Gene Silencing Oligos (GSOs) Third Generation Antisense

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1 Gene Silencing Oligos (GSOs) Third Generation Antisense Walter R. Strapps, Ph.D. Executive Director, RNA Therapeutics Idera Pharmaceuticals Cambridge, MA NASDAQ: IDRA

2 Idera is a leader in developing novel nucleic acid therapeutics to treat patients with orphan diseases NUCLEIC ACID THERAPEUTICS TOLL-LIKE RECEPTOR ANTAGONISM GENE SILENCING TARGETED CANCER THERAPY ORPHAN AUTOIMMUNE DISEASES GENETICALLY DEFINED DISORDERS 2

3 Gene Silencing Oligos: the 3rd generation of antisense OPPORUNITY Oligonucleotides are an important tool in the drug development landscape providing access to previously undruggable targets NEED While RNAi and 2 nd generation chemistries have demonstrated clinical proof of concept, optimal therapeutic index remains an issue for commercial success ADVANTAGE Idera Pharmaceuticals has developed a 3 rd generation technology called gene-silencing oligonucleotide (GSO) in order to mitigate these issues 3

4 Validation of antisense and sirnas as drug discovery platforms Established clinical activity against multiple gene targets Regulatory path of approval established Manufacturing/CMC validated Therapeutic index needs to be improved Dose and delivery Distribution of oligonucleotides Metabolism and excretion Mitigation of off-target and immune-stimulatory effects 4

5 Oligonucleotides: clinical proof of concept for multiple RNA targets Robust pipeline of antisense drug candidates: 1 approved, 10 in phase III, 38 in phase II, 47 in phase I and there is human proof of concept data Target ApoB (antisense and RNAi) PCSK9 (antisense and RNAi) TTR (antisense and RNAi) STAT3 Clinical proof of concept Lipid Lipid Protein Cytokine CRP ApoC - III Protein Triglyceride Second generation antisense is the most successful and widely employed chemistry to date Clinical dosing is high 3-6 mg/kg, biweekly to weekly dosing 5 Idera invention and IP

6 Limitations exist with the current technologies Mipomersen Flu like symptoms Injection site reaction Liver toxicity Santaris PCSK9 Program halted Ph. I Prosensa Dystrophin Ph. III didn t hit endpoints Therapeutic index remains an issue Injection site reactions Immunotoxicity is primarily due to tissue buildup Sequence dependent immune activation 6

7 Idera: Pioneering antisense development Introduced first-generation antisense development ( ) Activation of immune responses observed Created second generation antisense chemistry ( ) Increased stability led to weekly administration, reduced complement activation, and reduced immune activation Issuance of US patent #5,652,355 Licensed to ISIS, being used in all ISIS drug candidates Understanding of immune activation through TLRs (2001-Present) Developed agonists and antagonists of TLRs Introduced third generation antisense chemistry (GSOs) (2011) Incorporates our understanding of antisense mechanisms and TLRs Issuance of US patent #8,431,544 7

8 The solution: Gene Silencing Oligonucleotides Our GSO has a novel structure Novel single-stranded structure designed to result in greater potency: 19-mer to 23-mer length is tolerated Mitigation of immune activation: GSOs lack 5 -end, thereby avoiding immune activation through TLRs Systemic Delivery of GSOs: No vehicle is required US Patent # 8,431,544 Issued 2013; Published in J. Med. Chem. 2011, 54,

9 Insights into the features of GSOs Mitigation of immune activation Two Free 3 -ends are required for GSO activity Effect of length of GSO Effect of linker on the activity of GSO Improved Activity, Potency and Duration of GSO versus ASO Rapid, efficient path to in vivo proof of concept: proprietary design algorithm removes problematic sequences (GSOs for >15 targets ID d) Issued US Patent on GSO structure 9

10 GSO technology validated in preclinical models Mitigation of immune activation Improved therapeutic index Efficient path to in vivo proof of concept Attaching two antisense molecules at the 5 ends avoids TLR engagement Examples: PKCα, Bcl2, H-ras, C-raf Novel GSO structure results in increased potency with less tissue accumulation Examples: ApoB, mir-21, MyD88, TLR9, PCSK9 Creation of GSO drug candidates in under six months for a gene target Examples: ApoB, PCSK9, MyD88, TLR9, mir-21, and other mirnas 10

