1. Phytoquest Limited Discovery of new naturally-derived medicines and routes to market

2. Phytoquest Limited 2 | Current Trends Pharmaceutical development too expensive and slow for small companies/investors Public want healthier products Regulators such as EFSA want substantiation of claims Convergence of pharmaceuticals/ functional foods/ cosmetics/ herbal products 3. Phytoquest Limited 3 | Traditional Pharma Natural Product Discovery High throughput screening of tens of thousands of extracts complex mixtures unknown concentrations non-polar solvent focus Intensive data analysis to prioritise and select most promising hits for scale-up fermentation/extraction Bioassay-guided chromatographic purification for structure elucidation and secondary evaluation The process was very wasteful and not very successful We still know very little about the secondary chemicals in common plants We know many herbal medicines can work but dont know the active components 4. Phytoquest Limited 4 | Are there new medicines to be found in Nature? The active metabolites of very few herbal medicines are known Quality control is usually on production method or markers and not an activity or active component Most herbs were traditionally prepared in water but many products are alcohol based Analysis is usually of major non-polar compounds amenable to HPLC methods There is wide variation in commercial preparation methods There is controversy over most herbal medicines over whether they work and if so how often despite decades of research worldwide, e.g. Echinacea 5. Phytoquest Limited Iminosugars Iminosugars: Stable, small molecules Selective glycosylation inhibitors, immune modulators, protein stabilisers Orally available, distributed rapidly Metabolically inert (excreted in urine unchanged) Specialised expertise required for discovery and synthesis N H OH O H OH O H N H O H O H OH O H N O H OH OH O H H OH N H O H O H OH OH pyrrolidine piperidine pyrrolizidine indolizidine Examples: O OH H H H OH OH H OH H OH D-glucose equivalent iminosugar Analogues of sugars, with ring oxygen replaced by nitrogen N H OH H H H OH OH H OH H OH HN HO OH OH OH nortropane 6. Phytoquest Limited Carbohydrates: New Therapeutic Targets and Drug Classes One of ten emerging technologies that will change the world MIT Review 2003 Carbohydrates and associated receptors present excellent drug targets and a growing market opportunity Carbohydrate complexity and diversity greatly exceeds that of proteins and genes DNA RNA Protein Carbohydrates Traditional Drug Discovery PQ Drug Discovery Genome Ribome Proteome Glycome Molecular Information 7. Phytoquest Limited Casuarine Boosts Type-1 Immune Responses N OH OHH CH2OH HO OH MNLP462a N OH OHH CH2OH HO O O CH2OH HO OH HO MNLP462b Natural Occurrence Present in at least three distinct medicinal plants but very rare in nature. Guacatonga Casearia which has casuarine as a major alkaloid) claimed to treat AIDS, cancer, TB, leprosy, flu, herpes, wounds and diabetes; all used orally in water. N OH H OHHO HO CH2OH 3-epi-462a 8. Phytoquest Limited Casuarine B16 Tumour In Vivo Efficacy: Significant anti-cancer activity 80% tumour reduction80% tumour reduction 9. Phytoquest Limited Casuarine Adjuvant Flu Vaccine 1X 0.5ug MNL462a 0 0.5 1 1.5 2 2.5 10 100 500 1000 5000 10000 50000 100000 500000 1000000 5000000 10000000Dilution OD405 PBS 1 1ug 1 1ug 2 1ug 3 50ug 1 50ug 2 50ug 3 1+0.5B 1 1+0.5B 2 1+0.5B 3 Imino sugars decrease Ag dose requirement Imino sugars decrease Ag dose requirement COGS is a major factor in $4 Bn Flu market Significant increase in influenza Ab response increased efficacy lower COGs 10. Phytoquest Limited Gymnema sylvestre diabetes Proven to work in Man but wrong components studied One iminosugar isolated and appears to have all the in vivo activity of the plant , 11-Aug-2006 + 08:02:59Gynema from Anita 3.50 5.50 7.50 9.50 11.50 13.50 15.50 17.50 19.50 21.50 23.50 25.50 27.50 Time0 100 % mnl154103 Scan EI+ TIC 5.30e8 9.22 2.68 3.24 3.62 7.68 9.48 Diabetes N H OH OH OH O OH 11. Phytoquest Limited Iminosugar Suppresses Hyperglycaemia in Fasted