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In yet another engagement with big pharma, Exelixis (EXEL) has announced that it has granted to Merck (MRK) a worldwide exclusive license to its PI3K-delta research and development program, including XL499, the company’s most advanced preclinical PI3K-delta inhibitor and other related compounds.

Under the agreement, Merck will have sole responsibility to research, develop and commercialize compounds originating from the program. In addition, Merck will make an upfront payment of $12 million to Exelixis and Exelixis will be eligible for potential development and regulatory milestone payments for multiple indications of up to $239 million. In a related note, there are reports that Merck is giving back rights to anti-ADDL antibody therapeutics and diagnostics for Alzheimer disease to Acumen Pharmaceuticals.

A look at the Exelixis pipeline shows that the firm has many other compounds in development-- some each for several indications, so it makes sense that a promising compound like XL499 would be out-licensed in order to help share the burden of development costs.

Exelixis' well known Phase III drug candidate XL184, for example, has a therapeutic indication in Thyroid Cancer (Advanced Medullary Thyroid Cancer). That late stage program was once partnered with Bristol-Myers Squibb Company (BMY), but in the summer of 2010, the development-stage drugmaker announced that it was ending its year-and-a-half-old partnership. The compound is also in Phase II as a treatment of metastatic castration-resistant prostate cancer patients with bone metastases, as an oral formulation for the treatment of advanced malignancies. It is also is being developed as an oral formulation for the treatment of metastatic hormone-receptor-positive breast cancer and in combination with erlotinib (oral) for the treatment of non-small cell lung cancer as well as a first line treatment of glioblastoma.

After ending its year-and-a-half-old partnership with Bristol-Myers Squibb, Exelixis regained the full rights to the drug and out-licensing the drug again may still be in the cards. Despite what critics have said, success of EXAM was a critical milestone for the company because it marked the first time that a compound discovered and developed internally by Exelixis has progressed to and successfully completed a pivotal trial.

In Phase II for various indications, the firm has XL147-- a potent inhibitor of phosphoinositide 3-kinases (PI3K) signaling in human tumor cell lines. The drug being developed as capsules for the treatment of advanced or recurrent endometrial cancer. XL147 in combination with erlotinib hydrochloride is being developed as oral formulation for the treatment of non-small cell lung cancer (NSCLC). XL147 (oral) in combination with Trastuzumab (IV) and Paclitaxel (IV) is being developed for the treatment of refractory HER2 positive metastatic breast cancer. XL147 (tablets) is being developed in combination with Letrozole (tablets) as for the treatment of patients with hormone receptor-positive and HER2-negative breast cancer refractory to a nonsteroidal aromatase inhibitor. XL147 (capsule) in combination with paclitaxel (intravenous injection) and carboplatin (intravenous injection) is being developed for the treatment of advanced solid tumors.

Also in Phase II, the firm's small molecule anticancer compound, XL880 is partnered up with GlaxoSmithKline (GSK) as a possible treatment for papillary renal cell carcinoma and for the treatment of recurrent or metastatic squamous cell carcinoma of the head and neck as well as for the treatment of metastatic gastric cancer.

In partnership with Sanofi (SNY), currently in Phase I, XL147 is also being developed as capsules for the treatment of advanced solid tumors. Also with Sanofi in Phase I the firm is developing XL765 as capsules for the treatment of advanced solid tumors in adults.

“PI3K-delta is an interesting target with potential utility in a number of therapeutic areas, including inflammation and oncology,” said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. “Our PI3K-delta program builds on our prior interest in the PI3K family, which led to the advancement of pan-PI3K inhibitors into clinical development for cancer. Merck’s global presence and significant resources make it the ideal organization to carry the PI3K-delta program forward. At the same time, this agreement provides Exelixis with resources for the continued development and potential commercialization of our lead compound, cabozantinib, which is in late-stage development for medullary thyroid and prostate cancers.”

“Exelixis has established a strong reputation for innovation in the development of targeted kinase inhibitors,” said Don Nicholson, Ph.D., Vice President and Head of Worldwide Discovery, Respiratory and Immunology Franchise, Merck Research Laboratories. “Collaborations like this are an important part of our strategy as we seek new ways to address unmet needs in inflammatory disease and oncology.”

PI3K-delta is a member of the Class 1 family of phosphoinositide-3 kinases and is predominantly expressed in cells of the immune system. Activation of PI3K-delta occurs in response to a variety of immune cell stimuli, and inappropriate PI3K-delta activation is thought to contribute to multiple inflammatory and allergic disorders, including rheumatoid arthritis and allergic asthma. Selectively targeting PI3K-delta has also shown potential in the treatment of certain lymphomas.

Earlier this fall, Exelixis reported top-line results from the ongoing phase 3 clinical trial of cabozantinib in patients with advanced medullary thyroid cancer (MTC), known as the EXAM trial. The trial met its primary endpoint of improving progression-free survival (PFS) compared with placebo and substantially exceeded the threshold of a 75% increase in PFS originally assumed when the trial was designed. Cabozantinib significantly improved median PFS by 7.2 months compared with placebo. The median PFS on the cabozantinib arm was 11.2 months versus 4.0 months on the placebo arm.

Speaking of milestones, a look at the BioMedReports Calendar of Clinical Trials and World Wide Regulatory Catalysts shows several key milestones on tap for Exelixis including as many as four scheduled to take place in 2012.

With 14,896,000 of the firm's 276,890,000 shares positioned to the short side, we could see some covering and price pressure as good news is announced. Shares are trading at a 65.91 % discount from their 52-week high ($12.82).

With 59% of those shares now owned by institutions, this looks like a smart bet for speculators at these prices. EXEL shares are trading at a deep discount to their analyst target price.

Source: Exelixis' Dance With Big Pharma Continues