Silence Therapeutics - Gene Silencing - Corporate Presentation September 2011


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This presentation outlines the history and recent developments of Silence Therapeutics, a biopharmaceutical company developing novel therapeutics based on RNA interference. Silence Therapeutics is a world leader in the discovery, development and delivery of novel RNA interference (RNAi) therapeutics for the treatment of serious diseases.
With an experienced team leading pharmaceutical development, almost half of all on-going siRNA clinical trials are based on Silence technology. Find out more in the presentation or go to the website

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Silence Therapeutics - Gene Silencing - Corporate Presentation September 2011

  1. 1. Corporate Presentation September 2011
  2. 2. Forward-Looking Statements The statements made in this presentation may contain certain forward- looking comments. Actual events or results may differ from the Company’s expectations. In addition to the matters described in the presentation, future actions by the European Agency for Evaluation of Medicinal Products, the U.S. Food and Drug Administration or equivalent regulatory authorities in other countries and results of pending or future clinical trials, as well as other risk factors outlined from time to time in the Company’s regulatory filings, may affect actual results achieved by the Company. The Alternative Investment Market (AIM) has not reviewed and does not accept responsibility for the adequacy or accuracy of this presentation. 2 2
  3. 3. Background• Silence Therapeutics AG (formerly Atugen AG) was founded in 1998 as spin-off from RPI (later renamed to Sirna) and financed by MPM Capital, Apax and NVF• Target discovery and validation service company using antisense and delivery technologies -> over US$20m accum. service revenues from pharma companies• Developing delivery technologies for oligonucleotides since 1998• First AtuRNAi patent application filed in 2002, US patent granted in Nov. 2008• In 2005 reverse merger with SR Pharma plc (shell) listed on AIM, London• Renamed to Silence Therapeutics plc/AG in 2007 (LSE: SLN)• Acquired US siRNA therapeutics company Intradigm Corp. in January 2010• To date over £50m invested in RNAi platform• Well funded following successful £5.9m fundraising in May 2011• Current market cap. c.£11m -> technology value of only £5m 3
  4. 4. Overview• World leader in the discovery, development and delivery of novel RNA interference (RNAi) therapeutics for the treatment of serious diseases − RNAi offers a unique new class of drugs that overcomes hurdles of existing drugs• One of the sector’s most comprehensive RNAi platforms − Deliver to more target cells and tissues that anyone else (e.g. AtuPlex, DACC)• One of the industry’s broadest RNAi clinical pipelines − Five of the 12 siRNA (& 4 of the 5 Phase II) clinical programs worldwide are based on Silence technology − Clinical and pre-clinical pipeline in diverse therapeutic areas – metabolic, pulmonary, vascular, oncology − Encouraging Phase I data on lead internal candidate Atu027 recently presented at ASCO• Validating partnerships with leading global pharmaceutical companies − AstraZeneca, Pfizer/Quark, Novartis/Quark and Dainippon Sumitomo• Broad intellectual property portfolio − Issued patents covering aspects of delivery, sequences and structures 4
