Jefferies 2017 Global Healthcare Conference. Dr Sandy Macrae CEO June 9, 2017

Transcription

1 Jefferies 2017 Global Healthcare Conference Dr Sandy Macrae CEO June 9, 2017

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 1995, as amended. These forward-looking statements include, but are not limited to, the design of clinical trials and expected timing for release of data; the 2017 clinical development milestones and other potential value drivers in the future; the expected benefits of the collaboration with Pfizer, the expanded capability of Sangamo s technologies; the benefits of rebranding and reorganization, the research and development of novel gene-based therapies and the application Sangamo s ZFP technology platform to specific human diseases; corporate partnerships; and the potential of Sangamo s genome editing technology to treat genetic diseases. 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. Factors that could cause actual results to differ include, but are not limited to, the dependence on the success of clinical trials of lead programs, the lengthy and uncertain regulatory approval process, uncertainties related to the timing of initiation and completion of clinical trials, whether clinical trial results will validate and support the safety and efficacy of Sangamo s therapeutics, and the ability to establish strategic partnerships. Further, there can be no assurance that the necessary regulatory approvals will be obtained or that Sangamo and its partners will be able to develop commercially viable gene-based therapeutics. Actual results may differ from those projected in forward-looking statements due to risks and uncertainties that exist in Sangamo s operations and business environments. These risks and uncertainties are described more fully in Sangamo s Annual Reports on Form 10-K and Quarterly Reports on Form 10-Q as filed with the Securities and Exchange Commission. Forward-looking statements contained in this announcement are made as of this date, and Sangamo undertakes no duty to update such information except as required under applicable law. 2

3 We are committed to translating ground-breaking science into genomic therapies that transform patients lives 3

4 Recent organizational changes set direction for the new Sangamo Newly appointed leadership Expanded capabilities Redesigned organization CEO CFO, CMO, CBO Tech ops/manufacturing Product development Communications Clinical development Medical affairs Product development Commercial planning Research innovation Flattened reporting structure Cross functional therapeutic development Laboratory quality assurance processes 4

5 Platform for genomic therapies encompasses multiple technologies Gene Therapy Genome Editing Cell Therapy Gene Regulation 5

6 Key priorities for Clinical trial enrollment Platform development Novel delivery methods Corporate collaborations Hemophilia A Hemophilia B MPS I MPS II Extend ZFN advantages in specificity, design precision and speed to lead Advance lipid nanoparticle (LNP) research toward clinical development Hemophilia A Hemoglobinopathies Huntington s disease 6

7 Significant progress with 2017 clinical development milestones IND Open GMP Manufacturing Complete Orphan Drug Designation Other Special Regulatory Designations 1 st Site Open Data Safety Review SB-525* Hemophilia A Fast Track EMA OMPD SB-FIX** Hemophilia B Fast Track SB-318** MPS I SB-913** MPS II *Gene therapy **Genome editing Rare Pediatric Disease Rare Pediatric Disease Initial data from one or more studies by YE 2017 or early 2018 Independent safety review committees for each study will convene regularly Fast Track Designation: designed to facilitate the development and expedite the review of drugs and biologics to treat serious conditions and fill an unmet medical need. Rare Pediatric Disease (RPD) Designation: provides incentives to develop drugs and biologics for rare diseases primarily affecting children ages 18 years or younger. Companies that receive a new drug approval for a PRD may be eligible to receive a priority review voucher for a subsequent marketing application for a different product. The voucher may be sold or transferred. 7

8 Pfizer hemophilia A collaboration worth up to $545 million $70M Upfront payment $475M $300M Development and commercialization of SB-525 Total potential milestone payments: Development, regulatory and first commercial sale $175M Development and commercialization of potential follow-on hemophilia A gene therapy products Sangamo is also eligible to receive tiered doubledigit royalties on net sales Sangamo is responsible for conducting Phase 1/2 studies and initial process development and manufacturing. Pfizer operationally and financially responsible for subsequent research, clinical development, manufacturing and commercialization activities. 8

