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German Science Day

German Science Day. 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

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German Science Day

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  1. German Science Day

  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. Outstanding potential of RNAi therapeutics • Transforming technology • Allows therapeutic intervention of previously ‘undrugable’ targets • RNA interference (RNAi) recognised by the Nobel Prize in 2006 • Proof of concept already demonstrated in man using Silence‘s technologies • Commercial potential similar to monoclonal antibodies (sales 2010: US$48bn) Complex of siRNA and delivery vehicle (e.g. liposomes) siRNA/RISC Loss of function mRNA destroyed mRNA Normal function Protein DNA 3

  4. AtuRNAi: Best-in-class siRNA therapeutics platform • 2’-O-Methylation offers greater stability and better tolerability • No evidence of cytokine stimulation, activation of Toll-Like Receptors or toxic metabolites • Over 300 patients treated to date • 33 doses given to 1 patient over 9 months (compassionate use) • Fast preclinical development • Screening starts directly with modified siRNA • Same scale up process for all AtuRNAi products • Lower Cost of Goods compared to unmodified siRNA molecules Silence’s AtuRNAi (siRNA) antisense strand 3’ 5’ 5’ 3’ sense strand 2’-O-Methyl modifications • Issued patents in Europe and US • Licensed to Pfizer, Novartis, AstraZeneca, Quark 4

  5. Breakthrough delivery technologies Tumor bloodvessels Cancer & Metastases AtuPLEX™ Lung blood vessels Acute lung injury/ARDS Pulmonary Hypertension Lung cancer DACC Liver Hepatocellular carcinoma Ischemia Reperfusion Injury Acute liver failure DBTC 5

  6. Silence‘s DACC deliverysystemishighly specifictargetingthelung • 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 deliveryofsiRNAwith DACC siRNA [%ID/g tissue] 6

  7. Silence‘s DBTC deliverysystemishighlyspecifictoliver • 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 • No gene expression inhibition detected in other tissues Organ distribution after deliveryofsiRNAwith DBTC siRNA [%ID/g tissue] 7

  8. Strong validation through partnerships Research collaboration: $15M upfront and $400M in milestones plus royalties for 5 targets AstraZeneca Novel approaches to delivery of siRNA molecules Extension of both collaborations • Option & licence agreement with Quark: $82m in milestones plus royalties Delivery collaboration on AtuPLEX Delivery collaboration on AtuPLEX & DBTC 2007 2009 2012 2008 2011 2006 2010 AtuRNAifor acute renal failure and kidney transplantation (and 2008, now in Ph. I + II) siRNA delivery collaboration Delivery collaboration on DBTC AtuRNAifor diabetic macular edema and age-related macular degeneration; $95M in milestones plus royalties (now in Ph. II) Delivery collaboration on DACC Expansion of delivery collaboration Top 10 Pharma

  9. Industry’s broadest siRNAtherapeutics clinical pipeline 9 Five of 13 global clinical siRNA programs use Silence’s AtuRNAi – over 300 patients treated

  10. Atu027 targeting PKN3 for RNAimediated cancer therapy Growth factorreceptor AtuPLEX Deliverysystemtoendothelialtumorcells intracellular PI 3-K p110a PTEN p110b Ras Myc Akt-1 Hif-1 Akt-2 Lipid-based drugcarrier AtuRNAi inhibitor PKN3 PTB-1B p53 Redd1 Bcl-2 MetastasesMotility Glucose uptake Survival Tumor progression • PKN3 • Key regulator during angiogenesis • and lymphangiogenesis • Major regulator of metastasis/motility during • pathological processes 10

  11. Atu027: Strong preclinical efficacy data • Atu027 ‘silences’ the production of PKN3 • PKN3 is a key regulator of blood and lymph vessel formation • Inhibition of PKN3 leads to: • Reduced oxygen supply to tumour • Reduced tumour growth/metastases • Efficacy of Atu027 demonstrated in multiple cancer animal models • Data published in peer reviewed journals • PKN3 associates with Rho family GTPases, and preferentially with RhoC (Pfizer) 11

  12. Clinical Phase-I trial with “Atu027” in oncology “A prospective, open label, single-centre, dose finding phase I study with Atu027(an siRNA formulation) in subjects with advanced solid cancer - Atu027-I-01”   Patient End of Study Break Break         3-6 subjects per dose level (Treatment: 4h i.v. infusion, 500 mL) 12 Weeks -2 -1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Months 1 2 3 4 0

  13. Atu027 Phase I summary and outlook • 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

  14. Thank You

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