XL 119 Team

Clive Boulton Catherine

Sheppard Nisha Rose

Thomas

The XL-119 story

1988 19961995

Patented by Bristol Myers SquibbUS 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

Exelixis Evolution1995 Founded as a genomics based company1996 George Scangos appointed president and CEO1999 Bristol-Myers Squibb collaboration initiated2000 IPO / BMS collaboration extended2001 Receive exclusive worldwide license to develop and commercialize XL-119

Jeffrey R. Latts, M.D., appointed Chief Medical Officer2002 Annie Fong, Ph.D., appointed director, development

Harold Keer, M.D., Ph.D., appointed director, clinical R&DKimberly J. Manhard appointed VP, regulatory affairsSteven A. Lacy, Ph.D. appointed senior director, preclinical development

2003 Preliminary Phase 2 data on XL-119 in Hepatobiliary tumors announcedIND filed for XL-784Steven P. James appointed senior VP, commercial operationsInitiates phase I study with XL-784Shake-up of board of directorsSpecial Protocol Assessment for Phase 3 studies of XL-119 agreed with FDAIND filed for XL-119

2004 IND filed for XL-647XL-119 granted orphan drug status

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.

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 potentialIn phase II for pediatric solid tumorsIn phase II for non-small cell lung carcinoma.

Business Risks

Business risk is high Dependence on many larger drug

companies who provide financing All drug development is funded by

partners Gene to Drug platform R&D milestones

= payments (later = royalties) Partnering contacts depend on Exelixis

retaining key senior mgmt

Competitive risks Competitive risks from other forms of treatment is low

No approved standard therapy for bile duct tumors The prognosis for bile duct cancer patients is poor with

surgical resection, radiation therapy and chemotherapy being the only current treatments

XL119 targets people in the last stages of bile duct cancer so there is no competition from other drug treatments

Competitive risks due to other companies is low bile duct cancer is a small market that would not give a

good ROI orphan drug status gives market protection for 7 years

Technological risk

XL 119 molecule derived from natural product Inhibits Topo I ~ induces breaks in DNA Inducing DNA damage is an established

chemotherapeutic methodology Lack of efficacy in many cancer indications BUT FDA /NCI granted orphan drug status

reducing technological risk

Implementation risk Implementation risk is very high When Exelixis received rights for XL119 in 1999 it did not have:

a clinical trials group GMP/GLP facilities marketing and sales team

Actions taken by Exelixis to reduce the risk Appointed people with substantial experience who would then form their groups:

head of a corporate communications in March 2000 VP of clinical development appointed the in 2001 VP of pharmaceuticals in February 2002 head of commercial operations in June 2003

Current implementation risks Establishing cross functional teams that would run smoothly would require

extensive cooperation Problem of informational exchange as the compound has been developed by

BMS and the NCI Long time to conduct the phase 3 trials since rare disease makes patient

recruitment difficult

Operational risks

Operational risks are high Exelixis have no GMP/GLP facilities to

manufacture compounds for clinical trials so rely on third parties for manufacturing

Lacks procedures and project management maturity

Company transitioning to development Hired experienced VP PM (Feb 2004)

Market risk Market risk is low

The Rebeccamycin analogue was assigned no financial value while licensing from BMS

Phase 1 and 2 trails were not funded by Exelixis (It was conducted and funded by National Cancer Institute).

Exelixis only funding Phase 3 trials. Orphan drug status reduces phase 3 trial costs by giving tax credits, waivers FDA user fees and provides market protection for 7 years

Though market size is small, pricing could be favorable to Exelixis (the annual cost of life-long treatment with Credase for Gaucher's disease is about $150,000 per patient)

Exelixis Maturity Model

 Optimizing Process

L5

 

 Managed Process

L4 

 

NDA Mrkt

Institutionalized Process & Stds

L3 

 

IND Outsource

Structured Process & Stds

L2 

XL 119 / 784 / 647

Initial Process L1

Hypothesis - Why Exelixis accepted Rebeccamycin analogue

Exelixis was a genomics based company that wanted to focus on discovery and development of potential new drug therapies, specifically for cancer and other proliferative diseases

With Rebeccamycin analogue, an anticancer compound of Bristol-Myers Squibb, Exelixis received an exclusive worldwide license to develop and commercialize it. Exelixis did not have to pay for the in-licensing of the compound

Bristol-Myers Squibb agreed to provide access to its internal clinical development expertise to support Exelixis in the development of this compound

The low market risks and low competitive risks made it an attractive candidate

XL119 could serve as the pilot project that would help Exelixis assess their strengths and weaknesses and reduce the risk of other products in the pipeline. The pilot project could also help Exelixis build a relation with the FDA, NCI, oncology physicians and other stakeholders

Hypothesis - why BMS gave XL119 to Exelixis

XL119 was received as a part of cancer alliance with BMS The 2003 10-k form of Exelixis says, “Due to risk and

uncertainties with Rebeccamycin, and because the analogue had not reached technological feasibility and has no alternative use, the analogue was assigned no value for financial reporting purposes.”

This shows that: BMS did not consider it a worthy investment Even if it had been validated for bile duct cancer that

would not have given BMS a low ROI (opportunity cost)

XL119 - product portfolio strategy

XL119

Mode of Operation -- XL119 --Key to Exelixis

Keeping Key Partners happy to fundOperations. Allows the discovered gene to drug

pipeline XL 784 / 647 … to commercialize

Transitioning from Drug Discovery to Development

Maturing its Project Management and Processes

Sources http://www.exelixis.com http://www.ncbi.nlm.nih.gov/ http://patft.uspto.gov/ http://www.fda.gov/orphan/ http://www.cancer.org http://www.merck.com/about/feature_story/05192004_mectizan.html Phase I Clinical and Pharmacokinetic Study of Rebeccamycin Analog

NSC 655649 Given Daily for Five Consecutive Days. Journal of Clinical Oncology, Vol 19, Issue 8 (April), 2001: 2309-2318

Phase I Clinical and Pharmacokinetic Study of NSC 655649, a Rebeccamycin Analogue, Given in Both Single-Dose and Multiple-Dose Formats. Clinical Cancer Research Vol. 8, 2193-2201, July 2002

Phase I and Pharmacokinetic Study of NSC 655649, a Rebeccamycin Analog With Topoisomerase Inhibitory Properties. Journal of Clinical Oncology, Vol 19, Issue 11 (June), 2001: 2937-2947