Delivering on the Promise of RNAi Therapeutics


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This presentation outlines the pre-clinical and clinical development of Atu027, an siRNA developed by Silence Therapeutics and used in the treatment of cancer.

Silence Therapeutics Chief Scientific Officer, Klaus Giese, presented at the German Science Day: Fight Cancer! in Berlin, Germany, February 2nd 2012.

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Delivering on the Promise of RNAi Therapeutics

  1. 1. Fight Cancer! Eine Initiative der Deutschen BiotechnologieDelivering on the Promise of RNAi TherapeuticsDr. Klaus Giese, Chief ScientificOfficer
  2. 2. Silence today• Industry leader in RNAi therapeutics (a new drug class)• Strong expertise in delivering RNAi therapeutics in man• Listed on LSE (AIM) with operations centralised in Berlin (30 committed employees)• Strong validation through multiple partnerships supported by issued intellectual property (IP)• Building a strong pipeline targeting unmet medical needs with large commercial potential• Developing the first blockbuster RNAi therapeutic 2
  3. 3. Outstanding potential of RNAi therapeutics• Transforming technology Complex of siRNA and delivery vehicle (e.g.• Allows therapeutic intervention of previously liposomes) „undrugable‟ targets siRNA/RISC• RNA interference (RNAi) recognised by the Loss of function Nobel Prize in 2006 mRNA• Proof of concept already demonstrated in man destroyed using Silence„s technologies mRNA Normal• Commercial potential similar to monoclonal Protein function antibodies (sales 2010: US$48bn) DNA 3
  4. 4. AtuRNAi: Best-in-class siRNAtherapeutics platform• 2‟-O-Methylation offers greater stability Silence‟s AtuRNAi (siRNA) and better tolerability – No evidence of cytokine stimulation, activation of antisense strand 5’ 3’ Toll-Like Receptors or toxic metabolites – Over 300 patients treated to date 3’ 5’ – 33 doses given to 1 patient over 9 months sense strand (compassionate use) 2’-O-Methyl modifications• Fast preclinical development – Screening starts directly with modified siRNA • Issued patents in Europe and US – Same scale up process for all AtuRNAi products • Licensed to Pfizer, Novartis,• Lower Cost of Goods compared to AstraZeneca, Quark unmodified siRNA molecules 4
  5. 5. Breakthrough delivery technologies AtuPLEX™ Tumor blood vessels Cancer & Metastases Lung blood vessels DACC Acute lung injury/ARDS Pulmonary Hypertension Lung cancer Liver DBTC Hepatocellular carcinoma Ischemia Reperfusion Injury Acute liver failure 5
  6. 6. Silence„s DACC delivery system is highly specific targeting the lung• Novel lipid-based formulation to address lung-specific diseases (e.g. acute lung injury/ARDS/lung cancer)• DACC delivers siRNAs primarily to the lung• Single dose sufficient to inhibit target gene expression up to a month Organ distribution after delivery of siRNA with DACC 125 siRNA [%ID/g tissue] 100 75 50 25 0 6
  7. 7. Silence„s DBTC delivery system is highlyspecific to liver• Proprietary lipid-based formulation to address liver-specific diseases (e.g. hepatocellular carcinoma)• DBTC delivers specifically to the liver• Single dose inhibits target gene expression in the liver up to a week Organ distribution after delivery of siRNA with DBTC• No gene expression inhibition detected in 70 other tissues 60 siRNA [%ID/g tissue] 50 40 30 20 10 0 7