11 Unique design of GSOs avoids TLR engagement and decreases immune activation Same Bcl2 sequence comparing GSO vs. antisense dose response pg/ml KC MCP-1 IL-12 IP-10 TNF- IL-1 MIP-1 IL-6 IL-1 IL-2 IL-17 MIG 0 PBS 10 mg/kg 50 mg/kg 100 mg/kg 10 mg/kg 50 mg/kg 100 mg/kg PS Antisense GSO Experimental design: 2 hr 10, 50, 100 mg/kg BCL2 GSO or 11 Antisense, s.c. Serum Cytokine Analysis Sequences: Bcl2 antisense 5 -TCTCCCAGCGTGCGCCAT-3 Bcl2 GSO 3 -TACCGCGTGCGACCCTCT-X-TCTCCCAGCGTGCGCCAT-3 11

12 Turning an existing ASO into a GSO results in a more active and potent gene silencer A lead ASO sequence from the literature was made as a GSO and tested side by side. The GSO is ~3 times as active and ~5 times as potent as the ASO. 12

13 GSO is more potent than antisense in vivo Study design 24 hr 2 hr Serum Cytokine Analysis 0.5, 2 or 5 mg/kg GSO or 0.5, 2, 5, 15 or 30 mg/kg Antisense PS-oligo, s.c mg/kg TLR9 Agonist, s.c. Female C57Bl/6 mice 6-8 weeks old; N = 3/group. 13

14 Two free 3 -ends are required for GSO activity Study design 5 mg/kg compounds 1-4 or PBS, s.c hr 2 hr 10 mg/kg TLR7 Agonist, s.c. 5 5 Serum Cytokine Analysis IL-12 X X X % Inhibition of TLR7 agonist mediated IL 12 induction Female C57Bl/6 mice 6-8 weeks old; N = 3/group.

15 GSO has longer duration of action than ASO in vivo 24 hr 2 hr Serum Cytokine Analysis 5 mg/kg GSO or Antisense PS-oligo, s.c mg/kg TLR9 Agonist, s.c. 15

16 Creation of GSO drug candidates in under six months for a gene target GSOs for Target Gene Validation of Activity in Cell Culture In vivo Studies in Disease Models Lead Candidate 4-8 weeks 8-16 weeks 16

17 Example: Identification and validation of ApoB GSOs Screened 4 candidates GSOs in order to select a lead candidate Selection of lead by reduction of ApoB liver mrna and serum total cholesterol % inhibition of ApoB mrna Liver ApoB mrna Levels GSO-1GSO-2GSO-3GSO-4 PBS GSO4 ApoB100 tubulin % inhibition of serum cholesterol Serum Total Cholesterol 0 Levels GSO-1GSO-2GSO-3GSO-4 15 mg/kg, s.c., six doses, every other day in mice, liver and serum analysis 17

18 Evaluation of ApoB GSO dose response Study design ApoB GSO 7.5 and 15 mg/kg, or PBS, s.c. Day Collect blood for serum cholesterol assessment Dosing Period Collect liver for mrna and protein analysis and blood for serum cholesterol Collect blood for serum cholesterol recovery assessment Recovery Period Total Dose: 45 mpk or 90 mpk N = 6, C57BL/6 male mice, 6 weeks old, Animals were on high fat diet two weeks prior to treatment and until termination of the study. 18

19 ApoB GSO treatment reduces cholesterol in mouse model of elevated cholesterol 160 Total Cholesterol Serum Total Cholesterol, mg/dl Dosing period Post-dosing recovery period Day PBS 7.5 mg/kg 15 mg/kg P < 0.05 vs PBS ApoB protein GSO mg/kg ApoB mrna GSO mg/kg Specificity of ApoB GSO (15 mg/kg) and15 mg/kg, s.c., six doses, twice a week in high fat diet mice, liver and serum analysis

