Isis 2014 R&D Day. The product of 25. years of basic research at Isis A N T I S E N S E. Technology Today

Transcription

1 Isis 2014 R&D Day The product of 25 A N T I S E N S E years of basic research at Isis Technology Today May 22, 2014

2 Introduction Stan Crooke, M.D., Ph.D. CEO and Chairman, Isis Pharmaceuticals 2

3 Forward Looking Language Statement This presentation includes forward-looking statements regarding Isis Pharmaceuticals financial position and outlook, Isis business, and the therapeutic and commercial potential of Isis technologies and products in development. Any statement describing Isis goals, expectations, financial or other projections, intentions or beliefs is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain risks and uncertainties, particularly those inherent in the process of discovering, developing and commercializing drugs that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such drugs. Isis forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause its results to differ materially from those expressed or implied by such forward-looking statements. Although Isis forward-looking statements reflect the good faith judgment of its management, these statements are based only on facts and factors currently known by Isis. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Isis programs are described in additional detail in Isis annual report on Form 10-K for the year ended December 31, 2013, and its most recent quarterly report on Form 10-Q, which are on file with the SEC. Copies of these and other documents are available from the Company. In this presentation, unless the context requires otherwise, Isis, Company, we, our, and us refers to Isis Pharmaceuticals and its subsidiaries. Isis Pharmaceuticals and Vitravene are registered trademarks of Isis Pharmaceuticals, Inc. Regulus Therapeutics is a trademark of Regulus Therapeutics Inc. KYNAMRO is a registered trademark of Genzyme Corporation. 3

4 Participants Dr. Stan Crooke CEO and Chairman Isis Pharmaceuticals Dr. Richard Geary SVP Development Isis Pharmaceuticals Dr. Frank Bennett SVP Research Isis Pharmaceuticals Dr. Sanjay Bhanot VP Clinical Development & Translational Medicine Isis Pharmaceuticals Dr. Jeffrey Weitz Professor, Division of Hematology & Thromboembolism, Dept. of Medicine McMaster University 4

5 Agenda Introduction Dr. Stan Crooke, CEO & Chairman, Isis Pharmaceuticals ISIS-SMN Rx Dr. Frank Bennett, SVP Research, Isis Pharmaceuticals ISIS-TTR Rx and ISIS-APOCIII Rx Dr. Richard Geary, SVP Development, Isis Pharmaceuticals Diabetes Franchise Dr. Sanjay Bhanot, VP Clinical Development & Translational Medicine, Isis Pharmaceuticals ISIS-FXI Rx Dr. Sanjay Bhanot, VP Clinical Development & Translational Medicine, Isis Pharmaceuticals ISIS-FXI Rx Phase 2 Study Update Dr. Jeffrey Weitz, Professor, Division of Hematology & Thromboembolism, McMaster University Pipeline Overview Dr. Richard Geary, SVP Development, Isis Pharmaceuticals Isis Future: Focused on Value Dr. Stan Crooke, CEO & Chairman, Isis Pharmaceuticals Concluding Remarks Q & A Dr. Stan Crooke, CEO & Chairman, Isis Pharmaceuticals 5

6 Why Antisense Technology? Advantages Only direct route from genes to drugs Uniquely specific and broadly applicable Virtually no undruggable targets Almost universal applicability Efficient discovery and early development Dramatically reduced cost and increased success in R&D Investment amortized across the entire pipeline Chemistry, manufacturing, formulation, analytical methods Multiple antisense mechanisms Broad versatility: toxic RNA, splicing, direct protein down regulation Multiple routes of delivery SubQ, IV, intrathecal, intraocular, intradermal, inhalation, enema, oral Broad clinical activity Demonstrated clinical activity in multiple tissues 6

7 Why Antisense Technology? Advantages Only direct route from genes to drugs Uniquely specific and broadly applicable Virtually no undruggable targets Almost universal applicability Efficient discovery and early development Dramatically reduced cost and increased success in R&D Investment amortized across the entire pipeline Chemistry, manufacturing, formulation, analytical methods Multiple antisense mechanisms Broad versatility: toxic RNA, splicing, direct protein down regulation Multiple routes of delivery SubQ, IV, intrathecal, intraocular, intradermal, inhalation, enema, oral Broad clinical activity Demonstrated clinical activity in multiple tissues 7

8 Why Antisense Technology? Advantages Only direct route from genes to drugs Uniquely specific and broadly applicable Virtually no undruggable targets Almost universal applicability Efficient discovery and early development Dramatically reduced cost and increased success in R&D Investment amortized across the entire pipeline Chemistry, manufacturing, formulation, analytical methods Multiple antisense mechanisms Broad versatility: toxic RNA, splicing, direct protein down regulation Multiple routes of delivery SubQ, IV, intrathecal, intraocular, intradermal, inhalation, enema, oral Broad clinical activity Demonstrated clinical activity in multiple tissues 8

9 Why Antisense Technology? Advantages Only direct route from genes to drugs Uniquely specific and broadly applicable Virtually no undruggable targets Almost universal applicability Efficient discovery and early development Dramatically reduced cost and increased success in R&D Investment amortized across the entire pipeline Chemistry, manufacturing, formulation, analytical methods Multiple antisense mechanisms Broad versatility: toxic RNA, splicing, direct protein down regulation Multiple routes of delivery SubQ, IV, intrathecal, intraocular, intradermal, inhalation, enema, oral Broad clinical activity Demonstrated clinical activity in multiple tissues 9

10 Why Antisense Technology? Advantages Only direct route from genes to drugs Uniquely specific and broadly applicable Virtually no undruggable targets Almost universal applicability Efficient discovery and early development Dramatically reduced cost and increased success in R&D Investment amortized across the entire pipeline Chemistry, manufacturing, formulation, analytical methods Multiple antisense mechanisms Broad versatility: toxic RNA, splicing, direct protein down regulation Multiple routes of delivery SubQ, IV, intrathecal, intraocular, intradermal, inhalation, enema, oral Broad clinical activity Demonstrated clinical activity in multiple tissues 10

11 Why Antisense Technology? Advantages Only direct route from genes to drugs Uniquely specific and broadly applicable Virtually no undruggable targets Almost universal applicability Efficient discovery and early development Dramatically reduced cost and increased success in R&D Investment amortized across the entire pipeline Chemistry, manufacturing, formulation, analytical methods Multiple antisense mechanisms Broad versatility: toxic RNA, splicing, direct protein down regulation Multiple routes of delivery SubQ, IV, intrathecal, intraocular, intradermal, inhalation, enema, oral Broad clinical activity Demonstrated clinical activity in multiple tissues 11

12 Why Antisense Technology? Advantages Only direct route from genes to drugs Uniquely specific and broadly applicable Virtually no undruggable targets Almost universal applicability Efficient discovery and early development Dramatically reduced cost and increased success in R&D Investment amortized across the entire pipeline Chemistry, manufacturing, formulation, analytical methods Multiple antisense mechanisms Broad versatility: toxic RNA, splicing, direct protein down regulation Multiple routes of delivery SubQ, IV, intrathecal, intraocular, intradermal, inhalation, enema, oral Broad clinical activity Demonstrated clinical activity in multiple tissues 12

13 Why Antisense Technology? Advantages Only direct route from genes to drugs Uniquely specific and broadly applicable Virtually no undruggable targets Almost universal applicability Efficient discovery and early development Dramatically reduced cost and increased success in R&D Investment amortized across the entire pipeline Chemistry, manufacturing, formulation, analytical methods Multiple antisense mechanisms Broad versatility: toxic RNA, splicing, direct protein down regulation Multiple routes of delivery SubQ, IV, intrathecal, intraocular, intradermal, inhalation, enema, oral Broad clinical activity Demonstrated clinical activity in multiple tissues 13

14 Isis Antisense Technology is a Proven, Efficient Platform for Creating New Drugs Successful 3 commercialized drugs Approved January 2013 Named Patient Supply Approved

15 Isis Antisense Technology is a Proven, Efficient Platform for Creating New Drugs Successful 3 commercialized drugs Efficient 1 drug per 12 Isis employees Traditional Pharma 1 drug / ~1,000 employees ISIS 1 drug / 12 employees 15

