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Innovators Forum

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HSG 2016's Innovators Forum included presenters from Wave Life Sciences, uniQure, and Ionis Pharmaceuticals.

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Innovators Forum

  1. 1. HD Innovators Forum Thursday, November 3 4:45-4:45pm Moderators: Blair Leavitt and Christopher Ross HSG Scientific Advisory Committee Chairs
  2. 2. Presenters HSG 2016: DISCOVERING OUR FUTURE Mike Panzara, MD, MPH WAVE Life Sciences Pavlina Konstantnova, PhD uniQure Anne Smith, PhD Ionis Pharmaceuticals
  3. 3. Use of optimized stereochemistry to target the Huntington’s Disease allele mRNA by antisense oligonucleotide treatment Michael A. Panzara, MD, MPH Head of Neurology Franchise, WAVE Life Sciences November 3, 2016
  4. 4. Founded • Ontorii (USA)• Chemistry & Pharmacology • Chiralgen (Japan) • Manufacturing 2009 2013 Merger • WAVE Life Sciences 2015 Financings • 2 private rounds • ~$196MCash License • Tuschl ssRNAi • IPO (WVE) 2016 • Two IND filings expected for Huntington’s disease lead programs (WVE-120101, WVE-120102) YE 2016 • Clinical Trials expected to commence 2017 for 2 lead Huntington’s disease programs 2017 • IND filing and initiation of clinical trial for lead program in Duchenne Muscular Dystrophy in 2017 • Targeting 6 IND filings by end of 2018 • 20+ programs in early discovery and pre-clinical development • Strategic partnerships complement internal neurology focus areas (ex. Pfizer May 2016) • Cash runway into 2019 2018+ Pipeline Growth • GalNAc POC • 2 INDs expected YE 2016 6 IND Submissions by 2018 Manufacturing Capabilities Expanded Foundation of Intellectual Property • Collaboratio n• Metabolic disease • Hepatic targeting technology 2017:Clinical Platform Expansion & Pipeline Development WAVE Life Sciences A Genetic Medicines Company Developing targeted therapies for patients impacted by rare diseases Clinical Development • Initiate 3 clinical trials 2017 • 2 additional INDs YE 2017
  5. 5. BACKGROUND 3  Phosphorothioate (PS) backbone modification introduced into nucleic acid based therapies:  Provides good stability and bio-availability  Adopts random three-dimensional arrangements during synthesis  Results in exponentially diverse drug mixtures with 2N stereoisomers (N = number of PS)  Drug mixtures may suffer from efficacy, safety and distribution issues 19 phosphorothioate (PS) linkers 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Each PS linker = OR = 219 Mipomersen (219 = 524,288) Stereo-random Rp-stereoisomer Sp-stereoisomer Drug mixture Phosphodiester Phosphorothioate Sp Rp
  6. 6. • WAVE proprietary platform precisely controls oligonucleotide stereochemistry • Enables control of pharmacology and rational drug design with potential to improve stability, activity, stability, immunogenicity and specificity • Scalable synthesis • Applicable to any nucleic acid based therapy and targeting moieties • Unique ability to optimize pharmacology across the therapeutic class PLATFORM 4 Mixture s Rp Sp Nucleotide Linker WAVE Chemical Control WAVE Optimized Isomers Stability Activity Immune Specificity WAVE Design Antisense RNAi Exon skipping Optimized isomers