20 Targeting mir-21 with a GSO mir-21 Sequence 5 -UAGCUUAUCAGACUGAUGUUGA-3 Underlined segment is GSO target; nucleotides shown in orange represent seed region. mir-21 GSO 3 -CGAATAGTCTGACTACAAC-X-CAACATCAGTCTGATAAGC-3 DNA phosphorothioate; X represents glycerol linker. HeLa Cells HCT-116 Cell Line % change in mir-21 levels mir-21 GSO Control GSO 10 g/ml mir-21 GSO Control GSO g/ml -100

21 mir-21 GSO Exerts Antitumor Effect in Murine Colon Carcinoma Model CT26 3x10 5, i.p. mir-21 GSO or Control GSO, 5 mg/kg, or PBS, i.p. BALB/c N = 10 Day Monitor survival 100 Percent survival Treatment 44 days 22 days > 76 days p = Days post tumor implantation p = PBS mir-21 GSO Control GSO Median survival days Log-rank test mir-21 GSO shows antitumor activity in murine colon cancer model

22 Gene Silencing Oligonucleotides design decreases tissue accumulation without affecting potency Relative PCSK9 mrna Quantity PCSK9 mrna PBS GSO mg/kg Antisense, mg/kg GSO 15 mg/kg AS 50 mg/kg AS 100 mg/kg % inhibition of LDL-c compared to PBS LDL-cholesterol Day Day Dosing period Post-dosing recovery period Dose GSO or 1 st Gen ASO, s.c. Collect serum for analysis Harvest liver for mrna knockdown C57BL/6, female, normal Day Study design: diet, N=6 22

23 Unique GSO design decreases tissue accumulation without affecting potency Study design: PCSK9 GSO (15 mg/kg, s.c.) or PCSK9 antisense (15 mg/kg, s.c.) C57BL/6 mice (2 per collection group) Initial dose Collection of liver and kidney, extraction of oligo from tissues, Analysis of oligo by anion-exchange HPLC Hour % Full-length GSO Remaining in Kidney Kidney Time (hrs) % Full-length GSO Remaining in Liver Liver PCSK9 Antisense PCSK9 GSO Time (hrs) PCSK9 GSO: 3 -CCACGACTACCTCCTCTGG-X-GGTCTCCTCCATCAGCACC-3 PCSK9 2 ND Gen Antisense: 3 -CCACGACTACCTCCTCTGG-5 X = Glycerol Linker; Orange font nucleotides indicate 2 -O-Me-nucleotides; gray font indicates DNA; phosphorothioate backbone 23

24 GSO shows no immunotoxicity in organs GSO, 15 mg/kg, s.c. Week Measurements at week 14 C57BL/6 mice, 4/group Organ weight, Serum IL-12 Skin Spleen Liver Kidney Saline GSO 15 mg/kg Per dose (total dose = 195 mpk) 24 human VEGF GSO 3 -GAAAGACGACAGAACCCAC-X-CACCCAAGACAGCAGAAAG-3

25 GSOs provide a new platform for gene silencing therapeutics GSOs show greater activity, potency and duration than ASOs GSOs mitigate immune responses seen with ASOs GSOs show no obvious signs of organ toxicity after repeat dosing GSOs offer potential for both hepatic and extra-hepatic targets Next Steps: Prioritization of disease targets for human proof-of-concept studies SAR to further optimize drug-like properties of GSOs and potency 25

26 Prioritization of disease indications for treatment with GSOs Key Considerations: Strong evidence that the disease is caused by a specific protein Unmet medical need Clear criteria to identify a target patient population Biomarker for early assessment of clinical proof of concept Targeted therapeutic mechanism of action plus medical need allow for a rapid development path to approval 26

27 Idera is a leader in developing novel nucleic acid therapeutics to treat patients with orphan diseases NUCLEIC ACID THERAPEUTICS TOLL-LIKE RECEPTOR ANTAGONISM GENE SILENCING TARGETED CANCER THERAPY ORPHAN AUTOIMMUNE DISEASES GENETICALLY DEFINED DISORDERS 27

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