  5. 5. Silence Product Pipeline Products Indications Partners Target Delivery Pre- Phase I Phase II Target Tissue / Clinical Organ PF-4523655 Diabetic Macular Pfizer/Quark RTP801 Naked Local Delivery to the (AtuRNAi) Edema siRNA EyePartnered programs PF-4523655 Age-related Macular Pfizer/Quark RTP801 Naked Local Delivery to the (AtuRNAi) Degen siRNA Eye QPI-1002 Prevention of Delayed Novartis/ P53 Naked Systemic Delivery to (AtuRNAi) Graft Function Quark siRNA the Kidney QPI-1002 Acute Kidney Injury Novartis/ P53 Naked Systemic Delivery to (AtuRNAi) Quark siRNA the Kidney Atu027 GI & Lung & other Internal PKN3 AtuPLEX Systemic Delivery to (AtuRNAi) cancers Tumor Endothelium Atu134 Solid Tumors Internal AtuPLEX Systemic Delivery toInternal programs (AtuRNAi) Tumor Endothelium Atu111 Acute Lung Injury Internal DACC Systemic Delivery to (AtuRNAi) Lung Endothelium Atu195 Solid Tumors Internal AtuPLEX Systemic Delivery to (AtuRNAi) Tumor Endothelium Almost half of all ongoing siRNA clinical trials are based on Silence technology 5
  6. 6. Current Partnership Overview Silence’s RNAi therapeutic platform has been validated through multiple major partnerships • AstraZeneca - $15M upfront payment with up to $400M in milestones plus sales royalties for five targets (2007, extended 2010) • AstraZeneca – Novel approaches to delivery of siRNA molecules (2008, extended 2010) • Pfizer/Quark – Phase II products for diabetic macular edema and age- related macular degeneration; $95M in milestones plus royalties (2006) • Novartis/Quark – Phase I/II products for acute renal failure and kidney transplantation; $82m in milestones plus royalties (2010) • Dainippon Sumitomo – siRNA delivery collaboration (2009, expanded 2010) 6
  7. 7. Commercialisation Strategy• Out-license / co-develop internal candidates – e.g. Atu027 (in 2012), Atu111 (in 2012), Atu134 (TBD), Atu195 (TBD)• Form new collaborative alliances with pharmaceutical partners (target-specific) – e.g. AstraZeneca and Dainippon Sumitomo• Grant access to our proprietary technology platform (target- specific) – e.g. Quark/Pfizer and Quark/Novartis – securing near-term non-dilutive funding – build long-term platform value• Collaborate with biotech partners – e.g. for co-development of novel delivery approaches 7
  8. 8. PF-4523655: Opthamology• Silence licensed AtuRNAi technology to Quark in 2004 2010 Market size (AMD) $3.1bn• Pfizer licensed PF-’655 in 2006 from Quark DME 24%• Milestones to Silence total $95m – next milestone c$4m on phase III start• Phase II trial in diabetic macular oedema (DME) showed superiority over laser therapy – Phase IIb to start in 2011 AMD 76%• Phase II trial in age-related macular degeneration (AMD) data due in 2H11• Low single-digit effective royalty rate Potential Market size (DME) $1bn+ on end sales Source: company reports 8
  9. 9. QPI-1002: Renal disease• Silence licensed AtuRNAi technology to Quark in 2005 2010 Market size (transplant) $4.4bn• Novartis signed $10m option for QPI- Neoral 1002 in 2010 19%• Milestones to Silence of c.$82m Prograf – next milestone $3-11m on exercise of option 42% Myfortic 10%• Phase II trial in prevention of delayed graft function (DGF) initiated September 2010 (results due 2012)• Phase II trial in acute kidney injury Cellcept (AKI) expected to commence 2H11 29%• Low single-digit effective royalty rate Potential Market size (AKI) $1bn+ on end sales Source: company reports 9
  10. 10. Overcoming the Delivery Challenge AtuPLEX DBTCVascular endothelium Liver parenchyma • Cancer & Metastasis • Hepatocellular carcinoma • Inflammation • Ischemia Reperfusion Injury • Fulminant Fibrosis DACC Pulmonary endothelium • Acute lung injury/ARDS • Pulmonary Hypertension • Infection & Inflammation 10
