by GSK.
Exelixis and GSK had established a broad alliance to discover, develop, and commercialise novel therapeutics in the areas of vascular biology, inflammatory disease, and oncology in October 2002. Exelixis has strategic corporate alliances with major pharmaceutical and biotechnology companies, including GlaxoSmithKline, Bristol-Myers Squibb, Genentech, Wyeth Pharmaceuticals, and Daiichi-Sankyo.
Under the terms of the collaboration, Exelixis was required to deliver to GSK a number of small molecule compounds that met agreed-upon proof-of-concept criteria, and GSK had the right to select up to two of the compounds for further development and commercialisation.
GSK previously selected XL880, and it has now decided not to select any of the compounds remaining in the collaboration: XL184, XL281, XL228, XL820, and XL844. Exelixis and GSK will bring their six-year collaboration to a successful conclusion on 27 October 2008, as scheduled.
With GSK's decision not to exercise an option to any of the compounds, the six-year collaboration between Exelixis and GSK to discover and develop oncology compounds comes to an end. Exelixis will have the right to perform additional discovery, development, and commercialisation efforts against any collaboration target or compound that does not infringe upon the intellectual property associated with compounds selected by GSK for further development and commercialization.
GSK will continue development and commercialisation of XL880, a compound developed under the collaboration and previously in-licensed by GSK, with potential additional milestone payments of up to $90 million and double-digit royalty payments to Exelixis on XL880's successful development and commercialisation.
"Encouraging data on several of the compounds, including XL184 (MET, RET, VEGFR2), XL281 (RAF), and XL228 (BCR-ABL, IGF1R, SRC), were presented at the EORTC-NCI-AACR meeting this week, and there will be additional data presented on XL228 at the American Society of Hematology (ASH) meeting in December," Exelixis said in a statement.
George A. Scangos, PhD, president and CEO, Exelixis, said, "We are pleased to retain the rights to develop and commercialise XL184. This compound is our most advanced asset with a promising mechanism of action. It has generated compelling data in patients with medullary thyroid cancer, and data emerging from the phase 2 trial being conducted in patients with glioblastoma also are encouraging.
"We recently initiated a phase 3 registration trial for XL184 in MTC, and we look forward to the successful progress of this and other trials for the compound. We have had a significant number of inquiries about our willingness to partner the program and we are exploring all options to advance the program and maximize its value to the company. Additionally, we believe data recently presented on XL281 and XL228, and additional data that will be presented for XL228 later this year, indicate that they also have substantial potential as anti-cancer agents."
"Exelixis now has the rights to XL184, XL281, XL228, as well as two earlier compounds, XL844 and XL820," Dr. Scangos continued. "These compounds, together with the compounds already in Exelixis' proprietary clinical pipeline, XL147, XL765, XL019, and XL888, comprise a deep pipeline of promising oncology compounds. The clarity achieved through the expiration of the collaboration will allow Exelixis to further define its clinical, commercial, and financial strategies, which will become apparent over the next few months."
Paolo Paoletti, MD, Senior Vice President of GSK Oncology R&D, commented, "GSK and Exelixis have successfully concluded this long-term collaboration which has resulted in the discovery and development of a number of promising compounds with potential benefit to cancer patients."
Additional clinical studies with XL184 are ongoing to complement the pivotal trial in patients with MTC. This is part of Exelixis' strategy to rapidly advance compounds into areas of high unmet medical need, while potentially expanding into broader commercial markets by demonstrating activity in major tumor types. A phase 1b/2 trial of XL184 as a single agent and in combination with erlotinib was recently initiated in patients with non-small cell lung cancer. In addition, a phase 2 study of XL184 in patients with glioblastoma multiforme is ongoing.
XL184 inhibits MET, RET, and VEGFR2, which are key drivers of tumor growth, metastasis, survival, and angiogenesis. In pharmacodynamic studies in mice, oral administration of XL184 resulted in balanced and durable inhibition of these targets. The compound has also shown activity against common mutant forms of RET and MET. XL184 has exhibited dose-dependent tumor growth inhibition and tumor regression in a variety of preclinical tumor models, including breast cancer, colon cancer, MTC, non-small cell lung cancer, and glioblastoma.
In July 2008, on the basis of the encouraging phase 1 trial data, Exelixis initiated a phase 3 registration trial of XL184 for the potential treatment of MTC. Exelixis and the US Food and Drug Administration had previously reached agreement on this phase 3 registration trial via the Special Protocol Assessment process.
The American Cancer Society estimates that MTC accounts for 5 per cent of all thyroid cancers. MTC occurs in sporadic and inherited forms (approximately 80 per cent and 20 per cent of MTC, respectively). Patients with the inherited form of MTC invariably have an activating mutation in RET in their germline DNA. Activating mutations in RET are also present in the tumor DNA of up to 50 per cent of sporadic MTC patients with no familial history of thyroid cancer.
MTC may metastasize to lymph nodes or other organs before it is ever diagnosed. Additionally, MTC does not take up radioactive iodine, which is commonly used to treat other types of thyroid cancers and to diagnose metastases. As a result, MTC is more difficult to treat than other thyroid cancers. There are no approved therapies for MTC; however, common treatments for MTC include surgery to remove malignant tissue, radiation therapy, and chemotherapy, all of which are associated with potential side effects, some of which may be long-term.
XL228 is a protein kinase inhibitor with potent activity against wild-type and the T315I mutant forms of BCR-ABL, with additional activity against IGF1R, SRC, and Aurora A. These targets play crucial roles in cancer cell proliferation, survival, and metastasis. XL228 blocks downstream signaling from BCR-ABL T315I in cell lines and modulates phosphorylated CrkL levels in mouse xenografts consistent with inhibitory activity against BCR-ABL in vivo. XL228 has exhibited activity in a variety of solid tumor xenograft models.
XL281 is a novel small molecule designed to selectively inhibit RAF kinases, which lie immediately downstream of RAS and are key components of the RAS/RAF/MEK/ERK kinase signaling pathway. Genetic lesions that activate this pathway are common in human tumors, with activating mutations in KRAS occurring in 30 percent of tumors and activating mutations in BRAF occurring in approximately 60 per cent of melanomas.
The RAS/RAF/MEK/ERK pathway also plays a key role in the transmission of growth-promoting signals downstream of receptor tyrosine kinases. This suggests that deregulation of this pathway plays a pivotal role in the progression of many human tumors, and that inhibition of the pathway may be useful in the treatment of cancer. XL281 potently inhibits BRAF, mutationally activated BRAF, and CRAF in vitro, and does not interact with kinases outside of the RAF family. XL281 displays high oral bioavailability in multiple preclinical species, and strongly inhibits RAS/RAF/MEK/ERK signaling in human xenograft tumor models. This translates into substantial inhibition of tumor growth in preclinical models of human tumors that overexpress receptor tyrosine kinases or harbor activating mutations in RAS or RAF.
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