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Exelixis Reports Positive Clinical Pharmacodynamics Data for PI3K/mTOR Inhibitor XL765 at ASCO

Sunday, June 1, 2008 General News J E 4
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CHICAGO, May 31 Exelixis, Inc. (Nasdaq: EXEL)reported interim data from a phase 1 dose-escalation trial of XL765, a novelsmall molecule inhibitor of phosphoinositide-3 kinase (PI3K) and mTOR, whichare implicated in tumor cell proliferation, survival, and resistance tochemotherapy and radiotherapy. The trial is being carried out in patients withmetastatic or unresectable solid tumors for which known effective measures donot exist or are no longer effective. Kyriakos Papadopoulos, MD, ClinicalInvestigator at South Texas Accelerated Research Therapeutics (START) and alead investigator in the trial, presented the data in the PI-3 Kinase/mTORDirected Agents oral abstract session (Abstract #3510) at the 44th AnnualMeeting of the American Society of Clinical Oncology (ASCO).

There were 19 patients available for safety, pharmacokinetic, and tumorresponse analyses as of the May 1, 2008 cutoff. Results from pharmacodynamicsanalyses indicate that XL765 inhibits the PI3K/mTOR pathway in patients atwell-tolerated doses. Reductions of 80-90% in the phosphorylation of pathwaycomponents including AKT, 4EBP1, and S6, and a reduction of 54% in cellproliferation (as assessed by Ki67 staining) were observed in tumor tissuefrom a patient with chondrosarcoma at the 60 mg twice-a-day (BID) dose level.Reductions in the phosphorylation of these pathway components were alsoobserved at this dose level in surrogate patient tissues, including hairbulbs, skin, and peripheral blood cells. The pattern of inhibition of proteinphosphorylation observed in these tissues is consistent with observations frompreclinical studies, and suggests that XL765 inhibits PI3K and bothmTOR/raptor and mTOR/rictor in patients.

XL765 administration also resulted in the augmentation of food-inducedchanges in plasma insulin in an exposure-dependent fashion, but generally hadno effect on plasma glucose levels. PI3K is known to play a key role ininsulin signaling, and PI3K inhibition has been shown to increase insulinlevels in preclinical models.

Five patients with various cancers have experienced stable disease for atleast three months, including two patients (colon adenocarcinoma andmesothelioma) with stable disease lasting six months or longer.

Administration of XL765 at doses up to 60 mg BID has been generallywell-tolerated, with no dose-limiting toxicities reported. At the maximumadministered dose of 120 mg BID, dose-limiting toxicities included anorexia,hypophosphatemia, and reversible increases in liver enzyme levels. Thepreliminary maximum tolerated dose (MTD) is 60 mg BID, and dose ranging isongoing to establish the MTD for both twice-daily and once-daily dosingregimens.

"The encouraging pharmacodynamic results in this trial are consistent withthe target profile of XL765, and clearly demonstrate that XL765 inhibits bothPI3K and mTOR in patients at doses that are well-tolerated," said Michael M.Morrissey, PhD, President of Research and Development at Exelixis. "We arevery encouraged by these data, and believe they support the development ofthis compound both as a single agent and in combination with other anti-canceragents."

"These positive data set the stage for possibly major advances toward thedevelopment of treatments for the many different cancers that involve the PI3Kpathway," said Dr. Papadopoulos. "For perhaps the first time, we have seeninhibition of the PI3K pathway in humans, with good tolerability. The datasuggest that XL765 has potential both alone and in combination with othertherapies."

Phase 1b/2 clinical trials of XL765 as a single agent and in combinationwith other targeted agents or cytotoxic chemotherapy are planned to initiatelater this year.

Investor and Analyst Briefing at ASCO, Monday, June 2, 6 p.m.

Exelixis will host an investor and analyst briefing on Monday, June 2, at6:00 p.m. at the Hyatt McCormick Place (Reg
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