16 Isis Antisense Technology is a Proven, Efficient Platform for Creating New Drugs Successful 3 commercialized drugs Efficient 1 drug / 12 Isis employee Robust multiple mechanisms Single-stranded antisense drugs can effectively target RNAs in cytoplasm AND nucleus of the cell Reduces target RNA & prevents production of protein RNase H Increases production of therapeutic protein Removes toxic RNA DMPK Rx mrna for disease-causing protein RNase H Antisense Example: ISIS-APOCIII Rx Example: ISIS-SMN Rx Example: ISIS-DMPK Rx 16

17 Isis Antisense Technology is a Proven, Efficient Platform for Creating New Drugs Successful 3 commercialized drugs Efficient 1 drug / 12 Isis employee Robust multiple mechanisms Robust multiple routes of delivery 17

18 Isis Antisense Technology is a Proven, Efficient Platform for Creating New Drugs Successful 3 commercialized drugs Efficient 1 drug / 12 Isis employee Robust multiple mechanisms Robust multiple routes of delivery Robust broad clinical activity in multiple tissues 18

19 Isis Current Pipeline is Broad, Diverse and Mature Phase 2 Phase 1 Commercialized ISIS-SMN Rx ISIS-APOCIII Rx Spinal Muscular Atrophy FCS ISIS-GCCR Rx ISIS-PKK Rx Cushing s Syndrome Hereditary Angioedema KYNAMRO Homozygous FH ISIS-APOCIII Rx Severely High TGs ISIS-APO(a) Rx Very High Lp(a) Alicaforsen* Pouchitis ATL1103 Acromegaly ISIS-ANGPTL3 Rx Hyperlipidemia Vitravene CMV Retinitis ISIS-FXI Rx Clotting Disorders ISIS-FGFR4 Rx Obesity ISIS-CRP Rx CAD ISIS-HBV Rx HBV ISIS-GCGR Rx Diabetes RG-101 HCV ISIS-GCCR Rx ISIS-STAT3 Rx Plazomicin EXC 001 (PF ) ico-007 Diabetes ISIS-PTP1B Rx Diabetes 19 Phase 3 ISIS-EIF4E Rx Cancer ISIS-DMPK Rx Myotonic Dystrophy 1 Apatorsen ISIS-TTR Cancer Rx TTR Amyloidosis (OGX-427) ISIS-HTT Rx Huntington Disease KYNAMRO Custirsen (OGX-011) Severe HeFH Prostate / Lung Cancer Cancer Severe Bacterial Infection Scarring Diabetic Macular Edema RG-012 ISIS-FVII Rx ISIS-DGAT2 Rx ISIS-AR Rx Preclinical Alport Syndrome Clotting Disorders NASH Cancer ATL1102 Multiple Sclerosis ISIS-GSK4 Rx Ocular Disease Severe & Rare Cardiovascular Metabolic Cancer Other * Named Patient Supply 19

20 Maturing Pipeline Many Shots on Goal: Increasing Value, Decreasing Risk Programs in pipeline: Regulatory/Commercialization 7 Phase Phase Phase Preclinical (Projected) 20

21 Pharmaceutical Companies Are Excited About the Potential for Antisense Drugs to Provide Benefits to Patients Partnerships Provide Significant Reliable Revenue Stream Biogen Idec Focus: Upfront, Milestones and Licensing Fees: ISIS-SMN Rx $298M Biogen Idec Focus: Upfront, Milestones and Licensing Fees: ISIS-DMPK Rx $271M Revenue Potential to Earn >$6B Focus: Upfront, Milestones and Licensing Fees: GSK Roche Focus: Upfront, Milestones and Licensing Fees: Rare and Infectious Diseases ~$1.5B Huntington s Disease $392M Biogen Idec Focus: Upfront, Milestones and Licensing Fees: 3 Neurological Disease Targets >$660M Biogen Idec Focus: Upfront, Milestones and Licensing Fees: Neurological Disease Strategic Relationship >$3B AstraZeneca Focus: Upfront, Milestones and Licensing Fees: Cancer >$1.2B 21

22 Phase 3 data 2014 Phase 2 completing Phase 3 Mid-2014 Phase 3 ongoing Phase 3 Mid-2014 Near-term Drivers of Value 6 Drugs with Potential to File for Commercialization by ISIS-SMN Rx ISIS-TTR Rx ISIS-APOCIII Rx SMA: ~35,000 US, EU & Japan FAP: ~10,000 WW FAC: ~40,000 WW FCS: 3,000-5,000 WW Severe TG: ~50,000 in US/EU Phase (Potential) ISIS-STAT3 Rx A Gen 2.5 Antisense Drug Phase 2 expansion study in DLBCL Ongoing Phase 1/2 study in HCC Custirsen (OGX-011) Initial Phase 3 data negative Additional Phase 3 studies in CRPC and NSCLC enrolling EXC 001 Anti-scarring drug with potential for multibillion dollar market 22

23 ISIS-SMN Rx For Infants and Children with Spinal Muscular Atrophy Frank Bennett, Ph.D. Senior Vice President, Research

24 ISIS-SMN Rx for Spinal Muscular Atrophy (SMA) Severe Genetic Neuromuscular Disease Affecting Children SMA is a rare disease that affects approximately 30-35K children in United States, Europe and Japan Number one genetic cause of death in infants Characterized by progressive muscle atrophy and loss of motor function Caused by genetic defects in the SMN1 gene that result in the lack of functional SMN protein No currently approved therapies for SMA 24

25 Broad Phenotypic Spectrum of SMA Incidence of SMA Types Type 3 12% Type 4 1% Type 2 27% Type 1 60% Type 3 35% Prevalence of SMA Types Type 4 <1% Type 1 14% Type 2 51% 25

26 ISIS-SMN Rx Splicing Mechanism 26

27 ISIS-SMN Rx Clinical Studies Design Phase 1 Open-label Study Childhood SMA (Type 2 and 3) Single IT dose (1, 3, 6 or 9 mg) 28 patients: 15 Type 2 and 13 Type 3, 2 14 years of age Phase 2 Open-label Studies Childhood SMA (Type 2 and 3) Three (3 or 6 mg) or two (9mg) IT doses over three months 25 patients: 10 Type 2 and 15 Type 3, 2-15 years of age 12 mg dose cohort ongoing Infant SMA (Type 1) Three IT doses (6 or 12 mg) over three months 15 Type 1 patients: < 7 months of age All but one patient in the per protocol efficacy population had 2 copies of SMN2 Additional patients currently enrolling in 12 mg cohort 27

28 ISIS-SMN Rx : What Have We Learned? Magnitude of effect ISIS-SMN Rx has shown both dose and time dependent effects on motor function Effects have been consistent from Mouse to human Infant to children (Type 1 to Type 2/3) Study to study Effects on multiple measures of activity observed Increases in SMN protein levels in CSF consistent with drug mechanism ISIS-SMN Rx has been well tolerated to date Some patients have been treated for over 2 years 44 doses in 15 infants and 138 doses in 54 children as of April 7 28

29 ISIS-SMN Rx : Demonstrated Activity in Mice and Multiple Types of SMA Patients

30 ISIS-SMN Rx Increases SMN2 Splicing, Increases Production of SMN Protein In Mouse Spinal Cord Tissue and Human CSF 3.5 Fold Increase in Protein Achieved >90% Corrected Splicing SMN Targeting ASO Promotes a Dose Dependent Increase in SMN2 Splicing mg/day % incl Mouse # SMN Protein in mouse CSF (Mean ± SD) 3.5 fold Increase Increases in CSF SMN Protein in SMA Children with A Single 9 mg Dose Study Timing Change in CSF SMN Protein Phase months 160% increase (2.6 fold) Phase 2 3 months 115% increase (2.1 fold) 30

31 ISIS-SMN Rx Preserves Neuron and Muscle Function in a Transgenic Mouse Model of SMA ISIS-SMN Rx Treatment Preserves Neuromuscular Junctions ISIS-SMN Rx Treatment Maintains Muscle Fiber Size and Muscle Strength 31

