Jefferies 2016 Healthcare Conference Engineering Genetic Cures

Transcription

1 Jefferies 2016 Healthcare Conference Engineering Genetic Cures Edward Lanphier Founder Sangamo BioSciences, Inc. June 8, 2016

2 Forward Looking Statements This presentation contains forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of These statements are based upon our current expectations and speak only as of the date hereof. Our actual results may differ materially and adversely from those expressed in any forward-looking statements as a result of various factors and uncertainties in our strategy, sufficiency of our cash resources, product development and commercialization of our products, clinical trials, revenues from existing and new collaborations, our research and development and other expenses, our operational and legal risks and any other statements that are not historical fact. Sangamo BioSciences, Inc. Annual Report on Form 10-K, recent and forthcoming Quarterly Reports on Form 10-Q, recent Current Reports on Forms 8- K and 8-K/A, and other SEC filings discuss some of the important risk factors that may affect our business, results of operations and financial condition. We undertake no obligation to revise or update publicly any forward-looking statements for any reason. 2

3 New President and CEO Appointed 20 years of experience in Big Pharma across broad range of therapeutic areas Formerly Global Medical Officer at Takeda Pharmaceuticals Previous senior leadership positions in R&D and business strategy at Glaxo SmithKline: SVP, Emerging Markets R&D VP, Business Development Background M.B., Ch.B. from Glasgow University Ph.D., Molecular Genetics from King s College, Cambridge Sandy Macrae, M.B., Ch.B., Ph.D. President and CEO 3

4 Sangamo BioSciences Focused on the development of a new class of human therapeutics that function at the DNA level with the goal of Engineering Genetic Cures Driven by multiple robust technology platforms Zinc finger proteins (ZFPs) can be designed to bind to any DNA sequence with singular specificity Targeted genome editing and gene regulation Broad AAV and mrna delivery capabilities, manufacturing and IP Broad commercial applications in research reagents, transgenic animals, agriculture, manufacturing and human therapeutics Significant partnerships and strong balance sheet Dominant intellectual property position 4

5 Toolbox for Engineering Genetic Cures Zinc Finger Protein Gene Regulation Domain ZFP Transcription Factor (ZFP TF) ZFP Nuclease (ZFN) Gene Editing Domain Repress Activate Knockout Correct/Add 5

6 Successfully Monetized ZFP Technology Platform Partners Applications Proprietary ZFP Therapeutics Programs Hemoglobinopathies Sickle Cell Disease β thalassemia Huntington s Disease One Additional Disease Target Plant Agriculture Research Tools Transgenic Animals Protein Manufacturing 6

7 Current ZFP Therapeutic Development Programs In Vivo Strategy 1 Systemic (Liver) IVPRP Replacement Strategies Hemophilia Factors VIII & IX Lysosomal Storage Disorders (multiple) mrna ZFN Knockout/Knockdown Strategies RNAi / Antisense Targets (e.g. PCSK9) ZFP Therapeutics Strategies (AAV, mrna) 2 3 Direct Tissue Brain Huntington s disease Shire Heart Congestive Heart Failure Lung Cystic Fibrosis Monogenic Diseases Eye, Muscle Non-Stem Cells T-cells HIV T-cells Oncology Ex Vivo Strategy (mrna, AV) Blue = Partnered programs Green = Active proprietary Sangamo programs 4 7 Stem Cells CD34+ Hemoglobinopathies (SCD, β-thalassemia) - BIIB HIV/AIDS INR Rare Diseases (Several) Universal Donor Cells Several

8 Sangamo ZFP Therapeutics Pipeline In Vivo Protein Replacement Platform (IVPRP) Program Lead Indication ZFP Approach Product Strategy Goal HIV / AIDS Ex Vivo T-cells / Stem Cells Knock-out CCR5 gene Hemophilia In Vivo Systemic (Liver) F. VIII/F. IX gene inserted at Albumin promoter Lysosomal Storage Disorders In Vivo Systemic (Liver) LSD enzyme gene(s) inserted at Albumin promoter Huntington s Disease In Vivo Direct Tissue Repress mutant Huntingtin allele Hemoglobinopathies (e.g. Sickle Cell Disease) Ex Vivo Stem Cells Bcl11a enhancer knock-out activates Fetal-globin Other ZFP Therapeutics Various Various Engineered Genetic Cure 8

