Biotech Tobacco: Assessing Commercialization Potential

1. Biotech Tobacco:Assessing Commercialization Potential Kelly Tiller & Marie Walsh The University of Tennessee 42nd Tobacco Workers Conference Charleston, South CarolinaJanuary 18, 2006 This project was supported by Initiative for Future Agriculture and Food Systems Grant no. 2001-52100-11250 from the USDA Cooperative State Research, Education, and Extension Service. Agricultural Policy Analysis Center - University of Tennessee - 310 Morgan Hall - Knoxville, TN 37996-4519 www.agpolicy.org - phone: (865) 974-7407 - fax: (865) 974-7298

2. A P A C Biotech Tobacco: Advantages • Tobacco is not in the food/feed chain • Tobacco is easily manipulated using biotechnology tools • Fully mapped genome • Tobacco produces a lot of biomass, quickly • Tobacco grows well in a variety of locations and conditions

3. A P A C Genetic Modification • Expression of novel compounds in tobacco • The vast majority of the research identified to date involves expression of novel compounds • Hyper-expression of existing compounds in tobacco • Secondary metabolites, corrosion inhibitors • Modification of existing tobacco compounds to have new characteristics

4. A P A C Biotech Tobacco Applications • Biopharmaceuticals • The vast majority of activities • The fastest growing segment of pharmaceuticals • Bioterrorist vaccines and countermeasures • Miscellaneous other compounds • Food safety • Biomaterials • Industrial enzyme production

5. Biopharmaceuticals • Biopharmaceuticals (biologicals) include: • Protein and enzyme therapeutic compounds • Monoclonal antibodies • Subunit vaccines • Revenues $40b in 2003, $65b by 2008 • 600 biologicals currently under development and/or in clinical trials • Potential for follow-on biologicals (biogenerics) • Most either derived from animal tissue or produced in mammalian cell culture systems • Usually Chinese Hamster Ovary (CHO) system

6. A P A C PMP: Potential Positives • Upstream costs of plant based production systems may be 70-80% lower than mammalian cell culture • Lower capital costs and operating costs • Nearing capacity for mammalian cell culture systems?? Expensive to expand • High initial estimates of plant based system productivity • Easy scale-up of production to kg quantities • Potential to address illnesses of little interest to large pharmaceutical companies • PMPs may be safer than mammalian systems because they don’t contain mammalian viruses

7. Mammalian Cell Culture Capacity • Conventional wisdom that production capacity is strained • Growth in demand for giant bioreactors due to growth in monoclonal antibody drugs • As opposed to recombinant proteins • New facility construction costly and lengthy • May not be as bleak as thought • Expansion occurring • Mammalian cell line productivity increasing • Alternative production platforms still commercially unproven

8. PMP: Advantages? • Productivity of plant systems • Cost of producing biopharmaceuticals in plant systems • Upstream vs. downstream costs • Time to market of PMPs • Time needed to develop and scale-up • Time needed for regulatory approval • Embrace of Big Pharma

9. Erythropoietein Human Growth Factor β-Interferon Malaria epitopes Streptococcus Surface Antigen IgA (Dental Caries) Carcinoembryonic Antigen Colon Cancer Antigens Interleukin 10 (Chrohn’s Disease; Inflammatory Bowel Syndrome) Glucocerebrosidase (Gaucher’s Disease) Interleukin 4 Urokinase (Breaks Blood Clots) Human Serum Albumin Rabies Antigens Hepatitis B Surface Antigen Rotavirus VP6 Labile Eneterotoxin (Botulism) Zonna pellucida ZB3 Protein (Contraceptive) Gastric Lipase (Cystic Fibrosis) Creatine Kinase Protein C (Anticoagulant) Neutropenia (Granulocyte Macrophage Colony Stimulating Factor) Epidermal Growth Factor α and β Hemoglobin Angiotensin Converting Enzyme (Hypertension) Insulin Like Growth Factor (Diabetes) Tissue Necrosis Factor (Rheumatoid Arthritis) HIV-1 Peptide Lactoferrin Substance P (Neuropeptide) Animal Pharmaceuticals (Vaccines) Feline Parvovirus (Panleukopenia) Canine Parvovirus Bovine Foot and Mouth Status of Biotech Tobacco Pharmaceutical Production • Measles • Aprotinin (Protease Inhibitor) • α-Galactosidase (Fabry’s Disease) • Interferon α 2a and 2b • Personalized Non-Hodgkin’s Lymphoma Vaccines • Papilloma Virus Vaccines • Lysosomal Acid Lipase (Woman’s Disease; Atherosclerotic Plaques) • Personalized Vaccines for Follicular Lymphoma • α Trichosanthin (HIV) • Diagnostics for Ovarian Cancer • Diagnostics for Ecclampsia • Biomarkers for Alzheimers Disease