  7. 7. WAVE Pipeline Key : Est 2017 Clinical Trial I: Anticipated IND filings C: Candidate Nomination Estimated inflection point for candidate selection efforts This chart contains forward-looking statements. Core Neurolog y Portfolio (2)
  8. 8. Two lead programs in HD, IND filings expected in2016 The Disease • Autosomal dominant disorder, involving the HTT gene, characterized by chorea, psychiatric illness and cognitive decline • Approximately 30,000 individuals have symptomatic HD in the United States • No approved disease-modifying therapies available WAVE Approach • Selective reduction of mutant HTT while leaving wild-type HTT intact could be disease modifying • Targeting single nucleotide polymorphisms (SNPs) associated with causative mutations provides an approach to allele-specific gene silencing • Over two-thirds of patients are eligible to use WAVE’s first two programs due to prevalence of SNPs associated with the mutant alleles Huntington (HTT) Wild-type (healthy) allele Mutant allele SNP CAG repeat Disease causing mutations SNP associated with CAG repeat Enables targets for allele-specific silencing 100% 75% 25% 0 % Number of SNPs targeted HDPatients covered Cumulative HD Patient Coverage 50% Huntington’s Disease (HD) ~77% ~80% ~71% ~55% 1 2 3 4
  9. 9. WVE-120101 Selectively Cleaves mHTT RNA No Complement Immune System Response
  10. 10. WVE-120101 Selectively Reduces mHTT mRNA and Protein
  11. 11. Distribution of WVE-120101 in Cynomolgus NHP Brain Animal # 42, Slice 8 Red dots are WVE-120101. Arrow points to nuclear and perinuclear distribution of WVE-120101 in cingulate cortex In Situ Hybridization ViewRNA stained tissue WVE-120101 detectable in deep gray matter structures following intrathecal administration
  12. 12. Distribution of WVE-120101 in Cynomolgus NHP Brain WVE-120101 detectable in deep gray matter structures following intrathecal administration Animal # 42, slice 8 D Red dots are WVE-120101. Arrow points to nuclear and perinuclear distribution of WVE-120101 in caudate nucleus
  13. 13. • Two concurrent global Phase 1b/2a placebo-controlled studies targeting SNP1 and SNP2 • Primary Objective: Assess safety and tolerability of single ascending and multiple intrathecal doses in early manifest HD patients – Exploratory pharmacokinetic, pharmacodynamic, clinical and MRI endpoints – SNP determination at initial screening visit – Key inclusion criteria • Age ≥25 to ≤65 • Stage I or Stage II Huntington’s disease • INDs expected to file by YE 2016 WVE-120101 and WVE-120102 Clinical Development
  14. 14. Patient Selection for WVE-120101/2 Clinical Studies Patients with the targeted SNP on the same allele as the pathogenic CAG expansion will be eligible
  15. 15. • Control of oligonucleotide stereochemistry enables rational drug design and control of pharmacology of nucleic acid therapeutics – Potential to improve stability, activity, stability, immunogenicity and specificity – Scalable synthesis – Application to any nucleic acid based therapy and targeting moieties • In HD, WVE-120101 selectively decreased mHTT mRNA and protein levels compared with wtHTT in multiple cell lines with SNP1 allele with good brain distribution – Targeting SNP1 and SNP2 may provide the possibility of treating over two-thirds of the total HD patient population • The ability to selectively reduce mHTT protein, while retaining healthy HTT protein, might provide disease-modifying effects in HD Conclusions