9 Sangamo s In Vivo Protein Replacement Platform (IVPRP) Broad Applications in Hemophilia and LSDs Albumin Gene: Very strong promoter ZFN ZFN Requires < 1% for normal levels Donor: Homology Gene of Interest Homology Hemophilia A Hemophilia B Hunter Hurler Gaucher Fabry $6B per year $1B per year $500M per year $200M per year $1B per year $700M per year 9

10 IVPRP Systemic delivery of ZFP Therapeutics via AAV vectors allows in vivo correction of monogenic disease Human albumin ZFN Pair and Corrective Gene ZFN Nucleic Acids Coding for ZFNs and Corrective Gene in AAV Vectors AAV Vectors Peripheral IV Administration AAV Traffics to Liver And Permanently Inserts Corrective Gene into the Albumin Locus ZFN Homology Corrective Gene Homology Liver Cells Secrete Corrected Protein In Vivo Protein Replacement (e.g. Factor IX or Lysosomal Storage Disease) 10

11 Sangamo s IVPRP Reviewed in the NEJM These findings are exciting and suggest an improved armamentarium for effecting the safe, long-term expression of a variety of secreted proteins from the liver for permanent, functional cures for a variety of genetic and nongenetic diseases. Andrew M. Davidoff, M.D. and Amit C. Nathwani, M.D., Ph.D. 11

12 SB-FIX (Hem B): Phase 1/2 Clinical Trial Protocol Study Design Study Population Primary Endpoint Other Endpoints PI and Study Site Sponsor SB-FIX-1501 Phase 1/2 Study (N=9) Open-label, Ascending Dose Study -- 3 Cohorts 2 subjects per cohort 1 month treatment interval between subjects within cohorts 2 months between cohorts (SMC review of data) Male subjects 18 years old, with severe hemophilia B who are without inhibitors to FIX and have no hypersensitivity to rfix Evaluate safety and tolerability of AAV2/6 Factor IX IVPRP based therapy Change from baseline in: circulating FIX levels use of FIX replacement therapy frequency and severity of bleeding episodes Activated Partial Thromboplastin Time (APTT) Immune response to AAV2/6, FIX (steroid use if necessary) Nadia Ewing, MD and John Zaia, MD -- City of Hope, Duarte, CA Sangamo BioSciences, Inc. 12

13 Sangamo s IVPRP Approach for MPS I & MPS II ZFN Genome Editing vs Enzyme Replacement Therapy (ERT) Current ERTs require weekly infusion of replacement enzyme However, tissue enzyme concentrations are depleted within hours of infusion One-time administration of ZFNs enables permanent insertion of therapeutic gene at the albumin locus in patient s liver resulting in continuous enzyme production ZFNs ERTs Permanent enzyme production therapeutic levels Therapeutic Level Weeks

14 MPS II (Hunter Syndrome) Stable increase in hids activity in plasma Key Takeaway - Stable production of hids enzyme from the liver - Statistically significant increase in hids enzyme activity in the plasma of ZFN-treated MPS II mice at mid and high doses through 120 day study duration 14

15 MPS II (Hunter Syndrome) Increased hids activity and reduced GAGs in tissue 15

16 Histopathologic Analysis of Tissues Revealed Correction of Cellular Vacuolation Cellular vacuolation is the engorgement of lysosomes in cells due to the accumulation of GAGs, a disease characteristic of MPS I/II (Ohmi, 2003) Liver (4 month) WT mice MPS I mice MPS I ZFN + Donor Reduced levels of vacuolation were detected in treated MPS I mice in: - Liver, Spleen, Lung and Kidney - Heart, Skeletal Muscle - Bone Marrow, Thymus and Lymph Node - Bone and Femoral-tibial Joint - Spinal WT Cord mice MPS I mice MPS I ZFN + Donor 16

17 Barnes Maze Test MPS I and MPS II Mice Evaluating Spatial Learning and Memory Barnes Maze assesses ability of the animal to learn and memorize the location of a target zone using a configuration of distal visual cues Animal is presented with an aversive environment (bright light) Only 1 of 40 platform holes is not blocked and allows the animal to hide from the light above ( escape hole ) Thomas Wechsler 2015 Assess the ability of the animal to learn and memorize the location of the escape hole Visual cues on the walls aid the animal Time to find the escape hole is measured on six consecutive days 17