32 ISIS-SMN Rx : Infant Data Summary

33 Probability of Endpoint-Free Survival Natural History of Infantile-onset Type 1 SMA (Finkel et al., under review) Death/Permanent Ventilation (>16 hours/day ventilation continuously for >2 weeks, in the absence of an acute reversible illness) 3 SMN2 copies Isis Phase 2 infant SMA study well matched Comparable patient population 2 SMN2 copies Comparable standard of care Contemporaneous Similar physicians Similar sites 10.5 months Age (Months) With 2 copies SMN2: Median age at endpoint = 10.5 months At 18 months, 85% meet endpoint 33

34 Median Age of SMA Infants in 6 mg Cohort of ISIS-SMN Rx Phase 2 Infant Study Greater Than That Observed in Finkel et al., Natural History Study (Patient Status as of April 7, 2014) 6 mg Cohort Efficacy Population 1 Accidental Death Median age at event or April 7 = 14 months 12 mg Cohort Efficacy Population 1 Median age at event or April 7 = 9.6 months Patients in 12 mg cohort started study~ 6 months after patients in 6 mg cohort 2 1 Per protocol efficacy population = patients who receive 3 initial loading doses and Day 92 evaluation 2 16 hours hours/day of ventilation continuously for >2 weeks, in the absence of an acute reversible illness 34

35 ISIS-SMN Rx Increases SMA Infants Motor Function; Increases in CHOP INTEND Scores Observed (Efficacy Population: Data Cut-off April 7) Red=12 mg Cohort Blue=6 mg Cohort Natural History of Infantile-onset Type 1 SMA (Finkel et al., under review) Increases in CHOP INTEND scores were substantial Mean change from baseline = 8.3 points for 12 mg cohort Increases were observed in majority of patients 6/7 patients in 12 mg dose cohort had increases 5 points Increases were persistent Type 1 SMN Natural History CHOP INTEND scores show steady decline (1.27 points/yr) Few patients show increases Increases are short-lived 35

36 Achievement of New Motor Milestones Observed in Some Infants at Last Non-dosing Visit (Efficacy Population: Data cut-off April 7, 2014) Blue 6 mg, Red 12 mg Head control Unable to maintain upright Wobbles All the time upright Sitting Cannot sit Sit with support at hips Props Stable sit Pivots (rotates) Voluntary grasp No grasp Uses whole hand Index finger and thumb but immature grasp Pincer grasp Ability to kick (in supine) No kicking Kicks horizontally; legs do not lift Upward (vertically) Touches leg Touches toes Rolling No rolling Rolling to side Prone to supine Supine to prone Crawling Does not lift head On elbow On outstretched hand Crawling flat on abdomen On hands and knees Standing Does not support weight Supports weight Stands with support Stands unaided Walking No walking Bouncing Cruising (holding on) Walking independently 36

37 ISIS-SMN Rx : Childhood Data Summary

38 Increases in Muscle Function Scores Observed in the Phase 1 Study up to 14 Months After a Single Dose of ISIS-SMN Rx 1-3 Months Post Single Dose 9-14 Months Post Single Dose Mean + SEM Mean ± SEM 5.75 (p = 0.008) Observations on the 9 mg cohort At Day 85, mean change from baseline = 3.1 points (p=0.02) 6/10 patients with change 4 points At 9-14 months, mean change from baseline = 5.75 points (p=0.008) No patients declined 6/8 patients with change 4 points 38

39 Dose and Time Dependent Increases in Muscle Function Scores Replicated in Patients Treated With Multiple Doses of ISIS-SMN Rx * * Mean + SEM, *, p<0.05, compared to BL Time (months) 39

40 Results: Additional Measurements of Motor Function Are Consistent and Encouraging Results of Six Minute Walk Test (6MWT) and Upper Limb Module (ULM) test consistent with increases observed in Hammersmith Functional Motor Scale Expanded Mean increase of 22.7 meters (SEM ±12.3) observed at 9 months in 6MWT in 9 ambulatory patients (mean baseline m, SEM ±31.4) 6MWT measures the distance an ambulatory SMA patient is able to walk over a total of six minutes on a hard, flat surface Mean increase of 2.3 points (SEM ±0.9) observed at 9 months in the ULM test in 10 nonambulatory patients (mean baseline 10.5, SEM ±1.0) ULM Test used for SMA patients who were nonambulatory, in which a 9 item scale is scored as 0, 1 or 2 per item (max score 18) 40

41 ISIS-SMN Rx Lessons Learned Supporting Phase 3 Design and Conduct Data support selection of the 12mg dose for pivotal studies Long half-life of ISIS-SMN Rx in CNS supports infrequent dosing Two to three month loading dose schedule followed by infrequent maintenance administration In infants with SMA, data support time to death/permanent ventilation as primary endpoint with motor function (CHOP INTEND, motor milestones) as secondary endpoints Regulatory agencies agreement In children with SMA, data support change from baseline in Hammersmith motor function scale as the primary endpoint in pivotal study Regulatory agencies agreement 41

42 Lessons Learned About Type 1 SMA Isis successfully matched patients in Phase 2 infant study to those in Finkel et al. natural history study Similar patient population, sites, and standard of care In studies conducted, ISIS-SMN Rx has been active and well tolerated Early and aggressive treatment with ISIS-SMN Rx and supportive care are vital in this rapidly progressive disease 42

43 ISIS-SMN Rx Phase 3 Study in SMA Infants 13-month Study, Planned Initiation Mid 2014 A Phase 3, randomized, double-blind, sham-procedure controlled study in infants with SMA Global study in ~110 SMA infants 7 months old with 2 copies of SMN2 gene Planned mid-year initiation; study start up activities in progress 13 month study duration All patients eligible to roll over to open label extension (OLE) study Objectives Evaluate the efficacy and safety of ISIS-SMN Rx Primary efficacy endpoint is survival or permanent ventilation Additional efficacy endpoints include CHOP INTEND and motor milestones Cohort 2:1 12 mg R 21 days 2 months 11 months Study Complete OLE Screening 4 Induction Doses Maintenance Dose Every 4 Months M13 Last Visit 43

44 ISIS-SMN Rx Phase 3 Study in SMA Children 15-month Study, Planned Initiation 2H 2014 A Phase 3, randomized, double-blind, sham-procedure controlled study in children with SMA Global study in ~120 SMA children Planned 2H 2014 initiation; more detail on study design will be provided later in year 15 month study duration All patients eligible to roll over to open label extension (OLE) study Objectives: Evaluate the efficacy and safety of ISIS-SMN Rx Primary efficacy endpoint: change in Hammersmith Motor Function Scale Expanded Cohort 2:1 12 mg R 21 days Study Complete OLE Screening 3 Induction Doses Maintenance Dose Every 6 Months M15 Last Visit 44

45 Take Home Messages on ISIS-SMN Rx Magnitude of effect ISIS-SMN Rx has shown both dose and time-dependent effects on motor function Effects have been consistent Effects on multiple measures of activity observed SMN protein data supports mechanism ISIS-SMN Rx has been well tolerated to date Phase 3 studies about to begin 45

46 Strong Partnerships in Support of ISIS-SMN Rx Partnered with Dr. Adrian Krainer Dr. Yimin Hua 46

47 ISIS-TTR Rx and ISIS-APOCIII Rx Richard Geary, Ph.D. Senior Vice President, Development

48 ISIS-TTR Rx Toward a Better Treatment for Patients with Transthyretin (TTR) Amyloidosis

49 Partnered with: ISIS-TTR Rx A Potential Treatment for TTR Amyloidosis Unmet Medical Need Mutant TTR forms amyloid deposits in nerves, heart and other organs, resulting poor quality of life and eventually death Patient Population (World Wide) FAP: ~ 10,000 FAC: ~ 40,000 Current Treatment Options Treatments limited No treatments halt or reverse disease Liver transplant for early stage FAP (not FAC) 49

50 Partnered with: ISIS-TTR Rx Potential to Treat All Forms & Stages of TTR Amyloidosis Drug Mechanisms ISIS-TTR Rx Degrades RNA Prevents TTR protein production Reduces all forms of TTR (normal & mutant) Potential to be superior in halting disease progression vs. currently available strategies 50

51 ISIS-TTR Rx Phase 3 Various & Abundant TTR Mutations Currently Enrolled* Partnered with: FAP PH3 Reduces All Known TTR Mutations *Data available as of April 14 th,

