Pipeline
Knowledge Is Power
With a growing arsenal of targeted agents, Exelixis is taking aim at the key receptors and signaling molecules that are dysregulated in cancer.
Where cancer was once classified only at the level of cells and tissues, we now have a better understanding of the genes, proteins, and biochemical pathways that are implicated in various types of cancer. At Exelixis, this knowledge is the foundation of our drug discovery and development strategy.
Recognizing that diverse molecular pathways impact the development, progression, and metastasis of different cancer types, we are building a broad pipeline of compounds with unique target profiles. This approach allows us to develop individual drug candidates for those cancer indications and patient populations where the pharmacology of the compound most effectively addresses the biology of the disease.
By understanding target biology and compound activity early on, we seek to identify those patients most likely to benefit from a particular drug candidate and pursue a clearly defined path through the clinic and toward the market.
Based on our extensive knowledge of pathway and cancer biology, we are presently pursuing three distinct strategies for the identification and development of our anti-cancer compounds. The first is to target multiple cancer-associated receptor tyrosine kinases (RTKs) simultaneously, the second is to target downstream signaling cascades, and the third is to pursue investigations of how combinations of these targeted compounds might work together to the benefit of patients.
Targeting Multiple RTKs Simultaneously
Our most advanced clinical development candidates are designed to simultaneously target multiple RTKs, including EGFR, HER2, VEGFR2, MET, and RET. These proteins are involved in key cancer-related processes, and RTK inhibition has been validated as a therapeutic approach to treating cancer by the approval of numerous drugs designed to target individual RTKs.
We believe that our multi-targeted approach may provide a way to inhibit numerous cancer processes in a highly concerted manner with a single drug. In turn, this may achieve a clinically meaningful balance between the broad effects of chemotherapy and the favorable safety and tolerability profiles of targeted agents.
The RTK inhibitors currently in development include XL647 (EGFR, HER2, VEGFR2), XL880 (MET, VEGFR2), XL184 (MET, VEGFR2, RET), and XL820 (KIT, PDGFR, VEGFR2).
Targeting Downstream Signaling Cascades
Our second approach is to target critical downstream signaling cascades that are essential for transforming normal cells into malignant disease. These signaling pathways, such as the PTEN/PI3K, RAS/RAF/MEK/ERK, and JAK/STAT pathways, regulate growth and survival, and are mutationally activated in many cancers. Individual kinases within these pathways are points of convergence for multiple signaling cascades. Thus, inhibiting one of these downstream kinases could effectively shut down signaling from a number of different upstream pathways.
We have made significant progress in developing a portfolio of compounds that inhibit critical components of these downstream signaling pathways with high specificity and activity. These compounds include; XL019 (JAK2), XL147 (PI3K), XL765 (PI3K and mTOR), XL518 (MEK), XL228 (IGF1R, BCR-ABL, SRC), and XL281 (RAF).
Combination Approach
Our third approach is to pursue strategies for combining these targeted agents to provide potential patient benefit in various cancer types. A substantial body of data shows that cancers are heterogeneous in nature and can adapt to the inhibition of one signaling pathway by activating another one. Therefore, combining selective targeted therapies to inhibit multiple cancer-promoting pathways is a high priority in the development paths of these agents.
Biology Drives Discovery and Development
The knowledge we have accumulated around these targets, and our understanding of the roles they play in specific cancer indications, help define and focus our clinical development strategies. By keeping biology integral to the process, even as we advance into and through the clinic, we believe that we can increase the likelihood that we, and patients, will succeed.