10. Status of Biotech Tobacco Pharmaceutical Production • Expression does not equal commercialization • Clinical trials precede commercialization • Require several years to complete (7.8 years) • Average cost of bringing a new drug to market is $897 million • Costs for manufacturing the products only about 10-20% of total cost • Downstream costs similar for plant and animal systems

11. A P A C Tobacco PMP Clinical Trials • CaroRxTM – topical preventative intervention to prevent tooth decay • Planet Biotechnology • Phase II/III • Personalized non-Hodgkin’s Lymphoma cancer vaccines • Large Scale Biology Corporation • Phase I/II • RhinoRxTM – treatment of colds • Planet Biotechnology • Phase I

12. A P A C Commercially Available PMPs • Prodigene, produced in corn • Avidin – Glycoprotein used as a diagnostic • B-Glucuronidase – hydrolase used as visual marker in transgenic plants • Trypsin (TrypZean) – Protease enzyme used in processing pharmaceuticals • Aprotinin (Aprolizean) – Protease inhibitor used in cell culture • Large Scale Biology Corporation, produced in tobacco • Aprotinin – Protease inhibitor used in cell culture

13. A P A C Tobacco Demand Potential • Wide range of market potential • CaroRx: 55 acres to provide one treatment per year for every child in the U.S. and U.K. • Human blood serum albumin: 16,000 acres to displace world production • Most human therapeutic proteins have small markets, high value • < 10 kg/yr, > $10,000/gram

14. A P A C Field Production Challenges • Farms producing biopharmaceuticals are “manufacturing facilities” and have same FDA requirements • FDA says, “important to dispel notions that pharma crops are a value-added opportunity for a significant number of farmers.”

15. A P A C Bioterrorist Vaccines & Countermeasures • FY2004 Biodefense Research Budget: $41.3 billion • NIH-NIAID bildefense funding increased from $0 in 2000 to $1.7 billion proposed in 2006 • Tobacco transformed to produce potential bioterrorism vaccines or countermeasures including: • Heat labile enterotoxin (botulism), ricin (neurotoxin), anthrax, small pox, the plague • Fraunhofer USA, University of Maryland, Thomas Jefferson Medical Center particularly active

16. A P A C Other Novel Compounds • GM tobacco used produce antibodies to detect foodborne pathogens • Listeria, salmonella, E. coli, cryptosporidium • Toxin Alert developing food wrapping containing antibodies to several food poisoning bacteria and some pesticides • Working with University of Guelph and Mississippi State • Several biomaterial expressed in GM tobacco • Elastin, collagen, spider silk, polyhydroxyalkonates, polyaspartate, modified pectin

17. A P A C Cautions • Very expensive to develop and approve ANY of these products • Estimates of cost adventages are very preliminary • Very stringent FDA regulation and oversight, even at the farm level • The plant platform is still commercially unproven • Time to market is very long • Big Pharma vs. Little Pharma • So far, applications would not require significant field-grown quantity of tobacco

18. A P A C What’s Driving R&D? • Not mammalian cell culture capacity • Generally not upstream cost reductions • Potential for scale-up • Products with very large market potential • Marginal cost savings add up • Potential for individualized applications • Products with very high market value

19. A P A C Major Players (today) • U.S. firms: • Chlorogen / University of Central Florida • Large Scale Biology Corporation • Panorama Research • Planet Biotechnology • Phytomedica • SomaGenics • Non-U.S. firms: • Center for Genetic Engineering aned Biotechnology, ERA Plantech, Farmacule Bioindustries, Guardian Biotechnologies/Nexgen Biotechnologies, Icon Genetics AG, Meristem Therapeutics, Plantechno, Plantigen