52 Partnered with: ISIS-TTR Rx Pursuing Development to Treatment All Forms of TTR Amyloidosis ISIS-TTR Rx FAP HV PH1 Healthy Volunteers FAP PH3 FAP OLE Planned top-line data release ISIS-TTR Rx FAC (Cardiomyopathy) Currently Being Planned 52

53 ISIS-TTR Rx Phase 1 Potent & Durable Reductions in TTR Levels Partnered with: HV PH1 Screen Period (4-Week) Treatment Period (4-Week) Post-Treatment Evaluation (10-Week) D1 D3 D5 D8 D15 D22 D92 Robust, dose-dependent & significant sustained reductions in TTR levels Undetectable levels of TTR in some subjects ~ 90% reduction in some subjects > 75% reduction on average Safety and Tolerability Profile; 5 doses evaluated Very low incidence of flu-like symptoms Infrequent, mild injection site reactions Phase 1 data supported moving directly to Phase 3 53

54 Partnered with: ISIS-TTR Rx Potentially First-In-Class & Best-In-Class Max TTR Reduction Range ~ % ISIS-TTR Rx ALN-TTR IV ALN-TTR SC Phase 3 Development 15 months into study OLE Initiated Phase 3 Development Initiated <6 months First Patient dosed Early 14 Phase 2 Development Open label 15 patients Subcutaneous Injection (SC) 1 injection / week Self-Administered at Home 54

55 Partnered with: ISIS-TTR Rx Potentially First-In-Class & Best-In-Class Max TTR Reduction Range ~ % ISIS-TTR Rx ALN-TTR IV ALN-TTR SC Phase 3 Development 15 months into study OLE Initiated Phase 3 Development Initiated <6 months First Patient dosed Early 14 Phase 2 Development Open label 15 patients Subcutaneous Injection (SC) 1 injection / week Intravenous Infusion (>1hr) Pre-Medication Required to avoid infusion reaction Subcutaneous Injections (SC) 3-4 injections / week Self-Administered at Home 55

56 Partnered with: ISIS-TTR Rx Potentially First-In-Class & Best-In-Class Max TTR Reduction Range ~ % ISIS-TTR Rx ALN-TTR IV ALN-TTR SC Phase 3 Development 15 months into study OLE Initiated Phase 3 Development Initiated <6 months First Patient dosed Early 14 Phase 2 Development Open label 15 patients Subcutaneous Injection (SC) 1 injection / week Intravenous Infusion (>1hr) Pre-Medication Required to avoid infusion reaction Subcutaneous Injections (SC) 3-4 injections / week Self-Administered at Home In-Clinic Professionally Administered Potentially Self Administered (?) 56

57 ISIS-TTR Rx Phase 3 FAP Study Well Underway Partnered with: FAP PH3 Randomized, double-blind, placebo controlled International multicenter study 26 sites in 9 countries ~200 FAP patients randomized 2:1 Once-weekly SC injections Self administered at home Low volume single injection Treatment period 15 months Objective: Evaluate efficacy and safety of ISIS-TTR Rx Primary endpoints Modified NIS+7 (mnis+7) Norfolk QOL-DN questionnaire 57

58 % Patients % Patients % Patients ISIS-TTR Rx Phase 3 Well Balanced Disease Status Amongst Patients Enrolled Partnered with: FAP PH3 Current Demographics* 80 TTR TTR Mutation Mutation Status Status (V30M vs Non-V30M) 80 Stage Stage Disease Disease (Stage 1 vs Stage 2) 40 Previous Previous Treatment Treatment with Diflunisal or Tafamidis V30M Non-V30M TTR Mutation Status 0 Stage 1 Stage 2 Baseline Stage of Disease 0 Tafamidis Diflunisal Both Neither Baseline Stage of Previous Treatment *Data available as of April 14 th,

59 ISIS-TTR Rx Beyond Phase 3 FAP Open-Label Extension Study Partnered with: FAP OLE Initiated this quarter (2Q14) Open to Phase 3 FAP patients upon treatment completion to allow continuing access to drug treatment All patients receive 300 mg ISIS-TTR Rx Objectives: Evaluate long-term safety, tolerability Evaluate long-term efficacy Self administered at home with once weekly SC injections All clinical sites participating 59

60 ISIS-TTR Rx Phase 3 Program Well Underway Potential Best-in-Class Treatment for TTR Amyloidosis Partnered with: ISIS-TTR Rx Most Advanced TTR RNA Targeted Therapeutic Drug in Development 60

61 Partnered with: ISIS-TTR Rx Phase 3 Program Well Underway Potential Best-in-Class Treatment for TTR Amyloidosis ISIS-TTR Rx Most Advanced TTR RNA Targeted Therapeutic Drug in Development Convenient & Easy to Use At-Home Weekly Low-Volume S.C. Injection 61

62 Partnered with: ISIS-TTR Rx Phase 3 Program Well Underway Potential Best-in-Class Treatment for TTR Amyloidosis ISIS-TTR Rx Most Advanced TTR RNA Targeted Therapeutic Drug in Development Convenient & Easy to Use At-Home Weekly Low-Volume S.C. Injection Well Tolerated to Date 62

63 Partnered with: ISIS-TTR Rx Phase 3 Program Well Underway Potential Best-in-Class Treatment for TTR Amyloidosis ISIS-TTR Rx Most Advanced TTR RNA Targeted Therapeutic Drug in Development Convenient & Easy to Use At-Home Weekly Low-Volume S.C. Injection Well Tolerated to Date FAP On-Track to Complete Enrollment in

64 Partnered with: ISIS-TTR Rx Phase 3 Program Well Underway Potential Best-in-Class Treatment for TTR Amyloidosis ISIS-TTR Rx Most Advanced TTR RNA Targeted Therapeutic Drug in Development Convenient & Easy to Use At-Home Weekly Low-Volume S.C. Injection Well Tolerated to Date FAP On-Track to Complete Enrollment in 2015 Orphan Drug Designation: U.S. & E.U. Fast-track status in U.S. 64

65 Partnered with: ISIS-TTR Rx Phase 3 Program Well Underway Potential Best-in-Class Treatment for TTR Amyloidosis ISIS-TTR Rx Most Advanced TTR RNA Targeted Therapeutic Drug in Development Convenient & Easy to Use At-Home Weekly Low-Volume S.C. Injection Well Tolerated to Date FAP On-Track to Complete Enrollment in 2015 Orphan Drug Designation: U.S. & E.U. Fast-track status in U.S. FAC Study Currently Being Planned 65

66 ISIS-APOCIII Rx Toward a Better Treatment For Patients with Familial Chylomicronemia Syndrome (FCS) & Severely High Triglycerides

67 A Wholly Owned Program ISIS-APOCIII Rx Targeting Apolipoprotein C-III (ApoC-III) 67 ApoC-III is a pivotal target for lowering triglycerides (TG) Principally expressed in the liver Functions as a key regulator of serum TG levels Plays a key role in determining serum TG levels Inhibits lipoprotein lipase Inhibits hepatic lipase Inhibits hepatic uptake of TG-rich particles Independent risk factor for cardiovascular disease Genetically validated target 67

68 A Wholly Owned Program ISIS-APOCIII Rx The Significant Need for New TG-lowering Drugs High TG levels are a health risk, severely high triglyceride levels are associated with severe disease and death Pancreatitis For patients with severely high TGs, existing TG-lowering drugs are: Inadequate for achieving target TG levels Type 2 Diabetes Elevated blood pressure Smoking Elevated LDL Elevated blood glucose Inflammatory markers Abdominal adiposity Elevated triglycerides Insulin resistance Insufficient for reducing risk of pancreatitis Not used by most patients Low HDL CVD * Factors that can increase your risk of heart disease and diabetes Classic risk factors Emerging risk factors Metabolic risk factors 68 68

69 A Wholly Owned Program ISIS-APOCIII Rx FCS: A Rare Genetic Disease Due to Mutations in LPL European Orphan Drug Designation Unmet Medical Need FCS is associated with extremely high levels of TG, often >2,000 mg/dl) FCS patients are at extreme risk for acute pancreatitis events and other serious conditions Patient Population (World Wide) Approximately 3,000 5,000 patients Patient Serum Sample Current Treatment Options No currently available therapies 69