  16. 16. Refining experimental gene therapies for Huntington’s and other diseases Pavlina Konstantinova Director Emerging Technologies 24th of February 2016, CHDI meeting Development of HTT lowering gene therapy using AAV vectors Pavlina Konstantinova, PhD Director Emerging Technologies
  17. 17. THIS PRESENTATION CONTAINS FORWARD-LOOKING STATEMENTS THAT INVOLVE SUBSTANTIAL RISKS AND UNCERTAINTIES. ALL STATEMENTS, OTHER THAN STATEMENTS OF HISTORICAL FACTS, CONTAINED IN THIS PRESENTATION, INCLUDING STATEMENTS REGARDING OUR STRATEGY, FUTURE OPERATIONS, FUTURE FINANCIAL POSITION, FUTURE REVENUES, PROJECTED COSTS, PROSPECTS, PLANS AND OBJECTIVES OF MANAGEMENT, ARE FORWARD-LOOKING STATEMENTS. THE WORDS “ANTICIPATE,” “BELIEVE,” “ESTIMATE,” “EXPECT,” “INTEND,” “MAY,” “PLAN,” “PREDICT,” “PROJECT,” “TARGET,” “POTENTIAL,” “WILL,” “WOULD,” “COULD,” “SHOULD,” “CONTINUE,” AND SIMILAR EXPRESSIONS ARE INTENDED TO IDENTIFY FORWARD- LOOKING STATEMENTS, ALTHOUGH NOT ALL FORWARD-LOOKING STATEMENTS CONTAIN THESE IDENTIFYING WORDS. WE MAY NOT ACTUALLY ACHIEVE THE PLANS, INTENTIONS OR EXPECTATIONS DISCLOSED IN OUR FORWARD- LOOKING STATEMENTS, AND YOU SHOULD NOT PLACE UNDUE RELIANCE ON OUR FORWARD-LOOKING STATEMENTS. ACTUAL RESULTS OR EVENTS COULD DIFFER MATERIALLY FROM THE PLANS, INTENTIONS AND EXPECTATIONS DISCLOSED IN THE FORWARD-LOOKING STATEMENTS WE MAKE. THE FORWARD-LOOKING STATEMENTS CONTAINED IN THIS PRESENTATION REFLECT UNIQURE’S CURRENT VIEWS WITH RESPECT TO FUTURE EVENTS, AND UNIQURE ASSUMES NO OBLIGATION TO UPDATE ANY FORWARD-LOOKING STATEMENTS EXCEPT AS REQUIRED BY APPLICABLE LAW. FORWARD-LOOKING STATEMENTS
  18. 18. Idea of Gene Therapy is Simple 18 Replace in a one-time administration a gene that does not function with a functioning gene to “fix” what is causing disease Gene Therapeutic correction Vector Delivery vehicle Manufacturing Gene / vector copies Administration Target tissue
  19. 19. 19 Confidential natural AAV DIRECTED EVOLUTION optimized AAV Natural AAV Variants and Target Tissue Tailored Vectors TROPISM AAV1 Exclusivity for LPLD AAV2 AAV5 Exclusivity for LIVER and CNS AAV6 AAV8 AAV9 Synthetic AAV MutantsSynthetic AAV MutantsSynthetic AAV MutantsSynthetic AAV MutantsSynthetic AAV MutantsSynthetic AAV MutantsSynthetic AAV MutantsSynthetic AAV MutantsSynthetic AAV MutantsSynthetic AAV MutantsSynthetic AAV Super Mutants 4D Therapeutics
  20. 20. AAV5 uniQure’s Proprietary and Proven Vector • Validated delivery technology • 20 patients successfully treated • Lowest prevalence of pre-existing antibodies amongst natural AAV serotypes • Successful delivery in liver and brain tissues • Potential for a wide variety of indications across multiple therapeutic areas • Initial efficacy established in Hemophilia B and Sanfilippo B • Proven safety in three clinical trials 20 AAV5
  21. 21. 21 1Pringsheim et al. Mov. Disord. (2012) • Worldwide prevalence of 2.71 in 100,0001; • EU/US 5.70 in 100,0001 • No treatment available • Published proof of concept of therapeutically relevant knock- down in humanized mouse/rate models • Lead selection completed • Non-clinical safety toxicology studies ongoing • Initiate first-in-man study Market Status Data to Date Next Steps Huntington's Disease Program Overview Target indication - Reduction of mutant aggregating huntingtin to decrease toxic burden