  11. 11. Atu027/Atu134: Market opportunity• Anti-angiogenic market worth $8.2bn 2010 Market size (oncology) $53bn• Both Atu027 and Atu134 are anti- angiogenic drugs Anti-• Atu027 is only RNAi anti-angiogenic angiogenics, drug in clinical development 8.2• Atu027 will be used in the setting of Chemotherapy, highly vascularised tumours; prostate, 19.3 lung, ovarian & melanoma Hormone Therapies, 8.9• Results of on-going phase I trial expected at end 2011• Interim data to be presented at ASCO, Other Other small June 2011 antibodies, 10 molecules, 6.7• Partner Atu027 in 2012 – upfront, milestones and royalties Source: company reports Anti-angiogenic – works by disrupting blood supply to tumours 11
  12. 12. Atu027 deal structure Big Pharm a alliances 2005-9• Plan to partner in 2012 Upfront payment ($m) 35 30 25• Partnering discussions initiated 20 15 10• Typical deal structure 5 – Upfronts (double digit $m’s) 0 Lead Preclinical Phase I Phase II Phase III – Milestones (significant) – Royalties (double digit %) Early stage deals 2005-9• Variations 200 – Global rights 150 Payments ($m) – Regional rights 100 – Ex-US/Eu rights 50 – Opt-in rights 0 Upfront R&D Milestones Equity Source: RECAP Deloitte
  13. 13. Atu027: Strong preclinical efficacy data• Atu027 ‘silences’ the production of 0 20 - 45 46 days PKN3 Atu027 – PKN3 is a key regulator of blood and Avastin lymph vessel formation• Inhibition of PKN3 leads to: Vehicle – reduced oxygen supply to tumour – reduced tumour growth/metastases• Efficacy of Atu027 demonstrated in multiple cancer animal models Atu027 VEGF-R-siRNA-lipoplex – data published in peer reviewed Avastin journals VEGF-R-siRNA-lipoplex + Avastin Atu027 + Avastin• Atu027 has been shown to knock- down protein and mRNA expression of PKN3 in animal models• Impressive data led to start of Phase I trial in 2009 DU-146 prostate Xenograft (N = 8) Twice weekly treatment 13
  14. 14. Atu027: Phase I results promising BEFORE AFTER Baseline (pre-treatment) 1 week after 8th repeated treatment Note: vanished metastatic lesion in the left lower lobe of the lung (circle)• Data from Cohort 6: First dose level where efficacy was predicted based on preclinical work Of three patients treated: – one patient showed tumour shrinkage (above) – one patient showed stable disease at end of treatment phase – one patient discontinued treatment for non-drug related reasons 14
  15. 15. Atu134: Strong preclinical efficacy data• Atu134 has demonstrated efficacy in a In preclinical studies variety of preclinical cancer models – Orthotopic models Atu134 significantly reduced – Ectopic models tumour growth• Atu134 has demonstrated strong 4000 * p=0.003 efficacy against primary tumour * p=0.002 * p=0.014 Tumor volume [mm3] 3000• Targets CD31 – well validated target 2000• GMP manufacturing commencing 1000• Preclinical toxicology testing due to 0 start early in 2012 Sucrose Luciferase CD31 control (Atu134)• IND filing expected in 2012 Breast (mammary fat pad)• Plan to partner during Phase I – target double digit royalty rate 15
  16. 16. Atu111: treatment of acute lung injury• Acute lung injury (ALI) is an area of high unmet medical need• Significant market opportunity – Pneumonia is 2nd highest cause of hospital admissions – Pneumonia treatment costs $8bn/yr in US alone (mortality rate 12-30%) – ALI principle cause of mortality• DACC delivery system provides Organ distribution after delivery of siRNA with DACC exquisitely selective delivery to lung 125 (see chart) siRNA [%ID/g tissue] 100 75• DACC delivery system leads to prolonged 50 knock-down 25 – potential for only one dose in ALI 0• Aim to partner in 2012 – target high single digit royalties 16