70 A Wholly Owned Program ISIS-APOCIII Rx TG Levels >880mg/dL: Another Rare Disease Commercial Opportunity Unmet Medical Need TG levels >880 mg/dl are associated with severe disease >30% have diabetes and many more have metabolic syndrome Increased risk of recurring pancreatitis, often requiring hospitalizations High risk for cardiovascular disease Patient Population (U.S. & E.U.) Approximately 50K patients Potential for broader utility in patients with metabolic syndrome, including type 2 diabetes Current Treatment Options Standard therapies, including niacin, fibrates and fish oil are inadequate to achieve normal TGs 70

71 A Wholly Owned Program ISIS-APOCIII Rx Phase 2 Program Establishing the Profile of Lowering ApoC-III in Hypertriglyceridemia Phase 2 Studies in High to Very High TG Patients MONOTHERAPY ADD-ON TO FIBRATE HIGH TG WITH T2D * FCS Patients not on TGlowering therapy with TG levels 440 & 2000 mg/dl 100, 200, 300 mg 3:1 (active: placebo) Patients on stable dose fibrate TG levels 225 & 2000 mg/dl 200, 300 mg 2:1 (active: placebo) Patients with TG levels 200 & 500 mg/dl and T2D on stable metformin 1g 300 mg 2:1 (active:placebo) Insulin sensitivity and glucose control assessed FCS patients with TG levels 440mg/dL 300 mg Open label Screen Period/Diet Run In (8-Weeks) Study Design Treatment Period (13-Weeks) Post-Treatment Evaluation (13-Weeks) D1* D8 D15 D22 D29 D36 D43 D50 D57 D64 D71 D78 D85 *Patients in the T2D study were dosed on Day 1, Day 3 and Day 5 71

72 A Wholly Owned Program ISIS-APOCIII Rx Phase 2 Program Robust TG Lowering in All Patients Treated Triglyceride Reductions Mean % Decrease from Baseline MONOTHERAPY ADD-ON TO FIBRATE HIGH TG WITH T2D FCS TG TG TG TG -71% -64% -69% -69% 72

73 Metabolism of Triglyceride-Rich Particles in the Liver A Wholly Owned Program Sinusoid E C-III E TRL C-III E C-III E TRL C-III E C-III E TRL C-III Triglyceride-Rich Remnant Lipoproteins Endothelial cell Space of Disse E C-III E TRL C-III E C-III E TRL C-III E C-III E TRL C-III E C-III E TRL C-III TRL C-III TG-rich lipoprotein ApoC-III E C-III E TRL C-III E C-III E TRL C-III E HSPG ApoE ApoB Heparan sulfate proteoglycan LRP E C-III E TRL C-III HSPG LPL LDLR LRP LDL receptor LDL receptor-related protein LDLR LPL Lipoprotein lipase Hepatocyte 73

74 A Wholly Owned Program Metabolism of Triglyceride-Rich Particles in the Liver Clearance Dysregulated in FCS Patients (No Lipoprotein Lipase Activity) Sinusoid E C-III E TRL C-III E C-III E TRL C-III E C-III E TRL C-III Triglyceride-Rich Remnant Lipoproteins Endothelial cell Space of Disse E C-III E TRL C-III C-III E E TRL C-III C-III E E TRL C-III E C-III E C-III TRL C-III E E TRL C-III C-III E E TRL C-III C-III E E TRL C-III TRL C-III E HSPG TG-rich lipoprotein ApoC-III ApoE ApoB Heparan sulfate proteoglycan LRP E C-III E TRL C-III HSPG LDLR LRP LDL receptor LDL receptor-related protein LDLR Hepatocyte 74

75 Metabolism of Triglyceride-Rich Particles in the Liver Clearance Enhanced Post ISIS-APOCIII Rx Treatment by LRP and LDLR A Wholly Owned Program Sinusoid E E TRL E E TRL E E TRL Triglyceride-Rich Remnant Lipoproteins Endothelial cell Space of Disse E E TRL E TRL E E E TRL E E TRL TRL C-III TG-rich lipoprotein ApoC-III E E TRL E ApoE ApoB E E TRL E E TRL HSPG LDLR Heparan sulfate proteoglycan LDL receptor LRP E E TRL HSPG LRP LDL receptor-related protein LDLR Hepatocyte 75

76 A Wholly Owned Program ISIS-APOCIII Rx Phase 2 Program Significantly Improved Lipid Profile Across All Patient Groups 76 Consistent as a Single Agent or in Combination Mean % Lipid Changes in Phase 2 Studies* ApoC-III TG Non- HDL-C +42% to +78% -71% to -88% -64% to -71% -11% to -58% HDL-C Good Cholesterol * Data from 13 weeks 300mg ISIS-APOCIII Rx treatment 76

77 A Wholly Owned Program ISIS-APOCIII Rx Additional Profile Benefits Improved Glucose Control By Multiple Measures HbA1c Analysis in Diabetic Patients Important Added Benefit Reduced ApoC-III Improved Glucose Control Euglycemic Clamp A Measure of Tissue Insulin Sensitivity Decreased HbA1c 1.22 percentage-point decrease (Pbo-adjusted) Improved Insulin Sensitivity Decreased: Glycated Albumin Fasting Fructosamine 77

78 A Wholly Owned Program ISIS-APOCIII Rx Phase 2 Program Substantial and Consistent TG Reductions Across Four Patient Populations Dose-dependent, significant, rapid, robust and durable reductions in TG and ApoC-III Significantly improved lipid profile Significantly decreased atherogenic particles Equally effective as a single agent or in combination with fibrates Equally effective irrespective of the TG levels at entry Reduced TG levels by more than 1,500 mg/dl in FCS patients Significantly reduced HbA1c and improved measures of glucose control and insulin sensitivity 78

79 A Wholly Owned Program ISIS-APOCIII Rx Phase 2 Safety and Tolerability Summary Well Tolerated in Multiple Clinical Studies Well tolerated in ~100 subjects Placebo Drug Treated Adverse Events ALTs >3x ULN 3% 3% Renal Function No Change No Change Biochemical labs No Change No Change Flu-like Symptoms None None Injection site reactions None Infrequent/mild 79

80 A Wholly Owned Program ISIS-APOCIII Rx Potential to Provide Multiple Benefits for Patients with FCS and Patients with Severely High TG 80 What Patients Need Current TGlowering Drugs (1) ISIS- APOCIII Rx (2) Substantial TG lowering Equal lowering at all incoming TG levels Substantial ApoC-III lowering Improved glucose control, insulin sensitivity Improved lipid profile Increased HDL-cholesterol Safety and tolerability (1)Based on approved labels (2)Based on clinical trial results to date Rapid Path to Market for ISIS-APOCIII Rx 80

81 A Wholly Owned Program ISIS-APOCIII Rx Rapid Path Toward Commercialization 81 FCS and Patients with > 880 mg/dl Severely High Triglycerides Two Phase 3 programs planned to run in parallel End of Phase 2 meetings with US and EU regulators Finalize Phase 3 plan 1H 2014 Initiate Phase 3 studies Mid

82 A Wholly Owned Program Targeting ApoC-III Moving Beyond the Initial Indications 82 Follow-on to ISIS-APOCIII Rx identified 7-10 times more potent Potential for monthly dosing Potential to enhance patient convenience Potential for broader utility in patients with cardiovascular disease and metabolic syndrome, including patients with diabetes Extend ApoC-III product life cycle 82

83 Diabetes Franchise Sanjay Bhanot, M.D., Ph.D. Vice President, Clinical Development and Translational Medicine

84 Isis Type 2 Diabetes Pipeline Three Phase 2 Study Readouts in 2014/2015 * Late-breaker presentation at ADA (June 13-17, 2014); Investor event on June 15, 2014 at 7:00 a.m. PT Isis has created a franchise of multiple, novel late-stage drugs designed to treat type 2 diabetes and other metabolic disorders Isis metabolic drugs specifically reduce molecular targets, many of which are undruggable or difficult to target with small molecules Each drug in the franchise focuses on unique opportunities and is complementary 84

85 Isis Drugs for Type 2 Diabetes Focus on Distinct High-Value Opportunities ISIS-GCGR Rx Patients with severe diabetes failing OAD or injectable therapies ISIS-GCCR Rx Patients with Cushing s Disease or with diabetes driven by glucocorticoid dysregulation failing OAD or injectable therapies ISIS-PTP1B Rx Patients with diabetes and insulin resistance that could benefit from an insulin sensitizer 85

