Preparing Project Managers for Biotechnology (Arthur Miodozeniec PhD) April 2004 Dr Mlodozeniec, passed away in 2006, he was wonderful professor, rigorously taught us many critical skills, on risk management. Here reverse and forward engineering XL 119. Google his obituary.

2. The XL-119 story 1988 1996 1995 Patented by Bristol Myers Squibb US Pat. # 4,785,085 Pharmaceutical Reformulation US Pat. # 5,496,809 Clinical Brochure published by NCI 1997 Phase I study results published 1999 Pediatric Phase I study results published Phase I study results published 2001 Licensed to Exelixis 2004 Phase III study in Bile Duct cancer initiated 2003 IND for Bile duct cancer filed Granted Orphan Drug Designation 2002 Phase II study in bile duct cancer results published 2008 2016 Molecule patent expires Formulation patent expires

4. XL-119 the road to the clinic Discovered by Bristol-Myers Squibb (BMS) in 1986 the Rebeccamycin analogue (BMY-27557, BMS-181167) was found to be a potent inhibitor of cell proliferation both in vitro and in vivo. There were problems in the formulation of the compound, it was unstable for prolonged periods of time in solution. It was therefore reformulated and a patent for the new stable formulation was issued in 1996. It is assumed that BMS filed an IND for this compound, although the date of which remains unclear. However, a clinical brochure for the compound was released by the National Cancer Institute (NCI) in 1995. It is thought that at this time BMS were no-longer pursuing this molecule as a lead candidate as the Phase I and II trials were further sponsored by the NCI (compound renamed NSC-655649). Several Phase I trials were carried out and the results were published between 1997 and 2001. These established the maximum tolerated dose, efficacious dose, optimal dosing regime, toxicity and pharmacokinetic profile of the drug. Phase I studies also included analysis in pediatric solid tumors. Once optimal dosing had been established the indication for the drug was investigated. Phase I trials had determined that there was response to the drug in patients with hepatobiliary tumors, therefore a Phase II trial of 33 patients with bile duct carcinoma was carried out and in 2003 the results of these trials indicated an increase in median survival time for these patients. Results from phase II clinical trials in other indications were also published in 2003, these indicated that the drug was not efficacious in the treatment of metastatic colorectal cancer and showed modest antitumor activity in renal cell cancer. As part of a licensing agreement in a deal with BMS, Exelixis were granted an exclusive worldwide license to develop and commercialize the compound in 2001. With the efficacy of the drug in bile duct cancer Exelixis filed an IND for the compound in 2003. In 1Q04 Exelixis were granted orphan drug status by the FDA for XL-119 and announced they would start pivotal Phase III studies of the drug in patients with bile duct cancer in 2Q04.

5. XL-119 Target Market Bile duct cancer (gall bladder tumors and cholangiocarcinomas ) 30,000 patients world-wide (7,500-10,000 cases in the U.S. and in Europe, and a comparable number in Japan and other Asian countries) Median survival in patients with non-resectable tumors is approximately 5 months. Median survival of patients in Phase II clinical trials for bile duct cancer is 8.8 months. Patients will be dosed daily for 5 days which is then repeated 21 days later, therefore each patient will receive approximately 45 doses. XL-119 future potential In phase II for pediatric solid tumors In phase II for non-small cell lung carcinoma.

12. Exelixis Maturity Model L1 Initial Process XL 119 / 784 / 647 L2 Structured Process & Stds IND Outsource L3 Institutionalized Process & Stds NDA Mrkt L4 Managed Process L5 Optimizing Process

15. XL119 - product portfolio strategy XL119

16. Mode of Operation -- XL119 --Key to Exelixis Keeping Key Partners happy to fund Operations. Allows the discovered gene to drug pipeline XL 784 / 647 … to commercialize Transitioning from Drug Discovery to Development Maturing its Project Management and Processes