Sirna Therapeutics, Inc. - PDF Free Download

Sirna Therapeutics, Inc. UBS Presentation 4.25.2006

Forward Looking Statements Statements in this press release which are not strictly historical are "forward-looking" statements which should be considered as subject to many risks and uncertainties. For example, most drug candidates do not become approved drugs. The development of Sirna-027 and Sirna-034 as well as Sirna s other programs are still at a relatively early stage, are subject to significant unknowns, and require significant funding. Additionally, no single patent issuance predicts the likelihood of the rest of the pending Sirna patent estate issuing. Patent applications may not result in issued patents, and issued patents may not be enforceable or could be invalidated. Other risks and uncertainties include Sirna s early stage of development and short operating history, Sirna s history and expectation of losses and need to raise capital, Sirna s need to obtain clinical validation and regulatory approval for Sirna-027, Sirna-034 and the company s other product candidates, any of which could have negative results, Sirna s need to engage collaborators, Sirna s need to obtain and protect intellectual property, and the risk of third-party patent infringement claims. These and additional risk factors are identified in Sirna's Securities and Exchange Commission filings, including the Forms 10-K and 10-Q and in other SEC filings. Sirna undertakes no obligation to revise or update any forward-looking statements in order to reflect events or circumstances that may arise after the date of this release.

RNAi-based Therapeutics The next important drug class to impact human health > Potent and specific therapeutic effect utilizing an endogenous cellular mechanism > Selectively silences expression of pathological proteins and viral targets > Powerful catalytic mechanism > Applicable to classically non-druggable targets

Making RNAi-based Therapeutics a Reality Impact of Sirna s Chemistry Expertise The critical requirements to develop sirna therapeutics modification and formulation Serum Stability Half Life Circulation Time Tissue Targeting Duration of RNAi Activity Immune Response Unmodified sirnas < 1 min < 15 mins < 0.1% < 2 days Stimulatory Sirna s Compounds 17 days 4 days > 90% 22 days Regulated

Research and Development Programs Leveraging Chemistry and Delivery Across Multiple Therapeutic Areas Huntington s Disease Sirna target: HUNTINGTON Gene AMD Sirna target: VEGFR-1 Respiratory Viral Hepatitis Sirna target: HBV/HCV Diabetes Sirna target: Phosphatase 1B (PTP1B) Dermatology Sirna target: HAIRLESS TXN Factor

Pioneering Systemic sirna Delivery Viral Hepatitis Programs > Hepatitis C > 2.7 million US afflicted > $1 billion market worldwide > Hepatitis B > US ~ 1.25 million are chronic carriers > ~ 400 million chronic cases worldwide > Chronic HBV/HCV leads to fibrosis, cirrhosis, hepatocellular carcinoma and acute liver failure

Pioneering Systemic sirna Delivery Key Achievements in Viral Hepatitis > Chemically optimized sirnas which can target the conserved region of viral genome > sirna-based compounds designed to target multiple viral sequences to reduce drug resistant mutations > Sirna nanoparticle formulation targeting hepatocytes > Standard I.V. administration at low doses > Systemic efficacy in murine and non-human primate models

99.9% Reduction of HBV in Murine Model 1000.0 Day 3 Day 7 Serum HBsAg 100.0 10.0 1.0 99.9% Reduction Active sirna Control PBS Active sirna Control PBS 0.1 3mg/kg/day x 3 days

Anti-HBV sirna Dose Response in Murine Model 1000 Serum HBsAg 100 10 3 1 0.3 3 PBS Active Control mg/kg/day x 3 days

HCV Primate Study (Efficacy) > Three animals were infected with an HCV chimeric virus > Administered Sirna nanoparticle formulated, multisirna compound > Objective > Demonstrate delay in onset of establishment of viral infection > Demonstrate knock-down of viral load after established infection > Endpoints - safety and efficacy

sirna Mediated Knockdown of HCV Chimeric Infection in Non-Human Primate Model 7.5 7.0 Log Serum Titers 10 6.5 6.0 5.5 untreated 5.0 99.5% inhibition Three non-human primates were infected with an HCV chimeric virus at time zero 4.5 4.0 3 wk delay in onset of established infection 3.5 0 1 2 LOQ 3 4 Weeks 1-8 5 6 7 Dose = 3mg/kg 8

Summary of sirna mediated inhibition of HCV Chimeric Infection in Non-Human Primate Model > Efficacy > Delayed onset of establishment of viral infection > Demonstrated a 99.5% reduction in viral titers in an established infection > Safety > No increase in liver enzymes observed (ALT, AST) > Mechanism of Action > sirna-mediated target cleavage products detected by RACE analysis