86 Isis Drugs for Type 2 Diabetes Focus on Distinct High-Value Opportunities ISIS-GCGR Rx Patients with severe diabetes failing OAD or injectable therapies ISIS-GCCR Rx Patients with Cushing s Disease or with diabetes driven by glucocorticoid dysregulation failing OAD or injectable therapies ISIS-PTP1B Rx Patients with diabetes and insulin resistance that could benefit from an insulin sensitizer 86

87 Isis Drugs for Type 2 Diabetes Focus on Distinct High-Value Opportunities ISIS-GCGR Rx Patients with severe diabetes failing OAD or injectable therapies ISIS-GCCR Rx Patients with Cushing s Disease or with diabetes driven by glucocorticoid dysregulation failing OAD or injectable therapies ISIS-PTP1B Rx Patients with diabetes and insulin resistance that could benefit from an insulin sensitizer 87

88 ISIS-GCGR Rx Toward a Better Therapy for Patients with Severe Diabetes

89 Glucagon Receptor (GCGR) A Validated Target for the Treatment of Diabetes Glucagon is a hormone that opposes the action of insulin Increased glucagon action leads to increased glucose production by the liver Glucagon receptor reduction in animal models produces dramatic reductions in glucose even in the most severe models Several small molecule inhibitors have reduced glucose but have been associated with off-target side effects 89

90 Reasons to Develop ISIS-GCGR Rx : The Potential to Be Best in Class Likely to have greater glucose reduction than small molecules by directly reducing production of the receptor Likely not to have side effects associated with some small molecules Increases in LDL-cholesterol Increases in triglycerides Increases in blood pressure Increases in body weight Likely to have a broader separation of doses that produce glucose reduction from those that produce target-related ALT increases Optimal balance between glucose reduction and ALT increases achievable Robust and long lasting effect on glucose lowering provides opportunity to balance glucose control with liver safety Likely to be dual acting and potential to preserve pancreatic function To be developed for treatment of advanced diabetes 90

91 Glucagon Receptor Antisense Drug Key Attributes Dual sites of action Reduces hepatic glucagon action, which attenuates hyperglycemia Increases GLP-1, which improves insulin secretion and leads to pancreatic regeneration (potential for disease modification) Robust effects in very insulin resistant animals No fatty liver or increase in hepatic glycogen; no change in plasma lactate levels, liver ALTs or LDL cholesterol levels No hypoglycemia up to 24h fast in rodents and 16h in monkeys No effect on recovery from insulin-induced hypoglycemia in rodents No alpha cell hyperplasia or pancreatic tumors up to 6 month treatment in monkeys 91

92 Active GLP-1 (pm) Glucagon Receptor Antisense Treatment Significantly Reduces Glucose, Increases GLP1 Levels and Improves Insulin Production in Diabetic Rats Plasma Active GLP-1 Fed Male ZDF rats treated for 30 days Control ASO GCGR ASO Sloop et al, JCI 113(11): (2004) 92

93 Plasma Glucose (mg/dl) Efficacy of Glucagon Receptor Antisense in Extremely Diabetic Animals in Which Rosiglitazone is Ineffective Plasma Glucose - Fed Male ZDF Rats 14 Weeks Old at Study Initiation Saline GCGR ASO Rosiglitazone (3 mg/kg) Day 93

94 ISIS-GCGR Rx 13-week Phase 2 Study (Completed) Randomized, double-blind placebo-controlled study in patients with type 2 diabetes on stable metformin Objectives Evaluate effects of ISIS-GCGR Rx on HbA1c and other measures of glucose control Evaluate the safety & tolerability of ISIS-GCGR Rx in combination with metformin Reporting full analysis as Phase 2 late-breaker presentation at the American Diabetes Association Meeting (June 13-17) Cohorts n 100mg mg 200mg, no load 39 3 weeks Pre-Treatment 2:1 R Wk1 Loading Doses Treatment Period Once Weekly Dosing 13 weeks Post-Treatment f/u Period 13 weeks 94

95 ISIS-GCGR Rx Treatment Produced Robust Improvements in Glycemic Parameters and Was Well Tolerated Phase 2 Study Interim Top-line Data - Activity Robust, highly statistically significant improvements (vs. baseline) in glycemic parameters after only 13 weeks of treatment 200mg: >2 percentage-point reduction in HbA1c (p = 0.001) 100mg: >1 percentage-point reduction in HbA1c (p = 0.001) Placebo response was modest (~0.25 percentage-point reduction) Normal glucose levels (HbA1c 7%) achieved by a large fraction of patients in both dose groups Plasma GLP-1 increases observed; potential to preserve pancreatic function and enhance insulin secretion 95

96 ISIS-GCGR Rx Treatment Produced Robust Improvements in Glycemic Parameters and Was Well Tolerated Phase 2 Study Interim Top-line Data Safety and Tolerability Antisense specificity of ISIS-GCGR Rx avoided many off target effects seen with small molecules No changes in LDL-cholesterol No changes in triglycerides No changes in blood pressure No gain in body weight Safety Summary Well tolerated No flu-like symptoms Infrequent, predominantly mild injection site reactions, resolved rapidly No cases of symptomatic hypoglycemia Easily managed target-related ALT elevations consistent with the pharmacology of glucagon receptor inhibition and similar to those observed with small molecule glucagon inhibitors No severely elevated ALTs Very few ALT elevations in the 100 mg dose cohort ALTs declined during and after dosing discontinued No increases in bilirubin; no Hy s Law cases 96

97 ISIS-GCGR Rx Next Steps Towards Significant Value Inflection Opportunity Present Phase 2 Data Late-Breaker Presentation at the American Diabetes Association Meeting (June 13-17) Investor event June 15, 2014 at 7:00 a.m. PT Optimize dose and dosing schedule: Robust glucose lowering provides broad opportunity to optimize efficacy and safety Continue discussions with partners Strong partner interest to date Complete long-term toxicology studies to support long-term clinical studies 97

98 ISIS-GCCR Rx A Unique Approach to Treat Diabetes Patients with Glucocorticoid Dysregulation

99 Tissue-specific Inhibition of the Glucocorticoid Receptor A Unique Therapeutic Target for the Treatment of Diabetes Excessive glucocorticoids (GC) action in liver and fat is involved in obesity, insulin resistance and glucose intolerance Glucocorticoid receptor (GCCR) is an intracellular receptor that mediates the action of GCs Attenuation of GC action through its receptor is a very attractive therapeutic approach for type 2 diabetes and disorders related to excessive and chronic steroid action (e.g., Cushing s disease) Efficacy exceeds that observed with small molecule inhibitors of 11bHSD1 99

100 Tissue-specific Inhibition of the Glucocorticoid Receptor A Unique Therapeutic Strategy for the Treatment of Diabetes Small molecule inhibitors of GCCR have failed or have limited utility GCCR inhibition in the brain can cause increases in ACTH, adrenal insufficiency, hypokalemia and blood pressure ISIS-GCCR Rx has the potential to be best in class by taking advantage of distribution of antisense drugs Inhibits GCCR in liver and fat without crossing the blood-brain barrier Provides therapeutic benefits of inhibiting GC action systemically without central nervous system side effects 100

101 ISIS-GCCR Rx Phase 1 Study Design Randomized double-blind placebo-controlled study in healthy volunteers Objectives: Evaluate the effect on glucocorticoid action in the brain Evaluate effect on blood pressure Evaluate effects on lipid profile Evaluate safety & tolerability Cohorts n 60mg 9 120mg 9 210mg 9 420mg 12 DEXA Challenge (420 mg dose group) 2 Weeks Screening 2:1 R Wk1 Loading Doses Once Weekly Dosing 6 Weeks PD Endpoints Wk7 Post-Treatment f/u Period 10 weeks 101

102 ISIS-GCCR Rx Encouraging Activity and Safety Profile Results from Phase 1 Studies Parameter Triglycerides Total cholesterol LDL-cholesterol VLDL-cholesterol ACTH Aldosterone Renin Angiotensin II Blood pressure Hypoglycemia Result Decreased Decreased Decreased Decreased No change No change No change No change No change No Positive effects on lipid profile, consistent with preclinical data No evidence of GCCR antagonism in brain or other tissues outside of liver and adipose No change in blood pressure Observed safety profile suggests ISIS- GCCR Rx does not have the limitations observed with small molecule inhibitors of GCCR Best-in-class; no other liver and fat specific GCCR antagonist on market 102