Male ddy Mice Bloodglucoselevel(mg/dl) Maltose challenge of 2.5g/kg administered at time 0 Compound given at time of challenge (PO or IP) or 30mins prior to challenge (Predose-PO) 12. Phytoquest Limited **** Iminosugar Increases Plasma Insulin Levels After Glucose Challenge in Fasted Male ddy Mice Serum insulin concentrations of male ddy mouse 30 minutes after D-glucose oral load (2.5g /kg body weight). Each value represents the mean SEM (n = 3-4). * P < 0.05, ** P< 0.01. Non treatment D-Glucose iminosugar D-Glucose + iminosugar 13. Phytoquest Limited Iminosugars in the Literature 0 10 20 30 40 50 60 70 80 90 100 Number of publications 1923 1949 1964 1969 1977 1985 1990 1995 2000 2005 Year Iminosugar Publications by Year Majority of publications from 1980s onwards by PhytoQuest staff 14. Phytoquest Limited Review of the Discovery Paradigm Traditional med chem Can take up to 36 months1 and 500+ cpds for candidate identification Paradigm is Screen ATH HTL LO cand Focus is on activity, selectivity; addressing physiochemical, ADME issues The PhytoQuest approach Efficient coverage of glyco- and property space Gives higher value hits Potent and selective with good physicochemical properties built in Potential upside? Shorter timeframes (12-18 months) and lower metrics (100+ cpds) Paradigm refinement to Screen (LO) cand Chemistry know-how a fundamental advantage 1 Drug Discovery & Development, Technology in Transition; Elsevier; Rang (Ed) 2006 15. Phytoquest Limited Nucleoside Therapeutics Historical Perspective > 25 marketed nucleoside analogues since 1960s 1960s First Generation Based on naturally occurring compounds Toxicity 1980s Second Generation Unnatural sugar and base modifications Reduced toxicity Enhanced potency N N NH2 O NH N O O I NN N O NH2 O HO HO NH NN N O Idoxuridine N NN N NH2 O HO HO OH Vidarabine N N O O S HO NH2 Lamivudine NH N O OO HO N3 Zidovudine N N O O S HO NH2 Emtricitabine F HO NH NN N O NH2 Abacavir O HO NH NN N O NH2 Acyclovir O HO OHHO Ribavirin HN N O O O OH OH Telbivudine NH N O O F3C O HO HO Trifluridine O HO Didanosine N N N OO HO NH2 HO Decitabine O HO HO OH Cytarabine 20001960 199019801970 16. Phytoquest Limited Nucleosides Revisited: Key Learnings SAR of all marketed nucleoside drugs Limited tolerance to modification Basic structural motifs essential for activity Set of 120 basic structures would have provided starting point for all marketed drugs Reduced costs and development time Reduced toxicity Enhanced potency and selectivity O HO Base R 6 x Base 20 x sugar units 120 nucleosides 17. Phytoquest Limited PhytoQuest Representative Set Iminosugar Library PhytoQuest combines synthetic and natural approaches Improving on nature Maximising diversity Minimising lead time PhytoQuest Representative Set Iminosugar library Unique and diverse library High value novel structures Natural and synthetic Largest collection of naturally-derived structures Screening PhytoQuest Representative Set Building Blocks H N NN H N OH OH OH OH Novel Therapeutics PhytoQuest Representative Set Library 18. Phytoquest Limited Importance of Carbohydrates Growing understanding of how nature uses carbohydrates Protein/Cell recognition Immunology Cell adhesion, migration Inflammation, Metastasis Protein folding Neurodegeneration Receptor binding Opportunities for therapeutic intervention Mimic the carbohydrate directly Alter the carbohydrate coating of proteins or cells Iminosugars provide a mechanism for either of these O HO HO HO HO OH 19. Phytoquest Limited 19 | Pharmaceuticals Functional Foods Herbal Medicines Big Opportunities to Exploit Expertise in Areas of Market Overlap Personal care products 20. Phytoquest Limited Claims rejected by EFSA apple cider vinegar can improve bowel movement the horsetail plant (Equisetum arvense L.) can help maintain normal hair green tea is good for blood pressure, cholesterol levels, bones, teeth and eyesight or that it works as an antioxidant cranberry juice can reduce the risk of urinary tract infection in women the probiotic Lactobacillus plantarum supports the immune system sugar-free chewing gum can reduce dental plaque glucosamine can reduce the risk of osteoarthritis EFSAs Panel on Dietetic Products, Nutrition and Allergies (NDA) is responsible for verifying the scientific substantiation of the health claims. 