By Mike Nagle

24/05/2007 - At a time when pharma productivity is declining, anticancer specialists Exelixis has started more Phase I clinical trials this year than any other company.

The US biotech has today filed an Investigational New Drug (IND) application to US regulators at the Food and Drug Administration (FDA). It is the company's fourth such application this year, which are a precursor to beginning clinical development.

Also, a fifth drug is restarting clinical development in a new indication after concerns over side effects in previous Phase I and II trials. Exelixis has now started more Phase I clinical trials this year than any other company, according to figures complied by DrugResearcher.com; at least among those companies that disclose early stage development.

This latest application is for XL019, a small molecule inhibitor of the cytoplasmic tyrosine kinase JAK2. Mutations that lead to increased activation of JAK2 are frequently observed in patients with myeloproliferative disorders - where excess cells are produced in the bone marrow. Examples of this type of disorder are myelofibrosis, polycythaemia vera and essential thrombocythaemia.

JAK2 is also often found to be more active in many lymphomas and solid tumours.

"XL019 is a potent inhibitor of the JAK/STAT signalling pathway, which plays a critical role in cell growth and survival in a number of diseases where few clinical options currently exist," said Dr Gisela Schwab, chief medical officer at Exelixis.

"We believe that evaluation of XL019 in such indications may allow us to, early on in clinical development, observe biologic activity and potentially affect clinical outcome."

In January, the company submitted an IND for XL418, a protein kinase B (PKB or AKT) and S6 Kinase (S6K) inhibitor, which are key components of the phosphoinosotide-3 kinase (PI3K) signalling pathway.

At the time, Dr Schwab said: "To our knowledge, XL418 is the first dual inhibitor of AKT and S6K to enter clinical development."

Then, in March, a second IND was submitted. This time, the drug, called XL147, is a PI3K inhibitor. The third IND came a month later, this time for XL765. This drug again inhibits PI3K but it also blocks the action of mammalian target of rapamycin (mTOR), which also is activated frequently in human tumours and plays a central role in tumour cell growth.

"We believe XL765 is another example of our ability to generate insight into critical cancer-related pathways and to translate that understanding into potentially first-in-class compounds," explained Schwab.

"We are therefore evaluating multiple compounds that inhibit distinct components of the PI3K pathway," explained Schwab.

"With this strategy, we believe that we are well positioned to maximize the potential of inhibiting the PI3K pathway for the treatment of multiple cancers."

As well as drugs for these two pathways, in April, Exelixis reinitiated clinical development for XL999, which inhibits various receptor tyrosine kinases, including FGFR, VEGFR and PDGFR. The drug also blocks FLT3, an important driver of leukaemia cell proliferation in some patients with acute myelogenous leukaemia (AML).

Previous Phase I and II clinical trials for XL999 were stopped after some patients suffered from heart problems. However, the company will now focus on testing the drug as a treatment for non-small cell lung cancer (NSCLC), after the FDA accepted a new clinical trial protocol.

Other companies that have initiated nearly as many trials this year include Array BioPharma ARRY-797,ARRY-520 and ARRY-704. This latter drug is being developed with AstraZeneca. All three are anticancer drugs. In fact of the 96 Phase I clinical trials identified by DrugResearcher.com to have started this year, 37 are for anticancer drugs, making it by far the most popular therapeutic category for new Phase I trials so far.

Pharmacopeia has also started three Phase I clinical trials this year. The first of these, PS433540, has already been reported on by DrugResearcher.com in February. Since then, the company has also started trials for two drugs being developed in collaboration with Schering Plough. PS386113 and PS522501 are described as drugs to treat inflammatory disease and metabolic disorders respectively. However, a spokesperson for both companies refused to disclose their targets or any mechanism details.

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