18 Barnes Maze Test Significant Improvements in Cognitive Function MPS I MPS II Statistically significant improvement in cognitive learning and memory in MPS I and MPS II mice 18

19 MPS II (Hunter Syndrome) Data Summary Single intravenous administration of ZFNs and IDS donor sequence resulted in: Stable, continuous production of active hids enzyme from the liver into the circulation and secondary tissue through the end of 120 day study Statistically significant increase of hids enzyme activity in secondary tissue, including increase in the brain Statistically significant reduction of GAG biomarker levels in secondary tissue Enzyme crossing the blood brain barrier evidence of enzyme activity and reduction of GAGs observed in the brain 19

20 SB-318 (MPS I): Phase 1/2 Clinical Trial Protocol Study Design Study Population Primary Endpoint Other Endpoints PI and Study Site Sponsor SB Phase 1/2 Study (N=9, may expand to 12) Open-label, Ascending Dose Study -- 3 Cohorts 2 subjects per cohort 1 month treatment interval between subjects within cohorts 2 months between cohorts (SMC review of data) Adult subjects 18 years old, with attenuated or severe MPS I who are without inhibitors to IDUA or abnormal liver function tests Evaluate safety and tolerability of AAV2/6 IDUA IVPRP based therapy Change from baseline in: circulating IDUA levels urinary GAG levels % predicted Forced Vital Capacity (FVC) 6 Minute Walk Test (6MWT) Immune response to AAV2/6, IDUA (steroid use if necessary) Chester Whitley, M.D., Ph.D. University of Minnesota, Minneapolis Sangamo BioSciences, Inc. 20

21 IVPRP What s Next? Program Lead Indication Research Pre-clinical Phase 1 Upcoming Milestones SB-FIX Hemophilia B Initiate Trial 1H16 SB-318 Hurler Syndrome (MPS I) Initiate Trial mid-16 SB-913 Hunter Syndrome (MPS II) File IND 1H 2016 SB-FVIII Hemophilia A File IND 2H 2016 SB-LSD3 Gaucher Disease File IND 2H 2016 SB-LSD4 Fabry Disease File IND 2H

22 Sangamo ZFP Therapeutics Pipeline Hemoglobinopathies Program Lead Indication ZFP Approach Product Strategy Goal HIV / AIDS Ex Vivo T-cells / Stem Cells Knock-out CCR5 gene Hemophilia In Vivo Systemic (Liver) F. VIII/F. IX gene inserted at Albumin promoter Lysosomal Storage Disorders In Vivo Systemic (Liver) LSD enzyme gene(s) inserted at Albumin promoter Multiple Huntington s Disease In Vivo Direct Tissue Repress mutant Huntingtin allele Hemoglobinopathies (e.g. Sickle Cell Disease) Ex Vivo Stem Cells Bcl11a enhancer knock-out activates Fetal-globin Other ZFP Therapeutics Various Various Engineered Genetic Cure 22

23 Bauer et al. Science (2013) 342: 253 Hardison and Blobel Science (2013) 342: 206 We propose the GWAS-identified enhancer of BCL11A as a particularly promising therapeutic target for genome engineering in the β-hemoglobinopathies. Disruption of this enhancer would impair BCL11A expression in erythroid precursors with resultant HbF derepression while sparing BCL11A expression in nonerythroid lineages. 23

24 ZFN-Mediated BCL11A Enhancer Knock Out Bcl11a (enhancer) HSC Erythroid Lineage All Others RBC HbF Equivalent effect on fetal globin expression as BCL11A KO approach 24

25 BCL11A Enhancer Approach to Hemoglobinopathies Program Lead Indication Research Pre-clinical Phase 1 Upcoming Milestones Beta-thalassemia Sickle Cell Disease File IND in 1H16 File IND by 2H16 Milestones Expect to file INDs for: Beta-thalassemia in the 1 st half of 2016 Sickle Cell Disease in the 2 nd half of