Sirna-034 Development Candidate for Treatment of HCV > Sirna-034 targets multiple HCV sequences and is designed to reduce drug resistant mutations > Pre-IND package submitted to FDA > The Agency found the proposed IND program satisfactory and offered minimal additional recommendations > IND to be filed by Q4 2006

Huntington s Disease > Fatal untreatable CNS disease affecting 30,000 patients in the U.S. > 200,000 pre-symptomatic patients > CAG expansion causes intracellular aggregates resulting in neuronal cell death > Inhibition of mutant gene expression may be most important therapeutic approach > Current therapies only treat disease symptoms no approved therapies treat the underlying disease

Silencing Huntingtin Protein Expression In Vivo Relative Huntingtin Expression 1.2 1 0.8 0.6 0.4 0.2 0 Untreated 60% Reduction AAV-shRNA > Silencing of endogenous huntingtin protein was measured in entire striatum 2-weeks after introduction to mouse brain

Rotarod System for Measuring Motor Function In Collaboration with Dr. Beverly Davidson, University of Iowa

sirna Improves Motor Function in HD Transgenic Mouse Model 500 Time to Fall (sec) 400 300 200 100 50% - 60% Improvement 0 Day 1 Day 2 Day 3 Day 4 Normal Treated Untreated Harper et al. PNAS 2005: 102: 5820-25

Achievements in Huntington s Disease In Collaboration with Dr. Beverly Davidson, University of Iowa > First demonstration of animal efficacy in Huntington s Disease > 60% knockdown of HD gene in mouse model using an AAV vector expressed sirna > Mouse models demonstrate that reduction of mutant gene expression after disease onset improves neuropathology and motor symptoms > Select clinical development candidate in Q4 2006

External Collaborations Huntington s Disease Sirna target: HUNTINGTON Gene AMD Sirna target: VEGFR-1 Respiratory Viral Hepatitis Sirna target: HBV/HCV Diabetes Sirna target: Phosphatase 1B (PTP1B) Dermatology Sirna target: HAIRLESS TXN Factor

Sirna Allergan Strategic Alliance Key Industry Collaboration in Ocular Diseases > Strategic alliance in ocular disease with a global leader in eye care > $5MM initial payment > Up to $245MM clinical milestones > Worldwide royalties > Manufacturing revenues > Allergan is responsible for development of Sirna-027 > Phase II initiation planned for 2H 2006 > Collaboration leverages the strengths of both companies to develop novel and innovative ocular therapeutics > Sirna develops optimized sirna lead compounds > Allergan conducts and funds all pre-clinical development, clinical, regulatory, and commercialization activities > Allergan provides proprietary and novel delivery technologies

Sirna GSK Strategic Alliance Key Industry Collaboration in Respiratory Diseases > Strategic alliance with a global leader in respiratory diseases > $12MM initial payment > Over $700MM development and clinical milestones > Worldwide royalties > Manufacturing revenues > GSK funds all pre-clinical and clinical development > Collaboration leverages the strengths of both companies to develop novel and innovative respiratory therapeutics > Establishes the world s leading effort in RNAi-based therapeutics for the treatment of respiratory diseases > Sirna will develop optimized sirna compounds and formulations against Sirna and GSK targets > GSK will conduct and fund all preclinical and clinical development, regulatory and commercialization activities > GSK will provide proprietary and novel device technologies

Maximizing Value Through Partnerships > Established a reproducible deal structure > Therapeutic and/or target-focused > Partner with companies that dominate therapeutic and target areas > Supports Sirna s internal pipeline programs

Dominant Patent Estate in RNAi-based Therapeutics > Sirna s patent estate covers every aspect of drug design, synthesis, development & manufacturing > Use > Targets > Technology > Chemistry > Delivery > Manufacturing 51 Issued Patents and over 250 Pending Patents Worldwide

Sirna s RNAi IP Dominance Technology IP Licensed IP Target IP No Ribo sinas sina for Greater Potency and Stability Multifunctional sirnas Target Multiple Genes Simultaneously Micro RNAs Chemically-modified mirnas Conserved Sequence Targeting Multiple Genes or viral strains Tuschl, et.al. sirna for Therapeutic Use B. Davidson U of Iowa Huntington s & Other Neurological Indications A. Christiano Columbia Hair Removal Hair Growth Rana, et.al. UMASS Chemical Optimization AMD HD Hairless Asthma Hepatitis Diabetes VEGF Pathway HD Gene Hairless TX Factor IL-4 IL-4R IL-13 IL-13R HBV HCV PTP-1B Chemistry Chemistry & Chemically Modified sirnadelivery Improved PK Stability Potency Inhibition of Immune-stimulation Delivery Tissue & Cell Targeting Nanoparticles Conjugates Manufacturing Manufacturing Process Development Scale-Up cgmp manufacturing Raw Materials Reagents

