Smart Science for Serious Disease Company Overview March 2011 1 Board and Management 2 John Beadle: CEO GSK, Pfizer, PowderJect, PowderMed Michael Moore: Chairman Cantab, Xenova, Piramed, Roche Charles Swingland: NED PowderJect, Zeneus, Circassia Phil L'Huillier: NED Cancer Research Technology Simon Kerr: Investor NED Imperial Innovations Maina Bhaman: Investor NED Imperial Innovations Mark Payton: Investor NED Mercia Fund Scientific Advisory Board – Professor Stefan Anker Professor of Applied Cachexia Research, Charité Medical School, Berlin. Founding President of the Society for Cachexia and Wasting Disorders. – Professor Andrew Coats Norwich Research Park Professor at Large, University of East Anglia and Honorary Professor of Medicine, University of Sydney, Australia. – Professor Len Seymour Chair of Gene Medicine and Head of Department of Clinical Pharmacology, University of Oxford. President of the British Society for Gene and Stem Cell Therapy. – Dr Kerry Fisher 3 Lecturer, Oxford University. Young Investigator of the Year in 2009 for the European Society for Gene and Cell Therapy. Psioxus pipeline MT102 Preclinical Phase II ColoAd1 Research Preclinical Phase I/IIa Phase IIb PolySTAR Research Preclinical Phase I/IIa PolyMAP Research Preclinical Phase I/IIa 4 MT-102 ANABOLIC / CATABOLIC TRANSFORMING AGENT (ACTA) Cachexia and sarcopenia 5 MT-102: Finding unique products that can block the catabolic cycle 6 MT-102: Anabolic / Catabolic Transforming Agent (ACTA) 7 MT-102: Anabolic / Catabolic Transforming Agent (ACTA) 8 MT102 Yoshida Rat Hepatoma Model 9 MT-102 Reverses weight loss 40 ** * 20 g 0 -20 *** -40 ** ** * -60 placebo 0.5 2 MT-100 Sham: + 59.7±2.1 g 10 1 MT-101 0.3 3 MT-102 ANOVA: p<0.0001 MT-100 and MT-101 are early research compounds now superseded by MT-102, but data is presented here for comparison purposes Myotec’s Lead Compound MT-102 Enhances survival 100 Percent survival 80 MT-102 3 mg = Myotec’s Lead Compound 40 placebo 20 imida 10 mg = Vitor™ in Phase III with Ark Therapeutics 0 0 11 2 4 6 8 Time 10 12 14 16 MT-102 Clinical Trial • A multicentre, randomised, double-blind, placebo-controlled clinical study • 132 patients • Subjects with cachexia related to stage III and IV – non-small cell lung cancer – colorectal cancer • Dose-finding phase II study with 3 parallel groups: – 10mg MT-102 two times per day – 2.5mg MT-102 two times per day – Placebo • Over a sixteen week period 12 ColoAd1 A POTENT AND HIGHLY SELECTIVE ONCOLYTIC VIRUS Colorectal and hepatocellular carcinoma 13 ColoAd1: Evolved oncolytic virus 14 ColoAd1 Selectively destroys cancer cells Cell killing is determined by the MTS assay and the number of particles required to kill 50% of the cells is shown (IC50). A smaller number indicates that cells are more sensitive. 15 ColoAd1 Selectively destroys cancer cells Irinotecan ColoAd1 120 120 HUVEx(normal) >2100 Cell viability % Cell viability % HepG2 >2100 x (cancer) 100 100 80 60 >1200 x 40 80 60 n.s. 40 20 20 HUVEx(normal) >2100 HepG2 >2100 x (cancer) 0 0.001 0 0.01 0.1 1 10 ColoAd1 particles per cell 16 100 1000 0.001 0.01 0.1 1 10 100 1000 Irinotecan mM Differential killing activity of ColoAd1 on normal and tumour cells. Human hepatoma cancer cells and normal human endothelia cells (HUVE) were exposed to a range of concentrations of either ColoAd1 or Irinotecan. After 5 days the number of cells remaining viable was determined using the MTS assay. The differential IC50 or ‘therapeutic index’ for ColoAd1 was over 1200 fold while killing with irinoitecn was not appreciably different. ColoAd1 No treatment cisplatin ColoAd1 17 Cancer cells (A549) Fibroblasts (Wi38) 0 10 20 30 ColoAd1 40 50 60 70 Days In vivo treatment of orthotopic ovarian cancer Survival Curve SKOV-LUC i.p. study 2.5 120 a 100 * Percent survival Tumour burden (g) 2 b 1.5 1 0.5 80 ** PBS ONYX Ad11 Colo OvAd1 A OvAd1 B OvAd2 60 40 20 0 0 PBS ONYX Colo 0 10 20 30 40 50 60 70 70 Days of mice. After 5, 7 and 9 days SKOV3 cells were seeded into the peritoneal compartment mice were administered 1x1010 virus particles of ColoAd1 or ONYX-015 i.p in 100ul of saline. a. In the first study, animals were sacrificed after 18 days when the control groups showed signs of high cancer burden. Residual cancer burden was determined by quantitative PCR b. In a second study mice were left to determine survival. 