  22. 22. 22 Product development for AAV5 HD gene therapy Age/years Symptomseverity 10 20 30 40 50 60 70 80 Disease onset and diagnosis Single treatment AAV5-miRNA gene therapy • Slow down disease progression • Treatment after disease onset Slow down of disease progression Pre-symptomatic phase Symptomatic phase
  23. 23. 23 Companies developing HTT lowering therapies (both alleles are targeted)  IONIS PHARMACEUTICALS STARTED PHASE I/IIA TRIAL IN JULY 2015 WITH ASO TARGETING HTT  VOYAGER/GENZYME DEVELOP AAV1-MIRNA TARGETING HTT (TO BE IN GLP-TOX IN 2017)  SPARK IS PROCEEDING WITH AAV1-MIRNA TARGETING HTT (TO BE IN GLP-TOX IN 2016)
  24. 24. 24 AAV5-miHTT gene therapy for HD Therapeutic RNA interference binding to cell surface heparan sulphate proteoglycan internalization vesicle escape and transport to nucleus Uncoating and miRNA expression AAV vector cytoplasm nucleus AAA Target cell (neurons) Huntingtin mRNA binding Huntingtin degradation
  25. 25. AAV5-miHTT targeting HTT exon 1 Wild type HTT gene Mutant HTT gene CAG tract Expanded CAG tract  Silencing of both wild-type (wt) and mutant (mt) HTT alleles  In HD rodent models 75% knock-down of HTT is therapeutic (Drouet et al. 2009, Boudreau et al. 2009, Stiles et al. 2012)  In NHPs 50% knock-down of HTT is well tolerated (Kordasiewicz et al. 2012, McBride et al. 2012)
  26. 26. The miHTT therapeutic lead selection process Therapeutic candidate selection • In vitro selection • miRNA scaffold optimization – incorporate best miHTT in different cellular scaffolds • In vivo efficacy in HD mice – transduction, HTT silencing, phenotype improvement • Safety – ongoing Miniarikova et al. MolTher NA, 2016 CAG promoter polyAmiHTT-451 ~2.8 kb 5’ITR 3’ITR CAG, chicken beta actin promoter; ITR, inverted terminal repeats
  27. 27. Broad brain distribution of AAV5-GFP-miHTT – in mice Amber Southwell, UBC 27 Forebrain, striatum, cortex, and hippocampus
  28. 28. AAV5-miHTT AAV5-miScr miScr miHTT AAV5-miHTT AAV5-miScr miScr miHTT AAV5-miHTT induces strong HTT silencing in humanized HD mouse 28 Target specificity and miHTT efficacy Miniarikova et al, MolTher NA,2016 Amber Southwell, UBC 75% 50% Humanized HD mouse miHTT 128QhHtt - hHtt -
  29. 29. AAV5-miHTT treatment prevents neurodegeneration in HD rat model 29 Phenotype improvement Miniarikova et al. submitted AAV5-miHTTAAV5-miSCR DARPP-32 lesions
  30. 30. 30 AAV5 delivery studies in NHP and HD minipigs MRI-guided CED delivery to NHP
  31. 31. PutameninfusionThalamusinfusion Snapshot from the end of the infusion 127µL 207µL MRI-guided CED 13 consecutive acquisitions with 5min delay (total time: min) FirstcannulaplacementSecondcannulaplacement Left Right Thalamus + Putamen infusion
  32. 32. Broad distribution of AAV5-GFP - in NHP 32 Transduction efficiency NHP after MRI-CED 8 weeks post bilateral infusion α-GFPAAV5-CAG-GFP 127µL by CED AAV5-CAG-GFP 207µL by CED Valley Biosystems
  33. 33. AAV5-miHTT gene therapy demonstrates efficacy in TgHD minipig study 12 wild-type minipigs 12 TgHD minipigs 2-3 years of age -2 0 2 3 4 6 8 12-1 1 5 7 9 1110 CSF serum CSF serum CSF serum plasma CSF serum plasma CSF serum plasma CSF serum plasma CSF serum plasma CSF serum plasma N=3 formulation buffer N=3 1E+13 GC/pig AAV5-GFP N=3 1E+13 GC/pig AAV5-miHTT N=3 3E+13 GC/pig AAV5-miHTT Immunohistochemistry: - GFP - HTT - Iba1 - GFAP DNA isolation: - AAV5 distribution RNA isolation: - miHTT expression - mtHTT reduction Protein isolation: - mtHTT quantitation Weeks: Sampling: Bilateral CED infusion putamen and thalamus