First Broad sirna Target Patent Issued in the US > April 4, 2006 Sirna was issued U.S. Patent No. 7,022,828 for chemically modified sirna targeting IKK-γ > Broadly covers any sirna used to target entire gene - not limited to any specific sirna sequence or structure > Broadly covers any chemically modified sirnas targeting the gene not limited to any specific chemistry > Sets precedent for Sirna s patents covering over 250 important disease causing genes and viruses

Multi-Sequence Gene Targets Therapeutic Area Targets Metabolic PTP1B JNK1 p38 GIP SCD ERK-1 CETP ACADB Myostatin Oncology Her-2 RAF RelA Ras EGFR K-ras CHK1 c-fos PKC-α ERG-2 c-myc MDR-1 Egr-1 VEGFR p38 VEGF GAB2 Bcl2 c-jun PCNA XIAP cdk2 JNK1 Telomerase ECGF1 PRL3 ERG IGF-1R c-myb ERK-1 EGF-1 EZH2 HIF1 BCR/ABL Cyclin-D1 ANG-1 B7-H1 PDGF PDGF (R) P1GF-1 htr VCAM Inflammation/Fibrosis/ IGF-1R REL-A GAB2 p38 TGF-β TGF- βr c-fos Respiratory VEGF VEGFR IL4-R ADAM33 ANG-1 CHRM3 CXCR5 FAS GPRA ICAM IKK-γ IL-2 IL-4 IL-8 IL-13 IL-13R VCAM MMP13 IL-9 IL-5 RSV Cardiovascular/Renal c-myc c-myb VEGF VEGFR PCNA Egr-1 ANG-1 PDGF (R) FAS Neurology BACE (β-secretase) APP HD presenilins NOGO NOGOR Alpha-synuclein PARK2 SCA1 TRPM7 Infectious Diseases HCV HIV CCR-5 HBV SARS c-jun RSV Ocular VEGF VEGFR IGF-1R TGF- β TGF-b R ANG-1 PlGF-1 Dermatology IKK-γ Connexin43 Hairless B7-H1 VDR WHN EGFR WNT3A STAT3 Desmoglein-4 5-a-reductase IL-2 TNF a IL-4 IL-13

Sirna s RNAi IP Leadership Technology IP No Ribo sinas sina for Greater Potency and Stability Multifunctional sirnas Target Multiple Genes Simultaneously Micro RNAs Chemically-modified mirnas Conserved Sequence Targeting Multiple Genes or viral strains Licensed IP Tuschl, et.al. sirna for Therapeutic Use B. Davidson U of Iowa Huntington s & Other Neurological Indications A. Christiano Columbia Hair Removal Hair Growth Rana, et.al. UMASS Chemical Optimization Target IP AMD HD Hairless Asthma Hepatitis Diabetes VEGF Pathway HD Gene Hairless TX Factor IL-4 IL-4R IL-13 IL-13R HBV HCV PTP-1B Chemistry & Delivery IP Chemistry Chemistry & Chemically Delivery Modified sirna Improved PK Stability Potency Inhibition of Immune-stimulation Delivery Tissue & Cell Targeting Nanoparticles Conjugates Manufacturing IP Manufacturing Manufacturing Process Development Scale-Up cgmp manufacturing Raw Materials Reagents

Sirna Collaboration and Proprietary Pipeline Collaboration Programs Allergan - Sirna-027 (AMD) Allergan Ocular Targets GSK Respiratory Targets Targeted Genetics - Huntington s Discovery Pre-Clinical Clinical IND-PH1 PH2 2H 2006 Proprietary Programs Sirna-034 (Hepatitis C) Hepatitis B Hairless Diabetes Phosphatase-1B Hearing Loss Retinoblastoma 1 Q4 2006 Q4 2006/ Q1 2007

Financial Highlights > 2005 Use of cash: $23.9 million > Cash at 12/31/05: $45.7 million > Market cap at 4/21/06: $513 million > 2006 guidance - Use of cash of $25 million; excludes: > $12 million from GSK > Potential GSK 2006 milestones > Potential positive effect of additional deals

Key Value Drivers > Collaboration Programs > Initiate Phase II on Sirna-027 2H 2006 > Establish at least one additional corporate partnership > Proprietary Programs > HCV Program File IND in 4Q 2006 > Hair Removal Program File IND in 4Q 2006/1Q 2007 > Huntington s Disease Identify Clinical Development Candidate > Intellectual Property > Continued issuance of key sirna patents in the United States

Turning a Great Discovery into a Great Therapeutics Company Broad Therapeutic Pipeline Reproducible Collaborations Multifunctional & Micro RNAs Multi-layered IP Estate sirna Formulation & Delivery Discovery of RNAi in Humans RNA Chemistry & Biology sirna cgmp Manufacturing Seasoned Management

Sirna Therapeutics, Inc. UBS Presentation 4.25.2006