21. Phytoquest Limited 21 | Natural Active Components Identified Market Exclusivity AU 0.00 0.20 0.40 0.60 0.80 1.00 1.20 1.40 1.60 1.80 2.00 Minutes 1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00 9.00 10.00 11.00 12.00 13.00 4.768 5.9776.1146.235 6.727 7.182 7.478 7.7207.8788.030 8.2998.515 8.867 9.129 10.255 Enrich Activity Standardise Products Unlock New Activities Basis for Substantiation Market Challenges 22. Phytoquest Limited PhytoQuest Assets make us an Effective Innovation Partner Innovative analytical profiling coupled with isolation and in vitro screening Phytoquest Technology Platform Compound Libraries Phytopure Fraction Diversity Iminosugars Commercial Pipeline Chocolate Coffee Rice Chamomile Pumpkin Lycium (Goji) INVENT PROTECT IMPROVE Stevia Potatato 23. Phytoquest Limited Imino Force Casuarine rich Honey Naturally collected by bees in Africa Readily detected by GC- MS (tms derivatives by our lab). Quantified for reliable actvity , 26-Mar-2014 + 15:37:30Honey 574 11.94 12.94 13.94 14.94 15.94 16.94 17.94 18.94 19.94 Time0 100 % PHQ067003 Sm (Mn, 1x3) Scan EI+ TIC 3.29e8 Area 18.99;12427811 11.93;11518164 17.59 18430686 17.29 355109612.42 3441748 17.97 5068463 18.91 1441318 , 26-Mar-2014 + 15:37:30Honey 574 104 154 204 254 304 354 404 454 504 554 604 m/z0 100 % PHQ067003 3078 (18.995) Scan EI+ 6.88e7129 103 101 117 147 130 217 204170 148 191 361272 218 243 258 346305 284 319 476418 373 390 432 462 504 520 588550 608 24. Phytoquest Limited Honey Tests IFN 0.01 0.1 1 10 100 0 500 1000 1500 2000 2500 Day 0 EE Day 2 EE Day 0 NR Day 2 NR LPS ( g/ml) pg/ml 25. Phytoquest Limited Honey Data 0 50 100 150 pgofIFN/mlBlood 0 0.01 0.1 1 10 100 LPS (g/ ml) day 21 day 14 day 7 day 2 day 0 * P < 0.05 compared to respective concentration on day 0 * * * Effect of LPS on IFN release in whole blood following administration of 462a/3 * * * * * * * * * * IFN-g response increases and stays higher 26. Phytoquest Limited Diab. Block Extract Stevia - Stevia rebaudiana leaves (reduces glucose uptake) Gherkin - Cucumis sativus fruit (anti-inflammatory) Vegetable Marrow Cucurbita pepo fruit (controls blood sugar) Gymnema Gymnema sylvestris leaves (shown to regenerate beta cells) , 26-Mar-2014 + 21:06:24NON-EU DIABETES 4.45 6.45 8.45 10.45 12.45 14.45 16.45 18.45 20.45 Time0 100 % PHQ067013 Scan EI+ TIC 7.88e8 10.14 8.96 3.66 7.165.324.85 5.67 8.18 9.26 9.78 10.73 11.34 14.1113.2012.46 12.10 14.43 17.21 18.14 27. Phytoquest Limited Imino Gherkin Extract A single anti-inflammatory iminosugar present in certain varieties Compound reduces TNF-alpha directly Orally available and stable Reduces inflammatory responses like a steroid but is not steroidal , 01-Oct-2010 + 18:46:27cucumber 108/3 4.93 6.93 8.93 10.93 12.93 14.93 16.93 Time0 100 % PHQ015308 Scan EI+ TIC 5.67e7 5.45 4.57 4.02 10.63 6.73 6.34 28. Phytoquest Limited Imino Gherkin Extract 29. Phytoquest Limited Medical Foods Medical foods are distinct from the broader category of foods for special dietary use and from traditional foods that bear a health claim. In order to be considered a medical food the product must, at a minimum: be a food for oral ingestion or tube feeding (nasogastric tube) be labelled for the dietary management of a specific medical disorder, disease or condition for which there are distinctive nutritional requirements, and be intended to be used under medical supervision. 30. Phytoquest Limited Natural Active Components Identified Market Exclusivity AU 0.00 0.20 0.40 0.60 0.80 1.00 1.20 1.40 1.60 1.80 2.00 Minutes 1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00 9.00 10.00 11.00 12.00 13.00 4.768 5.9776.1146.235 6.727 7.182 7.478 7.7207.8788.030 8.2998.515 8.867 9.129 10.255 Enrich Activity Standardise Products Unlock New Activities Basis for Substantiation Market Challenges for foods, cosmetic ingredients providing opportunities for new Pharma products