  34. 34. Broad distribution after thalamic injection – in pigs 34 AAV5-GFP transduction efficiency mini pig Jan Motlík, Liběchov (Evers et al, in preparation) α-GFP
  35. 35. Broad AAV5-miHTT vector distribution correlates with transgene expression and HTT lowering in HD minipig > STRONG CORRELATION BETWEEN VECTOR GENOME COPIES AND MIHTT EXPRESSION 35 0 . 1 1 1 0 1 0 0 1 0 2 1 0 3 1 0 4 1 0 5 1 0 6 1 0 7 1 0 8 m a t u r e m i H T T m o l e c u l e s p e r c e l l AAV5-miHTTgenomecopies pergDNA R 2 = 0 . 8 7 4 4 P = 1 . 1 1 2 e - 0 1 3 Evers et al, in preparation
  36. 36. AAV5-miHTT treatment results in strong mutant HTT mRNA reduction in TgHD minipig brain Evers et al, in preparation C a u d a t e n u c l e u s mtHTTmRNAexpression(%) (normalizedbyGAPDH,relativetoSaline) S a lin e 1 E + 1 3 A A V 5 - G F P 1 E + 1 3 A A V 5 - m iH T T 3 E + 1 3 A A V 5 - m iH T T 0 5 0 1 0 0 1 5 0 T h a l a m u s mtHTTmRNAexpression(%) (normalizedbyGAPDH,relativetoSaline) S a lin e 1 E + 1 3 A A V 5 -G F P 1 E + 1 3 A A V 5 -m iH T T 3 E + 1 3 A A V 5 -m iH T T 0 5 0 1 0 0 1 5 0 C o r t e x mtHTTmRNAexpression(%) (normalizedbyGAPDH,relativetoSaline) S a lin e 1 E + 1 3 A A V 5 -G F P 1 E + 1 3 A A V 5 -m iH T T 3 E + 1 3 A A V 5 -m iH T T 0 5 0 1 0 0 1 5 0
  37. 37. GLP-TOX studies path > GLP-TOX STUDIES PLANNED IN TWO RELEVANT LARGE BRAIN SPECIES > Cynomolgus monkeys - full GLP-TOX study to mimic the clinical trial design > Targeting striatum and/or thalamus > MRI guided CED infusion filling 80% of structure > Vector distribution > Safety > HTT lowering and biomarkers > Minimum 6 months in-life > HD minipig – long term safety, up to 5 years > Mimic clinical trial design > Demonstrate long term vector persistence > Evaluate long-term consequences of HTT lowering > Generate long-term safety data prior product approval 37 Gene Therapy is a new technology, so long-term safety is crucial
  38. 38. uniQure’s HD clinical trial concept > GENE TRANSFER WILL BE A THERAPEUTIC TREATMENT > MAIN GOAL: DELAY OR STOP DISEASE PROGRESSION > BASED ON THE MOA AND CHANGES IN BRAIN VOLUMES AND MORPHOLOGY WE PROPOSE: > THERAPEUTIC INTERVENTIONS IN PATIENTS IN EARLY HD STAGES > THE CONCEPT OF EARLY INTERVENTION IS IN DISCUSSION WITH PHYSICIANS AND REGULATORY AGENCIES. 38 Treat patients in early stage of disease progression J-P Vonsattel, 1985 Atrophy of the striatum (caudate and putamen) Cortical thinning Ventricular enlargement Neuropathology of HD Normal Grade 2 Grade 3 Grade 4 caudate and putamen
  39. 39. 39 Acknowledgements and collaborators uniQure Jana Miniarikova Juliana Bronzova Sebastian Kugler Melvin Evers Jean-Marc Burgunder Cynthia Brouwers Bernhard Landwermeyer Jolanda Snapper Bas Blits Raygene Martier Tom van der Zon Sander van Deventer Nicole Deglon Charles Richard Virginie Zimmer Harald Petry Amber Southwell Ilaria Zanella Michael Hayden Angelina Huseinovic Annemart Koornneef Piotr Maczuga Richard van Longestein Huining Li Florie Borel Evelyn Hanenmaijer GHI, Munster Ralf Reilmann IAPG, Libechov Jan Motlik Stefan Juhas Zdenka Eledorova Taneli Heikkinen Outi KontkanenUCSF/Valley Ignacio Munoz-Sanjuan Douglas Macdonald David Howland