26 Sangamo ZFP Therapeutics Pipeline SB-728 for HIV/AIDS Program Lead Indication ZFP Approach Product Strategy Goal HIV / AIDS Ex Vivo T-cells / Stem Cells Knock-out CCR5 gene Hemophilia In Vivo Systemic (Liver) F. VIII/F. IX gene inserted at Albumin promoter Lysosomal Storage Disorders In Vivo Systemic (Liver) LSD enzyme gene(s) inserted at Albumin promoter Multiple Huntington s Disease In Vivo Direct Tissue Repress mutant Huntingtin allele Hemoglobinopathies (e.g. Sickle Cell Disease) Ex Vivo Stem Cells Bcl11a enhancer knock-out activates Fetal-globin Other ZFP Therapeutics Various Various Engineered Genetic Cure 26

27 SB-728-T: ZFN-mediated CCR5 Knockout in CD4+ T-cells CD4 T-cell + HIV 5 T A C C C A A C G C G A A T T A T G G C G G C G T G C G C T T A A C G C A T G G G T 3 A T G G G T T G C G C T T A A T A C C G C C G C A C G C G A A T T G C G T A C C C A ZFNs CCR5 3 5 SB-728-T (CCR5 K-O) Reservoir Reduction Acute effect on viral load (VL) Viral load Copies/ ml Treatment Interruption Days from Baseline Subject Hypothesis Maximizing biallelic CD4 / CD8 CCR5 KO provides functional control of HIV Absolute CD4 Count Pentamer VIral Load Set Point Pentamer Duplication / L Cells / L SB Cohort 3* (Phase 2) - CTX Pre-treatment - Ad-ZFN modified CD4+ and CD8+ T-cells 27

28 SB-728-T HIV Program Clinical Trial Update Phase 2: SB Cohort 3* (N=8) Adenoviral delivery of ZFNs to cells Single dose of Ad-ZFN modified CD4+ and CD8+ T-cells 2/3 subjects sustained functional control of viral load w/o ART, remain on TI over 1 year Additional 5 subjects have been treated, data readout expected in 2H 2016 Key Takeaways Adenoviral delivery of ZFNs superior to mrna delivery for SB- 728-T manufacturing - Adenoviral delivery may be uniquely immune-stimulatory for acute control of viral load and HIV reservoir reduction Data from additional 5 subjects in Cohort 3* expected 2H 2016 Phase 1/2 SB-728mR-HSC HIV Stem Cell Clinical Trial underway at City of Hope Plan to partner for pivotal studies and commercialization 28

29 Sangamo ZFP Therapeutic Pipeline 6 New INDs and Multiple Clinical Read-outs by YE2016 Program Lead Indication Research Pre-clinical Phase 1 Phase 2 File IND: SB-728-T HIV / AIDS SB-728-HSPC HIV / AIDS SB-FIX Hemophilia B SB-318 Hurler Syndrome (MPS I) SB-913 Hunter Syndrome (MPS II) 1H16 SB-FVIII Hemophilia A 2H16 SB-LSD3 Gaucher Disease 2H16 SB-LSD4 Fabry Disease 2H16 Beta-thalassemia Sickle Cell Disease Huntington s Disease 1H16 2H16 TBD 29

30 2016 Financial Guidance Cash and Investments: at least $150 million at the end of 2016 inclusive of research funding from existing collaborations, but exclusive of funds arising from additional new collaborations or partnerships, or other new sources Revenues: in the range of $20 to $25 million - inclusive of research funding from existing collaborations Operating Expenses: in the range of $85 to $95 million 30

31 New President and CEO Appointed 20 years of experience in Big Pharma across broad range of therapeutic areas Formerly Global Medical Officer at Takeda Pharmaceuticals Previous senior leadership positions in R&D and business strategy at Glaxo SmithKline: SVP, Emerging Markets R&D VP, Business Development Background M.B., Ch.B. from Glasgow University Ph.D., Molecular Genetics from King s College, Cambridge Sandy Macrae, M.B., Ch.B., Ph.D. President and CEO 31

32 Summary Sangamo s ZFP technology is the most robust platform for genome editing and gene regulation Focused on the development of a new class of human therapeutics that function at the DNA level with the goal of Engineering Genetic Cures Important partnerships and sufficient cash to move all programs through value inflection points Our strategy creates significant near term value and mitigates risk via diversification and leverage Business model partnerships and proprietary programs Diverse therapeutic product development strategies Variety of addressable and well validated targets Balance sheet strength 32

33