103 ISIS-GCCR Rx Phase 2 (ongoing) Six-Week Study, Data Planned for Late 2014/Early 2015 Randomized double-blind placebo controlled study in patients with type 2 diabetes on metformin Objectives: Evaluate short-term measures of glycemic control Evaluate the safety and tolerability of ISIS-GCCR Rx Changes in markers of GCCR antagonism in the brain Hypoglycemia Evaluate effects on lipid profile Provide supportive data to move into longer-term studies Data planned for late 2014/early 2015 Cohorts n 210mg 40 3 weeks Pre-Treatment Once Weekly Dosing 2:1 6 weeks R Wk1 Loading Doses Post-Treatment f/u Period 12 weeks 103

104 ISIS-GCCR Rx Potential Opportunities and Next Steps Toward Market Near Term, High Value Patient Populations Cushing s Disease orphan indication Subset of dyslipidemic type 2 diabetes patients most likely to benefit from reduced glucocorticoid drive Next Steps Initiate Phase 2 study in patients with Cushing's Disease - 2H 2014 Complete Phase 2 study and report data in patients with type 2 diabetes late 2014/early

105 ISIS-PTP1B Rx Toward a Safer, More Effective Insulin Sensitizer for Patients with Type 2 Diabetes

106 ISIS-PTP1B Rx Toward A Safer, More Effective Insulin Sensitizer Other insulin sensitizers, such as glitazones, are transcriptional activators with limitations due to their significant side effects ISIS-PTP1B Rx is the only insulin sensitizer with a novel mechanism of action currently in development ISIS-PTP1B Rx selectively targets protein tyrosine phosphatase 1B (PTP1B), a negative regulator of insulin action, to enhance cellular insulin response PTP1B inhibition has been shown to improve glycemic control in human studies There remains a significant unmet need for safer insulin sensitizers 106

107 ISIS-PTP1B Rx : Potential to Have an Ideal Profile as a Novel and Safe Insulin Sensitizer Drug Glucose reduction Hypoglycemia Lipids reduction Body Weight reduction GI Side Effects Insulin Sensitivity & Adipocytokines Target Toxicity PTP-1B Antisense 1 Yes No Yes Yes No Yes, adiponectin increase No PPAR- 2 Yes Yes (Minimal) No or Minimal No, wt gain No Yes Yes (Cardiac, BW gain & bone loss) 1. Based on preclinical data and preliminary clinical data 2. Based on published data including label claims 107

108 ISIS-PTP1B Rx Phase 2 (Ongoing) Six-Month Study, Data Planned YE 2014 Randomized double-blind placebo-controlled study in obese patients with type 2 diabetes taking metformin or metformin + sulfonylurea Objectives: Evaluate efficacy and potency versus previous PTP-1B drug Evaluate the safety and tolerability of ISIS-PTP1B Rx Enrollment complete, data planned for YE 2014 Once Weekly Dosing Post-Treatment f/u Period Cohorts n 200mg 75 3 weeks 2:1 R 26 weeks 12 weeks Pre-Treatment 108

109 PTP1B Inhibition Encouraging Activity and Safety Profile Results from Preclinical and Clinical Studies Preclinical and Clinical Profile Phase 1 Results: Insulin Parameter Glycemic control Hypoglycemia HOMA-insulin resistance Body weight Adiponectin Lipids Potency Result Improved No ISIS-PTP1B Rx lowered insulin levels and reduced insulin resistance (as measured by HOMA-IR) ISIS-PTP1B Rx increased plasma adiponectin, a biomarker associated with weight loss Effects observed at doses as low as 100 mg in Phase 1 study, demonstrating increased potency vs. previous PTP-1B inhibitor (ISIS ) Favorable safety and tolerability profile with no hypoglycemia 109

110 Isis Type 2 Diabetes Pipeline Three Phase 2 Study Readouts in 2014/2015 * Late-breaker presentation at ADA (June 13-17, 2014); Investor event on June 15, 2014 at 7:00 a.m. PT Isis has created a franchise of multiple, novel late-stage drugs designed to treat type 2 diabetes and other metabolic disorders Isis metabolic drugs reduce novel molecular targets many of which are undruggable or difficult to target with small molecules Each drug in the franchise focuses on unique opportunities and is complementary 110

111 ISIS-FXI Rx Toward a More Effective, Safer Antithrombotic for Patients at High Risk for Thrombosis Sanjay Bhanot, M.D., Ph.D. VP, Clinical Development and Translational Medicine

112 ISIS-FXI Rx for Thrombotic Disorders Significant need for anticoagulants with superior benefit to risk profile 112 Thrombosis (heart attacks, strokes, pulmonary embolism) is the leading cause of morbidity and mortality worldwide Although effective, warfarin, new Factor Xa and thrombin inhibitors do not prevent all thromboembolic events Safety concerns of warfarin, Factor Xa and thrombin inhibitors limit their use in some therapeutic settings Because of its novel mechanism of action, ISIS-FXI Rx has the potential to have a benefit-to-risk profile superior to existing anticoagulants Potential to be of high value in a broader array of indications Potential to perform better than existing drugs in many indications 112

113 Factor XI is a Genetically Validated Target for Antithrombotic Therapy Factor XI contributes to thrombosis in humans Patients with Factor XI levels in the upper 10% have an increased risk of venous and arterial thrombosis Patients with elevated Factor XI levels have a higher incidence of stroke Patients with lower levels of Factor XI have a decreased incidence of venous thrombosis Congenital deficiency of Factor XI in humans is not associated with spontaneous bleeding In animal models, Factor XI deficiency or inhibition is associated with attenuated thrombosis without increased bleeding 113

114 ISIS-FXI Rx Reduces Clot Propagation, but NOT Clot Initiation Therefore, Risk of Bleeding is Low Intrinsic Pathway XII XI ISIS-FXI Rx VIII XIIa IX XIa VIIIa IXa X Xa VII VIIa X Extrinsic Pathway Thrombin Prothrombin Platelet Activated Platelet Fibrin Polymer Fibrin Fibrinogen Common Pathway Endothelium Collagen / Tissue Factor Vascular Injury (TF/Collagen Exposure 114

115 ISIS-FXI Rx Reduces Clot Propagation, but NOT Clot Initiation Therefore, Risk of Bleeding is Low 115 FXI In contrast to Factor Xa or Factor VIIa, Factor XI is involved in clot stabilization and expansion, not clot initiation, resulting in a low risk of bleeding 115

116 Selective Antisense Inhibition of Factor XI 116

117 Thrombosis (normalized) Tail Bleeding (Blood/grams) Thrombosis (normalized) Tail Bleeding (Blood/grams) Thrombosis (normalized) Tail Bleeding (Blood/grams) Antisense Inhibition of Factor XI Reduces Thrombosis Without Increased Bleeding in Mice Warfarin Thrombosis Bleeding Apixaban (FXa inhibitor) Thrombosis Bleeding Warfarin (mg/kg) Apixaban (mg/kg) 160 Factor Xl Antisense Drug Thrombosis Bleeding FXI Antisense (mg/kg) 117

118 ISIS-FXI Rx Reduces Thrombosis Without Increased Bleeding in Baboon Consistency of Effect Between Species A Wholly Owned Program Platelet deposition x Control Day Time (min) Crosby et al ATVB 118

119 A Wholly Owned Program ISIS-FXI Rx Preclinical Data Summary Significant Antithrombotic Activity Without Bleeding Specifically reduces Factor XI levels in several animal species Even with Factor XI levels reduced by over 90% No spontaneous bleeding No change in other coagulation factors Antithrombotic activity comparable to that of currently available anticoagulants, but less bleeding demonstrated in multiple animal models Potential for safer therapy as single agent or as combination therapy with antiplatelet drugs 119