  40. 40. 40 Thank You! From the uniQure Team
  41. 41. IONIS-HTTRx: An Antisense Oligonucleotide in Development for the Treatment of Huntington’s Disease 03 November 2016 Anne Smith, PhD Ionis Pharmaceuticals
  42. 42.  Founded: 1989  Location: Carlsbad, CA  ~400 employees  Focus:  Drug discovery  Early clinical development  Manufacturing Ionis Pharmaceuticals, Inc. 42
  43. 43. The number of new drugs approved by the US FDA per billion dollars (inflation adjusted) spent on research and development from 1950 to 2010. Drug Discovery Productivity is Declining Scannell et al. 2012. Nature Rev Drug Discov. 100 10 1 #drugs/billion$spent 0.1 1950 1960 1970 1980 1990 2000 2010 FDA tightens regulation post-thalidomide First wave of biotechnology- derived therapies FDA clears backlog following PDUFA regulations plus small bolus of HIV drugs 43
  44. 44. Drug Discovery Platforms Small Molecules Proteins Lipitor Nucleic Acids antisense oligonucleotides (ASOs) Gene Therapy antibody insulin 44
  45. 45. DMPKRx RNase H Removes toxic RNA Antisense Oligonucleotide (ASO) Mechanisms RNase H1 Antisense mRNA for disease-causing protein Reduces production of a toxic protein Increases production of a therapeutic protein Example: IONIS-HTTRx Example: nusinersen Example: IONIS-DMPKRx 45
  46. 46. Broad Clinical ASO Activity in Multiple Tissues 46 Ionis Clinical Experience: >6000 subjects dosed >100 clinical studies
  47. 47. Antisense Technology Uniquely Addresses Challenging Neurological Diseases
  48. 48. ASOs are Poised to Capitalize on Advances in Biology and Molecular Medicine  Advances in biology  dramatic shift in neurology  From empiric diagnoses (treat the symptoms)  To diagnoses based on understanding of the underlying disease pathophysiology (treat the root cause)  Sound translational science to create ASO drugs to genetically-identified targets  Basic science – validate target mechanism of the ASO  Animal models –  test ASO potency, delivery and distribution to the target  develop PK/PD models to guide dose selection  Clinical studies – early assessment of target engagement and effects on disease pathology 48
  49. 49.  Ideal target for an ASO  HD neuropathology appears to be due to gain-of-toxic function of the mutant huntingtin protein (muHtt)  Decreasing muHtt synthesis is expected to target the primary disease mechanism  Patients can be identified with certainty via genetic test  IONIS-HTTRx  An ASO that targets mRNA transcribed from the human huntingtin gene  Not allele-specific; targets both mutant and wild-type huntingtin mRNA ASO Development for Huntington’s Disease 49
  50. 50. IONIS-HTTRx Activity via RNase H1 Mechanism 50 1
  51. 51. IONIS-HTTRx: A “Generation 2+” ASO A G T C T G A T T C MOEDNA G C A T C G A A C C gap MOE 5’-wing 3’-wing O O B HO O O B P O S O O O OCH3 OCH3 O O B O O HO B P O S O O O OCH3 OCH3 O O B O O O B P O S O Miller et al. Archives of Neurology, 2008 “Gapmer” design  20 bases  DNA in middle (to activate RNase H1)  MOE modification at ends 51 Gen 2+ ASOs  Diffusible  Stable  Dose-dependent  Reversible
