Exelixis has submitted an investigational new drug application (IND) to the US Food and Drug Administration (FDA) for XL820, a novel small molecule anticancer compound that inhibits receptor tyrosine kinases (RTKs) implicated in tumour proliferation and vascularisation.
XL820 inhibits the VEGF receptor, KIT and the PDGF receptor, which are clinically validated targets implicated in a variety of human cancers. XL820 exhibits dose-dependent growth inhibition in models of breast carcinoma, gliomas and leukaemia.
In an animal model of more advanced malignancy, significant tumour regression was seen. In non-clinical studies, XL820 has shown good oral bioavailability and sustained inhibition of target RTKs in vivo following a single oral dose. Pending clearance by the FDA, Exelixis intends to initiate a Phase I clinical trial for XL820.
"Before the end of 2005, we anticipate having eight compounds in clinical development, each of which potentially represents an important therapeutic advance." said George Scangos, president and chief executive officer of Exelixis.
"We filed three INDs last year, and XL820 is the first of three anticipated INDs for this year."
The majority of current cancer drugs are cytotoxic agents that exert its effects on proliferating cells, both normal and cancerous. This is the case even for recently successful drugs such as irinotecan in colorectal cancer, taxanes in breast, ovarian and lung cancer and carboplatin in ovarian cancer.
Since cytotoxic agents have a selectively 'antiproliferative' action rather than selective 'anticancer' properties, the therapeutic window for tumour versus normal tissue is modest at best.
A popular choice of treatment is Gleevec, a small molecule that is approved in the treatment of chronic myeloid leukaemia and gastrointestinal stromal tumours via inhibition of the Bcr-Abl and c-Kit receptor tyrosine kinases respectively.
Herceptin is a humanised antibody approved in ErbB2 positive breast cancers while Iressa is a small molecule inhibitor of the EGF receptor tyrosine kinase approved in non-small cell lung cancer and active in other tumour types.
Cancer is the second leading cause of death in the United States. This year, one in four deaths in the US is expected to be due to cancer and 1.4 million new cases will be diagnosed. For all forms of cancer combined, the 5-year relative survival rate is 64 per cent
Despite the fact that the cancer mortality rate in the US has risen steadily for the past 50 years, scientific advances appear to have begun to turn the tide. 1997 was the first year in the past half-century in which fewer Americans died of cancer than the year before - the start of what researchers hope will be a long-term decline in cancer deaths.
The cost of cancer to the healthcare system is significant. The National Institute of Health (NIH) estimates that the overall cost of cancer in 2003 was $189.5 billion (€146 billion) This cost includes $64.2 billion for direct medical expenses, $16.3 billion for indirect morbidity costs, and $109 billion for indirect mortality costs.