9 Strategy for therapeutic development and commercialization Innovation Platform Delivery LNP AAV Retain Criteria: Assets with breakthrough potential Development and commercialization by Sangamo is financially and operationally feasible Synergies across programs and platforms Partner Criteria: Therapeutic areas with several competing franchises Very significant investment required Requires special disease area expertise and/or complementary assets Indications MPS I MPS II Fabry disease Indications Hemophilia Beta-thalassemia Sickle cell disease CNS/tau Oncology 9

10 Robust clinical and preclinical pipeline designed to generate significant value over the next 8 12 months Research Preclinical Phase 1/2 Phase 3 Collaborator Hemophilia A Hemophilia B MPS I MPS II SB-525 SB-FIX SB-318 SB-913 Fabry disease Beta-thalassemia Sickle cell disease CNS / Tauopathies ST-920 ST-400 BIVV-003 Oncology Huntington s Disease Gene Therapy Genome Editing Cell Therapy Gene Regulation 10

11 Genome Editing Platform SB-318: Mucopolysaccharidosis Type 1 (MPS I) SB-913: Mucopolysaccharidosis Type 2 (MPS II) SB-FIX: Hemophilia B 11

12 In vivo genome editing of albumin: harnessing the liver s most highly expressed locus Packaging into AAV vectors Delivery In the liver zinc finger nucleases transgene + albumin gene AAV vectors Strong albumin promoter H TG H transgene 12

13 SB-318 for MPS I and SB-913 for MPS II: Statistically significant GAG reduction in key tissues GAG Levels IDUA activity Key potential benefits Genome editing ensures sustained IDUA (MPS I) and IDS (MPS II) synthesis through life MPS I Murine Model, Tissues Wild type, Untreated MPS I, Untreated MPS I, SB-318 * One-time treatment frees patients and caregivers from weekly, 3 to 4-hr ERT infusions Constitutive IDUA (MPS I) or IDS (MPS II) production may uncover CNS benefits * * Liver Heart Lung Brain AAV delivery is validated in the clinic IDUA: alpha-l-iduronidase lysosomal enzyme missing in MPS I IDS: iduronate 2-sulfatase lysosomal enzyme missing in MPS II GAG: Glycosaminoglycan complex sugar molecule that accumulates in lysosomes in the absence of IDUA or IDS, resulting in toxic build-up and loss of cell function MPS I, SB-318 vs. MPS I untreated P-value: *p< * * * Liver Heart Lung Brain 13

14 Wild type, control MPS I, Untreated MPS I, SB-318 Evidence of phenotypic correction: Reduced tissue vacuolation and preservation of cognitive function Escape Latency (seconds) Escape Latency (seconds) Escape Latency (seconds) Tissue Vacuolation Mesenteric lymph node MPS I, Grouped Male mice * * ** MPS I MPS I, SB-318 Wild type MPS II, Grouped * * MPS II MPS II, SB-913 Wild type MPS II, Individual mice, Day 6 MPS Treated vs MPS Untreated P-values: *p<0.05, **p<0.001 Mice analyzed 4 months post-dosing Wild type MPS II MPS II SB

15 SB-318 and SB-913 clinical program summaries Regulatory Designations Study Title Study Population Study Design Primary Endpoints Data Readout U.S. FDA Orphan Drug and Rare Pediatric Disease Designations Phase I, Multicenter, Open-label, Single-dose, Dose-ranging Study to Assess the Safety and Tolerability of SB-318 / SB-913, a raav2/6-based Gene Transfer in Subjects With Mucopolysaccharidosis I (MPS I) / MPS II Male / female subjects over 18 years old (MPS I) with attenuated MPS I Male subjects over 18 years old (MPS II) with attenuated MPS II N = 9 3 dose cohorts (2 subjects / cohort), expand optimal dose by 3 subjects Safety review period between cohorts Evaluate safety, tolerability and effect on IDUA (MPS I) / IDS (MPS II) enzyme activity levels of ascending doses of SB-318 / SB-913 Late 2017 / early 2018; pivotal pediatric studies expected