  52. 52. IONIS-HTTRx History Year Event 2003 Initiated first neuro program 2005 Initiated Huntington program Screened for ASOs and tested in mice for tolerability and mRNA knockdown First huntingtin-targeting ASOs introduced into HD mouse models 2011 First medical advisory board meeting to shape IONIS-HTTRx clinical program 2013 Isis/Roche partnership 2015 IONIS-HTTRx entered clinical testing in a multi-site Phase 1/2a study 52
  53. 53. IONIS-HTTRx: Preclinical Pharmacology and Toxicology Summary  ASOs targeting HTT mRNA have pharmacologic activity in mouse models of HD  improve motor function, hypoactivity and stress response in BACHD mice  improve motor function and protect against gene expression changes in YAC128 mice  preserve striatal volume and increase survival in R6/2 mice  Identified several ASOs targeting HTT mRNA that are well tolerated in mice (up to 1 year of dosing)  ASOs targeting HTT mRNA distribute widely in the non-human primate CNS; huntingtin suppression is well-tolerated 53 Kordasiewicz et al. 2012, Stanek et al. 2013
  54. 54.  Safety/tolerability study in 36 patients  Placebo-controlled  Each patient receives 4 doses of study drug by IT injection, spaced 28 days apart  After 4th dose, patients participate in a 4-month post- treatment period  NCT02519036 IONIS-HTTRx First Clinical Study 54
  55. 55. IONIS-HTTRx First Clinical Study: Study Progression Post-Treatment Period Post-Treatment Period Post-Treatment Period Post-Treatment Period Cohort B (N=8) Cohort C (N=8) Cohort D (N=16) each represents one dose followed by a 28-day observation period Cohort A (N=4) 55
  56. 56.  Primary Objective  To evaluate the safety and tolerability of IONIS-HTTRx in patients with early Huntington’s disease  Secondary Objective  To characterize the CSF PK of IONIS-HTTRx  Exploratory Objectives  To assess plasma PK properties of IONIS-HTTRx  To explore effects of IONIS-HTTRx on PD markers and on clinical endpoints relevant to HD IONIS-HTTRx First Clinical Study: Objectives 56
  57. 57.  Safety assessments include:  Laboratory tests  Neurological exams  Assessments of cognitive, motor and neuropsychiatric function  Vital signs  ECG  Potential markers of target engagement and pharmacodynamic effect include:  Neuroimaging  Clinical, cognitive and functional scales  CSF huntingtin protein and CSF markers of brain health IONIS-HTTRx First Clinical Study: Assessments 57
  58. 58.  First dose in Sept 2015  Recently completed enrollment of 3rd dose level and obtained Data Safety Monitoring Board agreement to initiate 4th dose level  Study completion expected late 2017 IONIS-HTTRx Status of First Clinical Study 58
  59. 59. Acknowledgements ►Thank you to the patients and families who give their time to HD studies◄ IONIS-HTTRx FIH Clinical Study PIs and KOLs Sarah Tabrizi – global lead PI Roger Barker, David Craufurd, Bernhard Landwehrmeyer, Blair Leavitt, Carsten Saft, Ed Wild Roche Christian Czech, Irene Gerlach, Hansruedi Loetscher, Scott Schobel UCSD Don Cleveland CHDI Foundation Robi Blumenstein, Doug Macdonald, Cristina Sampaio Ionis Pharmaceuticals Frank Bennett Holly Kordasiewicz Kristin Balogh, Tiffany Baumann, Bethany Fitzsimmons, Sue Freier, Marc Gleichmann, Sarah Greenlee, John Grundy, Scott Henry, Gene Hung, Roger Lane, John Matson, Curt Mazur, Dan Norris, Michael Oestergaard, Erika Paz, Noah Post, Frank Rigo, Punit Seth, Eric Swayze, Ed Wanciewicz, Andy Watt, Tom Zanardi

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