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PRODUCT DESCRIPTION
TroVax is a novel therapeutic cancer vaccine that has potential application in most solid tumour types. The vaccine is designed to induce an immune response against the tumour-associated antigen 5T4. The 5T4 tumour antigen is a unique target, which is expressed at high levels in the majority of epithelial-derived cancers such as colorectal, renal, prostate, lung and breast.

INDICATION
All solid tumours where the 5T4 tumour antigen is present.

MARKET
The global cancer market is expected to generate sales in excess of US$60 billion by 2010. The market for therapeutic cancer vaccines, although minimal at present, has the potential to mirror the growth seen in the monoclonal antibody market, and reach sales in excess of US$5 billion by 2012 (Research and Markets). With potential application in most types of solid cancer, TroVax could capture a significant share of this market opportunity.

TECHNICAL DESIGN
TroVax consists of a Modified Vaccinia Ankara (MVA) poxvirus, which is engineered to express the gene for the 5T4 tumour antigen.

CLINICAL STATUS
TroVax is being developed in collaboration with sanofi-aventis. Over 900 patients have been enrolled in clinical trials to-date. Results are available from nine completed Phase I/II and II trials in renal, colorectal and prostate cancer. A Phase III trial in renal cancer is ongoing and Phase III trials in metastatic and post-adjuvant colorectal cancer are planned.

A cross-trial analysis of the Phase I/II and II trials was presented at the EORTC-NCI-AACR Symposium on 'Molecular Targets and Cancer Therapeutics' in October 2008. The analysis was based on survival and immunological response data from 189 evaluable patients with colorectal (four trials, n=73), renal (four trials, n=89) and prostate (one trial, n=27) cancer. The median number of TroVax vaccinations received was five with a range of one to 12. TroVax was well tolerated in all cancer types and in combination with both chemo and cytokine therapies. Of 180 patients tested for antibody responses post-vaccination, 159 (88%) and 176 (98%) showed positive responses for the 5T4 antigen and the Modified Vaccinia Ankara (MVA) vector respectively. The kinetics of the magnitude of 5T4 antibody responses was similar across all cancer types irrespective of co-medications. Peak median 5T4 antibody titres were detected following four vaccinations of TroVax.

The analysis of all evaluable patients showed a statistically significant association between immune responses to 5T4 and overall survival, which was also evident in an analysis of patients with colorectal cancer alone. There were no correlations between the immune response to MVA and patient survival, suggesting that clinical benefit is independent of patients' health status and immune competence. Across all nine trials, a doubling in the 5T4 antibody response between the first and third TroVax vaccinations was associated with a reduction in the relative risk of death of 16% (p < 0.002). The effect was strongest in colorectal cancer patients with a reduction in relative risk of death of 19% (p < 0.01).

Phase III Development

Renal Cancer

A Phase III trial in patients with advanced and metastatic renal cell carcinoma (TRIST: TroVax Renal Immunotherapy Survival Trial) was initiated in November 2006 and reached full recruitment of 733 patients in March 2008. In July 2008, the Data Safety Monitoring Board (DSMB) recommended that the trial should continue but that further vaccinations are discontinued. The DSMB advised that TroVax administered according to the protocol will not meet the predefined primary efficacy endpoint, but there is important scientific merit and more to be learned by additional follow up of all patients. In October 2008, the US Food and Drug Administration (FDA) agreed to a series of amendments to the TRIST study, following the DSMB's statement. The amendments to the study are designed to explore whether patient outcome is dependent on the number of doses, background standard of care and patients' prognostic factors at baseline. Under the revised plan, an interim analysis is scheduled for Q1 2009.

Colorectal Cancer

Sanofi-aventis is planning to start two Phase III trials pending FDA agreement. Both trials are expected to start patient recruitment in Q2 2009:

• A Phase III trial in patients with metastatic colorectal cancer (FLAMENCO: First Line treAtment of patients with MEtastatic (N) COlorectal cancer). The trial is expected to recruit approximately 1,300 patients.
• A Phase III trial in colon cancer patients who have had surgical resection of their primary tumours and been treated with adjuvant chemotherapy (QUASAR V: Quick And Simple And Reliable, Vaccine). The trial is expected to recruit approximately 3,000 patients. The clinical trial network, QUASAR, is supporting the trial with sanofi-aventis and Oxford BioMedica.

SANOFI-AVENTIS COLLABORATION
Oxford BioMedica signed a global licensing agreement with sanofi-aventis in March 2007 to develop and commercialise TroVax for the treatment of cancer. Under the terms of the agreement, the companies are co-funding the ongoing Phase III TRIST study in renal cell carcinoma. Sanofi-aventis will fund all future research, development, regulatory and commercialisation activities. Oxford BioMedica retains an option to participate in the promotion of TroVax in the United States and the European Union.

PARTNERS / FUNDING
Cancer Research UK, UK
QUASAR, UK
sanofi-aventis, France