16 SB-FIX: the potential for one-time, life-long Factor IX replacement Wildtype mice SB-FIX treatment resulted in stable FIX plasma levels through 60 weeks Non-human primates Dose-dependent relationship between AAV dose, gene modification in liver and plasma FIX levels Plasma hf.ix (ng/ml -1 ) hfix (ng/ml) Plasma hfix expression (ELISA) Time (weeks after Injection) 1 Low Dose Mid Dose Dose (vg/kg) High Dose 16

17 SB-FIX clinical program summary Regulatory Designations Study Title Study Population Study Design Primary Endpoints Data Readout U.S. FDA Orphan Drug and Fast Track Designations Phase I, Open-Label, Ascending Dose Study to Assess the Safety and Tolerability of AAV2/6 Factor IX Gene Therapy Via ZFN Mediated Targeted Integration of SB-FIX in Adult Subjects With Severe Hemophilia B Male subjects over 18 years old, with severe hemophilia B, without inhibitors to FIX and no hypersensitivity to rfix N = 12 3 dose cohorts (2 subjects / cohort), option to expand optimal dose cohort Safety review period between cohorts Evaluate safety, tolerability and effect on FIX antigen and activity levels of ascending doses of SB-FIX Late 2017 / early 2018; pivotal pediatric studies expected

18 Gene Therapy Platform SB-525: Hemophilia A ST-920: Fabry Disease 18

19 Sangamo s AAV6 cdna gene therapy provides a potent therapeutic solution for genetic diseases Packaging into AAV vectors Delivery In the liver transgene liver cell DNA nucleus therapeutic gene liver cell AAV vectors 19

20 In non-human primates, SB-525 appears more potent than competing products Average Peak FVIII (% of Normal) NHP Factor VIII Average Peak Levels 250% 229% 200% 150% 153% 100% 56% 62% 50% 33% 6% 12% 22% 24% 23% 5% 0% 6.0E E E E E+13 Dose (vg/kg) 100% of normal Sangamo Spark Tx BioMarin Sources: Jefferies LLC, Gena Wang, PhD, ONCE/SGMO/DMTX: Read-through from BMN-270 WFH Update in HemoA, July 27, 2016 BioMarin Pharmaceuticals, Inc., R&D Day 2016, April

21 SB-525 clinical program summary Regulatory Designations Study Title Study Population Study Design Primary Endpoints U.S. FDA Orphan Drug and Fast Track Designations EMA Orphan Medicinal Product Designation Phase I/II, Open-Label, Ascending Dose Study to Assess the Safety and Tolerability of AAV2/6 Factor VIII Gene Therapy in Adult Subjects With Severe Hemophilia A Male subjects over 18 years old, with severe hemophilia A, without inhibitors to FVIII and no hypersensitivity to rfviii N = up to 20 subjects 6 potential dose cohorts (3 subjects / cohort), option to expand optimal dose cohort Safety review period between cohorts Evaluate safety, tolerability and effect on FVIII antigen and activity levels of ascending doses of SB-525 Data Readout Late 2017 / early 2018; hand-off to Pfizer for pivotal studies 21

22 n m o l/h r/m l ST-920 AAV-cDNA gene therapy for Fabry Disease: x wild type levels in α-gal A activity in plasma and target tissue α-gal A activity in plasma α-gal A activity in tissues (2 months) x wild type 10x wild type wild type Fabry mouse model** wild type original cdna optimized 10x wild type 1 Fabry mouse model** liver heart kidney spleen tim e (d a y s ) Original GLA cdna construct Optimized GLA cdna construct **GLAKO used as Fabry mouse model of disease α-gal A overproduced in liver is safe, secreted at high levels and taken up by other tissues in active form 22

23 ST-920: Significant lipid substrate clearance in target tissues after single administration of Fabry gene therapy **GLAKO used as Fabry mouse model of disease a-gal A produced in liver leads to significant Gb3 and Lyso Gb3 reduction in target tissues like kidney and heart 23