18 N=7 Significance determined by t-test and log rank test. ColoAd1 In vivo treatment of orthotopic metastatic colorectal cancer * Serum CEA level (ng/mL; Mean ± SEM) 1.01.00 250 * 0.80.80 0.60.60 0.40.40 200 150 100 50 0.20.20 0.00.00 Serum CEA level * 300 300 300 CEA levels Serum(ng/mL; ng/ml Mean ± SEM) 1.21.20 (grams, Mean ± SEM) burden day tumourweight RemainingTumor 1.40 2 ColoAd1 3 Ad11p 4 ONYX-015 n=10 250 250 Significance was determined by MannWhitney analysis, 200 200 150 150 100 100 Cancer burden analysis was performed blinded. * 50 50 * * Data taken from Khun **et al 2008.* 00 0 1 Buffer * Buffer ColoAd1CJ132 Buffer ColoAd1CJ132 ColoAd1, low ColoAd1, ColoAd1, low middle ColoAd1, ColoAd1, high middle ColoAd1, high HT-29 colon cancer cells were seeded into the livers of nude mice. After hepatic cancers were established, ColoAd1, wild type Ad11 or ONYX-015 were administered by tail vein injection. 12 days post infection mice were sacrificed and regions of remaining metastatic disease were removed and weighed (figure a). In addition to cancer burden analysis, serum CEA was measured as an indicator of viable cancer load (figure b). In this second study, activity of ColoAd1 was compared against a non-replicating virus control (ColoAd1D) to demonstrate the importance of replication. 19 ColoAd1 Excellent competitive profile • Highly selective for cancer cells • High anticancer potency • Potential for intravascular delivery • Killing by necrosis • Overcomes drug resistance • Kills cancer stem cells 20 PolySTAR ANTIBODY RESISTANT “STEALTHED” VIRAL VECTORS Vaccines and gene therapy 21 PolySTAR Antibody-resistant ‘stealthed’ viruses + Ad5 virus 22 Multivalent Hydrophilic Polymers PolySTAR Vector PolySTAR Pre-immune mice: luciferase expression 23 PolySTAR Targeting to Dendritic Cells: expression 24 PolySTAR Targeting to Dendritic Cells: stimulating PBMCs 25 PolyMAP HIGHLY POTENT SYNTHETIC TOLL LIKE RECEPTOR ADJUVANTS Vaccines and cancer immunotherapy 26 PolyMAP Polymerised multivalent synthetic adjuvants • Synthetic lipopeptides designed to mimic bacteria cell wall components. • Stimulating TLR 2 / 1, they have been developed as adjuvants for peptide vaccines. Synthetic TLR ligand + Inert polymer PolyMAP • Linking synthetic adjuvants together provides a more natural multiple-display pattern, equivalent to the fragments of bacteria cell walls. 27 PolyMAP Mechanism of action polymer adjuvant Cooperative multivalent interaction Cross-link receptor Signal transduction 28 • • • • Increased affinity (avidity) Enhanced receptor clustering and cross-linking Improved adjuvant solubility Improved adjuvant localisation PolyMAP IL-8 stimulation in BM derived dendritic cells 50ng/ml of polymer-display TLR ligand produces 5x greater IL8 expression relative to 50ng/ml free TLR ligand alone. • But the TLR ligand represents only 5% of the mass of the polymer conjugate (95% polymer) • So the 5 fold improvement in activity is achieved with 20 fold less adjuvant specific activity of TLR ligand is improved 100 fold Note that polymer alone is non-immunogenic 29 PolyMAP NF-kB simulation in macrophages • 100 ng/ml of polymer-display-TLR ligand produces 25x greater NF-kB expression relative to free TLR ligand alone • PolyMAP is equivalent to 100ng/ml LPS • But: Pam3Cys represents only 4 % of the mass of the polymer conjugate • So: specific activity of Pam3Cys is improved 600 fold • And: 4ng of polymerised Pam3Cys is equivalent to 100ng/ml LPS 30 PolyMAP Adjuvanting ova in mice 31 PolyMAP Adjuvanting ova in mice But: total weights are used and the polymer conjugates contain only 4% TLR ligand So: 40ug or 2ug of PolyMAP equals 1.6ug and 0.08ug TLR ligand respectively And: both are better than 40ug pure TLR ligand without polymer 32 PolyMAP As a direct cancer immunotherapeutic B16 growth rates with TLR ligand or PolyMAP given simultaneously with tumour cells (day 0) or 10 days after implantation (day 10). But: TLR ligand represents only 4% of the mass of the polymer conjugate So: Potency of the TLR ligand is increased much more than 20 fold through polymerisation 33 Smart Science for Serious Disease 34