  17. 17. DBTC: Targeting the Liver• Proprietary lipid-based formulation targeting liver• Significant market opportunities – Liver cancer – Ischemia reperfusion injury – fibrosis• DBTC delivers siRNAs primarily to liver (see chart) Organ distribution after delivery of siRNA with DBTC 70• DTBC delivery system leads to persistent siRNA [%ID/tissue] 60 knock-down 50 – Single dose knocks down gene expression 40 for up to 1 wk 30 20 10• DTBC well tolerated 0 – Dosed up to 8.3mg/kg no functional delivery of siRNA to spleen no knockdown in spleen tissue. 17
  18. 18. Burn rate significantly reduced in 2H10£000s 1H10A 2H10A 2010ARevenue 716 1,650 2,366R&D spend (4,401) (1,420) (5,821)Admin costs (3,227) (1,976) (5,203)Operating loss (6,912) (1,746) (8,658)Other income/(exp.) (142) 5 (137)Loss before tax (7,054) (1,741) (8,795)Loss after tax (7,054) (1,741) (8,795)Net cash 6,836 3,567 3,567 ~ £5.9m raised in May 2011 ~ 18
  19. 19. Expected Milestones for 2011Update on progress of Atu027 Jan. 2011Update on PF-’655 in diabetic macular oedema (DME) Mar. 2011Full year results for 2010 April 2011Fundraising May 2011Present interim Phase I data of Atu027 at ASCO June 2011Completion of Phase II trial of PF-’655 in AMD (Pfizer/Quark) 2H11Start of Phase IIb trial of PF-’655 in DME (Quark) 2H11Extension of Dainippon Sumitomo collaboration 2H11Start of Phase II trial of QPI-1002 in AKI (Quark/Novartis) 2H11Further issuance of Zamore patents 2H11Completion of Atu027 trial 2H11 19 19
  20. 20. Corporate plans 2011-13Event Timing StatusComplete fundraising 1H11 Completed May 2011Present interim Phase I results at ASCO 1H11 Completed June 2011Complete Atu027 ‘in patient’ Phase I 2H11Milestone on delivery of final results in collaboration 2H11 Non-dilutive funding opportunityAnnounce Atu027 clinical plans 2H11Complete restructuring 2H11Present Phase I final results of Atu027 1H12‘Platform technology deal’ 1H12 Non-dilutive funding opportunityInitiate Atu027 Phase Ib 1H12License DACC/Atu111 2H12 Non-dilutive funding opportunityFile IND for Atu134 2H12License Atu027 2H12 Non-dilutive funding opportunityStart Atu134 Phase I 2H12Complete ‘in-patient’ Atu027 Phase Ib 1H13File IND on third internal drug candidate 1H13Announce Atu027 Phase Ib results 2H13Complete Atu134 Phase I study 2H13Start Atu027 Phase II trial 2H13 20
  21. 21. ManagementExperienced team with proven pharmaceutical development track record — Max Herrmann ACA, acting Chief Executive Officer and CFO Intercytex Group PLC, Onyx Pharmaceuticals, ING — Klaus Giese, Ph.D., Chief Scientific Officer Chiron Corporation, UCSF and Max-Planck Institute — Thomas Christély, Chief Operating Officer, OXO Chemie Inc., Löschen & Partner, Enskilda Securities — Jörg Kaufmann, Ph.D., VP Research Chiron, Howard Hughes Medical Institute 21
  22. 22. Summary• World leader in the discovery, development and delivery of novel RNA interference (RNAi) therapeutics for the treatment of serious diseases• One of the sector’s most comprehensive platforms for the discovery, development and delivery of targeted RNAi Therapeutics• One of the industry’s broadest RNAi clinical pipelines addressing diverse therapeutic areas• Validating partnerships with leading global pharmaceutical companies• Broad intellectual property portfolio• Strong upcoming newsflow• Well funded following successful £5.9m fundraising in May 2011 22 22