  8. 8. Strong validation through partnerships Research collaboration: $15M Option & licence Delivery upfront and $400M AstraZeneca agreement with Delivery collaboratio in milestones plus Novel approaches Quark: $82m in collaborati n on royalties for 5 to delivery of siRNA Extension of both milestones plus on on AtuPLEX & targets molecules collaborations royalties AtuPLEX DBTC 2006 2007 2008 2009 2010 2011 2012 Top 10 PharmaAtuRNAi for diabeticmacular edema and AtuRNAi for acuteage-related macular renal failure anddegeneration; $95M in kidney transplantation Expansion of Delivery Deliverymilestones plus (and 2008, now in Ph. siRNA delivery delivery collaboration on collaboration onroyalties (now in Ph. II) I + II) collaboration collaboration DACC DBTC 8
  9. 9. Industry‟s broadest siRNA therapeuticsclinical pipelineProducts Partners Target Delivery Market Pre-Clinical Phase I Phase II Tissue / method size($m) OrganPF-4523655 RTP801 Naked siRNA $1bn+Diabetic Macular - Local Delivery (potential)Edema to the EyePF-4523655 RTP801 Naked siRNA $3.1bn (2010)Age-related Macular - Local DeliveryDegeneration to the EyeQPI-1002 P53 - Systemic Naked siRNA $4.4bn (2010) Delivery to thePrevention of Delayed KidneyGraft FunctionQPI-1002 P53 - Systemic Naked siRNA $1bn+ Delivery to the (potential)Acute Kidney Injury KidneyAtu027 PKN3 - Systemic AtuPLEX $8.2bnSolid Tumors Delivery to (angiogenesis Tumor mkt 2010) EndotheliumAtu134 Systemic AtuPLEX $8.2bnSolid Tumors Delivery to (angiogenesis Tumor mkt 2010) EndotheliumAtu111 Systemic DACC $1bn+ Delivery to Lung (potential)Acute Lung Injury EndotheliumAtu195 Systemic AtuPLEX $8.2bnSolid Tumors Delivery to (angiogenesis Tumor mkt 2010) Endothelium 9 Five of 13 global clinical siRNA programs use Silence’s AtuRNAi – over 300 patients treated
  10. 10. Atu027 targeting PKN3 for RNAi mediated cancer therapy Growth factor receptor AtuPLEX Delivery system to endothelial intracellular PI 3-K p110a PTEN tumor cells p110b Ras Akt-1 Myc Hif-1 Akt-2 Lipid-basedPTB-1B PKN3 drug carrier p53 Bcl-2 Redd1 AtuRNAiGlucose Survival Tumor Metastasesuptake progression inhibitor MotilityPKN3 Key regulator during angiogenesis and lymphangiogenesis Major regulator of metastasis/motility during pathological processes 10
  11. 11. Atu027: Strong preclinical efficacy data• Atu027 „silences‟ the production of Origin Model T/C tumor T/C metastasis PKN3 prostate PC-3 iprost 0.42 0.22 – PKN3 is a key regulator of blood and PC-3 iprost 0.50 0.15 lymph vessel formation LNCaP iprost 0.36 - DU-145 s.c. 0.56 -• Inhibition of PKN3 leads to: PC-3 s.c. 0.62 - – Reduced oxygen supply to tumour – Reduced tumour growth/metastases pancreas MiaPaCa ipanc 0.55 0.24 Dan-G ipanc 0.66 -• Efficacy of Atu027 demonstrated in L3.7pl ipanc 0.64 0.71 multiple cancer animal models V332 ipanc 0.73 - – Data published in peer reviewed lung Lewis Lung 0.55 - journals i.v. B-16V i.v. 0.46 -• PKN3 associates with Rho family A-549 ipulm 0.84 0.34 GTPases, and preferentially with RhoC breast MDA-MB-435 0.77 0.40 (Pfizer) MDA-MB-231 0.86 0.67 melanoma B-16V s.c. 0.59 - colon LS 174T ihep 0.14 - 11
  12. 12. Clinical Phase-I trial with “Atu027”in oncology “A prospective, open label, single-centre, Atu027 -dose finding phase I study with Atu027(an siRNA formulation) Dose level Dose (mg/kg) in subjects with advanced solid cancer - Atu027-I-01” based on the siRNA content) 1 0.001  Patient Break Break End of Study 2 0.003  3 0.009  Weeks -2 -1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 4 0.018  0.036  Months 0 1 2 3 4 5 6 0.072  7 0.120  8 0.180  9 0.253  10 0.336  11 0.447 3-6 subjects per dose level (Treatment: 4h i.v. infusion, 500 mL) 12
  13. 13. Atu027 Phase I summary andoutlook• Atu027 is positioned to treat vascularised tumours• Eleven patients confirmed with stable disease• Potential biomarkers identified• Final data expected by mid–2012• Current discussions for phase II - Atu027 in combination with standard of care to treat solid tumors - Mono-therapy (salvage therapy) in recurrent Glioblastoma 13
  14. 14. Thank You