24 Cell Therapy Platform ST-400: Beta-thalassemia BIVV-003: Sickle Cell Disease Oncology 24

25 Potential life-changing therapies for beta thalassemia and sickle cell disease Key differentiating benefits Ex-vivo, non-viral delivery and precise genome editing for improved safety Fetal Hb expression mimics a naturally-occurring compensation mechanism Knocks out BCL11A enhancer, eliminating repression of fetal hemoglobin gene Hardison and Blobel Science (2013) 342:

26 Gene Regulation Platform Tau Reduction Alzheimer s Disease and Tauopathies 26

27 Gene regulation with ZFP Transcription Factors blocks all forms of tau with a single administration small molecules ASO immunotherapy chaperones ZFP-TF aggregation inhibitors vaccines vectorized Abs "Of the many approaches to reduce tau expression that we've studied, zinc finger protein gene regulation technology is especially promising for its exquisite specificity, its potent reduction of tau protein expression, and its potential to provide a durable, long-lasting effect with only a single administration. - Bradley Hyman, M.D., Ph.D., Director, Massachusetts Alzheimer's Disease Research Center and Alzheimer's Unit Director, MassGeneral Institute for Neurodegenerative Disease, and Professor of Neurology, Harvard Medical School. 27

28 Up to 90% tau reduction in the mouse hippocampus Wild-type 3 months old + OR OR 8 weeks AAV9 hsyn1-zfp AAV9 CamKIIa-ZFP AAV9 MeCP2-ZFP qrt-pcr tau ELISA **** P < tau mrna tau protein PBS: phosphate buffered saline control injection hsyn1 / CamKII / MeCP2: well characterized neuron-specific promoters delivered with the zinc finger protein transcription factors (ZFP) in an AAV9 construct. 28

29 Single-gene specific repression in primary neurons Tau mrna Affymetrix Genechip Assay P < Tau is the only gene repressed by >2 fold out of 26,491 coding transcripts assayed 0.01 Mouse Cortical Neurons Fold Repression Fold Activation Neurons were infected on DIV2 with raav9-zfp (1x10 5 vg/cell) and harvested for Affymetrix GeneChip analysis on DIV9 (N=5) 29

30 Optimizing ZFN Design Density and Specificity 30

31 ZFN platform offers diverse options for optimization intermodule linkers Fok linker module module module NH 2 5 T T G AT A C CCAACGCG 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 GGTT T G A3 3 AACTAT G GGTT G C G C T T A A T A C C G C C G C ACGC G A A T T G C G T A C CCAAACT5 NH 2 module module module Fok linker intermodule linkers Unlimited targeting capabilities and extremely high specificity New architectures increase design density (>1:2 bp) and options for a given target Fine tuning of base contacts and linker length adjustments Alternative dimer configurations (4x increase in targeting power) Backbone variants that globally suppress off-target cleavage 31

32 Further improvements increase specificity while maintaining high levels of gene modification Removal of conserved, non-specific phosphate contacts from zinc finger proteins increases targeting specificity Modified Fok nuclease-dna contacts significantly reduces off-target cleavage events zinc finger DNA Conserved Arg phosphate contact Elrod-Erickson et al., Structure AAY.pdb 32

33 % Indels ZFNs are highly efficient and specific in clinical scale studies high on-target modification (80%) No significant off-target modification seen compared to control.0 Position Specificity determined via state of the art unbiased oligo capture methods, followed by deep sequencing Low assay background (generally <.1%) 47 capture loci examined in CD34 cells treated with ZFNs at clinical scale 33

34 Numerous potential value drivers in the next months 1 2 Clinical Data Pipeline Progress SB-525: Hemophilia A POC SB-FIX: Hemophilia B POC SB-318: MPS I POC SB-913: MPS II POC Lead programs toward pivotal studies Advance 3 additional candidates into clinic (ST-920, ST-400, BIVV-003) LNP and novel AAV ZFN Partnership Deals CNS / tau Oncology 34

35 Thank you