  23. 23. APPENDIX
  24. 24. m Atu027: Gene knock-down of PKN3 confirmed in preclinical studies Plasma level of siRNA strand (1st infusion) Protein knock down in lung tissue (Western blot) 1000 1.0mg/kg sucrose 0.3 1.0 3.0mg/kg antisense strand [pmol/ml 0.3mg/kg animal # 1 2 3 4 5 6 7 8 antisense strand [ng/ml 1000 100 0.1mg/kg plasma] PKN3 plasma] 0.03mg/kg 10 3.0mg/kg 10 p110 1 Actin 0 0 0 4 8 12 16 20 24 time [h] RNAi in lung tissue (5‘-RACE) mRNA knock down in lung tissue (B-DNA) Sucrose 0.3mg/kg hPKN3/hPPIB mRNA 1.2 229 bp 16S rRNA 5´-RACE 0.8 (internal control) 0.4 166 bp PKN3 RNAi 5´-RACE 0.0 vehicle 0.03 0.1 0.3 1.0 3.0 cleavage site control mg/kg ATU027/23H verified 24
  25. 25. Atu027: Phase I Study Design• Atu027 - targeting PKN3 for the treatment of advanced solid cancer • PKN3 is a key regulator during angiogenesis and lymphangiogeneis• Prospective, open label, single-centre, dose finding study • Male and female subjects with advanced or metastatic solid tumors not amenable to curative standard therapy • Approx 33 subjects - 3-6 subjects per dose level • 11 dose levels, dose escalation: modified Fibonacci Scheme• Treatment: 4h i.v. infusion• 24 patients treated (end March 2011) 25 25
  26. 26. We have achieved Predictable Pharmacokinetics For Atu027 Cynomolgus Monkey Human 4 h infusion 4 h infusion 120 120 0.180 mg/kgA strand concentration in plasma 0.3 mg/kg A strand concentration in plasma - mean of dose groups [ng/mL] 0.120 mg/kg - mean of dose groups [ng/mL] 0.1 mg/kg 0.072 mg/kg 0.03 mg/kg 0.036 mg/kg 80 80 0.018 mg/kg * * 0.009 mg/kg 0.003 mg/kg 40 40 0.001 mg/kg 0 0 0 4 8 12 16 20 24 0 4 8 12 16 20 24 Time [hours] Time [hours] In vitro: IC50 ≈ 1 to 10 nM * Final/verfied data pending Predictable PK tells that Atu027 is behaving in humans as it did in pre-clinical models
  27. 27. Atu027: Positive Phase I Data to Date• Phase I trial on-going – expected to complete 2H2011− No dose limiting toxicities to date, dose escalation continuing Atu027 - Dose (mg/kg) Dose level• Generally well tolerated to date (based on the siRNA content)− 173+ doses administered to 24 patients across 8 dose levels 1 (starting dose) 0.001− Up to 26 doses administered to a single patient (study 2 0.003 followed by compassionate use)− No cytokine activation observed 3 0.009 4 0.018• No pre-medication required 5 0.036• > 210 timepoints analysed for complement 6 0.072 system and cytokine activation 7 0.120 8 0.180• Limited Atu027-related transient activation of 9 0.253 the alternative pathway of the complement system - (as published and expected for 10 0.336 liposomal formulations) not dose dependant 11 0.447• Human plasma PK shows dose dependent increase with no evidence of drug accumulation during repeated treatment 27
  28. 28. Atu134 (CD31/PECAM-1): A wellvalidated target 28
  29. 29. Efficacy of Atu134 in Various Ectopic Tumor Xenograft Models 3200 1600 sucrose siRNALuc- sucrose 800 sucrose lipoplex Tumor volume [mm³] Tumor volume [mm3]Tumor volume [mm3] 1200 2200 siRNAPTEN- 600 Atu134 lipoplex 800 Atu134 1200 400 Atu134 400 200 200 0 24 26 28 30 32 34 12 14 16 18 25 31 37 43 49 Days post cell challenge Days post cell challenge Days post cell challenge PC-3 s.c. 3Y1-RasV12 s.c. DU-145 s.c. Atu134 shows anti-tumor activity in different established subcutanuous tumor xenografts in comparison to control treatment. Silence Therapeutics 29
  30. 30. Thank you