120 A Wholly Owned Program ISIS-FXI Rx Phase I Study Design 120 Randomized, double-blind, placebo-controlled, dose-ascending study in healthy volunteers Objectives Evaluate effects on Factor XI levels Evaluate the safety and tolerability of ISIS-FXI Rx Cohorts n 50 mg mg mg mg 12 2 Weeks Screening 3:1 R Wk1 Loading Doses Once Weekly Dosing 6 Weeks Wk7 PD End Point Post-Treatment f/u Period 12 weeks 120

121 A Wholly Owned Program 121 ISIS-FXI Rx Produced Dose-dependent and Sustained Reductions in Factor XI Levels 121

122 A Wholly Owned Program ISIS-FXI Rx Phase 1 Study Summary ISIS-FXI Rx reduced Factor XI levels in a dose-dependent fashion; maximum reduction with 200 and 300 mg doses No major bleeding or clinically relevant non-major bleeding No change in bleeding time (measured 24h after last dose) Well tolerated Infrequent, mild injection site reactions No changes in liver function No changes in kidney function No clinically meaningful changes in laboratory values

123 ISIS-FXI Rx Phase 2 Study Update Jeffrey Weitz, M.D. Professor, Division of Hematology & Thromboembolism, Dept. of Medicine, McMaster University

124 A Wholly Owned Program ISIS-FXI Rx Phase 2 Six-week Study (Completed) 124 Open-label, randomized, active comparator-controlled* study in patients undergoing knee replacement surgery VTEs determined by blinded independent adjudication committee Bleeding events determined by blinded independent adjudication committee Objectives Compare the effects of ISIS-FXI Rx on incidence of venous thromboembolism (VTE) and bleeding to enoxaparin Evaluate the safety and tolerability of ISIS-FXI Rx Planned presentation of complete analysis at upcoming medical meeting Cohorts 40 mg Enoxaparin* n** mg ISIS-FXI RX mg ISIS-FXI Rx wks 3:1 R Treatment Surgery Screening W1 W2 W3 W4 W5 W6 (6hr post surgery) *Patients treated with enoxaparin (40 mg, s.c.) the evening before surgery, 6-8hrs post surgery and daily injections for at least 8 additional days; **Data as of May 7, wks 8-12 d Bilateral Venography 3d post surgery Post-Treatment f/u Period 12 wks

125 ISIS-FXI Rx : Dose-dependent Reduction of VTEs with a Low Incidence of Bleeding Data Cutoff May 7, 2014 A Wholly Owned Program With 200 mg ISIS-FXI Rx, rate of venous thromboembolism (VTE) is similar to enoxaparin 200 mg cohort expanded to further enhance comparison to enoxaparin With 300 mg ISIS-FXI Rx, rate of VTE is 7-fold lower than enoxaparin (p<0.0001) Patients treated with enoxaparin and ISIS-FXI Rx experienced a very low rate of bleeding ISIS-FXI Rx -treated patients experienced numerically fewer bleeding events than with enoxaparin 125

126 ISIS-FXI Rx : Safety and Tolerability Equivalent to Enoxaparin Well tolerated No flu-like symptoms Infrequent, mild injection site reactions No drug-related SAEs No observed differences in safety compared to enoxaparin group

127 A Wholly Owned Program ISIS-FXI Rx : Conclusions from Phase 2 Study Enoxaparin efficacy and bleeding rates were within expected ranges in this patient population Findings provide proof-of-principle that ISIS-FXI Rx is an effective and safe anticoagulant ISIS-FXI RX decreases VTE in a dose-dependent fashion Rate of VTE in 300 mg cohort is substantially lower than published reports of Factor Xa or thrombin inhibitors in this therapeutic setting Bleeding rates were very low in the enoxaparin group and numerically lower in the ISIS-FXI Rx -treated patients Only Factor XI inhibitor in clinical studies Pathway validated by Isis

128 A Wholly Owned Program ISIS-FXI Rx : Potential Best-in-Class Profile for an Novel Anticoagulant Efficacy Parameters Safety Parameters Drug Arterial Thombosis Venous Thombosis Low Bleeding Risk No Drug-drug Interactions No Routine Monitoring Antidote Available ISIS-FXI Rx Yes Yes Yes Yes Yes Yes Warfarin Yes Yes No No No Yes Heparins Yes Yes No Yes No Partial Factor Xa Inhibitors No Yes No No Yes No Thrombin Inhibitors No Yes No No Yes No

129 A Wholly Owned Program Potential Indications for ISIS-FXI Rx Initial Patient populations with an unmet need in which relatively small studies can be conducted Long-term Unprovoked VTE Atrial fibrillation in patients with end-stage kidney disease Prevention of secondary events in patients with cardiac diseases Acute coronary syndrome High-risk patients with atrial fibrillation Mechanical heart valves

130 A Wholly Owned Program ISIS-FXI Rx : Next Steps Present full analysis Phase 2 results at an upcoming medical meeting Publish results in medical journal

131 Pipeline Overview Richard Geary, Ph.D. Senior Vice President, Development

132 Isis Robust, Mature Pipeline Phase 2 Phase 1 Commercialized ISIS-SMN Rx ISIS-APOCIII Rx Spinal Muscular Atrophy FCS ISIS-GCCR Rx ISIS-PKK Rx Cushing s Syndrome Hereditary Angioedema KYNAMRO Homozygous FH ISIS-APOCIII Rx Severely High TGs ISIS-APO(a) Rx Very High Lp(a) Alicaforsen* Pouchitis ATL1103 Acromegaly ISIS-ANGPTL3 Rx Hyperlipidemia Vitravene CMV Retinitis ISIS-FXI Rx Clotting Disorders ISIS-FGFR4 Rx Obesity ISIS-CRP Rx CAD ISIS-HBV Rx HBV ISIS-GCGR Rx Diabetes RG-101 HCV ISIS-GCCR Rx ISIS-STAT3 Rx Plazomicin EXC 001 (PF ) ico-007 Diabetes ISIS-PTP1B Rx Diabetes 132 Phase 3 ISIS-EIF4E Rx Cancer ISIS-DMPK Rx Myotonic Dystrophy 1 Apatorsen ISIS-TTR Cancer Rx TTR Amyloidosis (OGX-427) ISIS-HTT Rx Huntington Disease KYNAMRO Custirsen (OGX-011) Severe HeFH Prostate / Lung Cancer Cancer Severe Bacterial Infection Scarring Diabetic Macular Edema RG-012 ISIS-FVII Rx ISIS-DGAT2 Rx ISIS-AR Rx Preclinical Alport Syndrome Clotting Disorders NASH Cancer ATL1102 Multiple Sclerosis ISIS-GSK4 Rx Ocular Disease Severe & Rare Cardiovascular Metabolic Cancer Other * Named Patient Supply 132

133 Isis Cardiovascular Pipeline

134 Isis Lipid Franchise

135 KYNAMRO Treatment For HoFH

136 KYNAMRO (mipomersen sodium) Injection 200 mg/ml 1 st Systemic Antisense Drug Approved for Chronic Use Marketed in the U.S. and approved in additional countries Winner of 2014 NORD Corporate Award In 2014, Genzyme will continue to invest significantly in KYNAMRO Increased sales growth in 2014 Minimal investment by Isis to reach profitability Continuing investment in market with FOCUS FH Enrollment completed 2013 FOCUS FH data planned early

137 ISIS-APO(a) Rx Toward a Better Treatment For Patients with Severely High Lp(a)

138 ISIS-APO(a) Rx Targeting Apolipoprotein(a) to Reduce Lipoprotein(a) 138 Apo(a) is liver-derived and linked to the apob-component of LDL via disulfide Lp(a) is an independent risk factor for cardiovascular disease No other drugs directly affect Lp(a) levels Apo(a) + LDL = Lp(a)

139 Fraction of Population Very High Lp(a) is a Risk Factor for Cardiovascular Disease Lp(a) Distribution - Copenhagen General Population 139 MEN WOMEN Very High CHD Risk Very High CHD Risk Modified from Nordestgaard et al., Eur Heart J Dec;31(23):

140 ISIS-APO(a) Rx Target Patient Populations Severely elevated Lp(a) with existing cardiovascular disease and controlled LDL-C Orphan patient population Lp(a) reduction planned as study endpoint Very high Lp(a) (>50 mg/dl) with early stage aortic valve stenosis Medium size and growing patient population Benefits can be measured by echocardiogram in modest number of patients in a reasonable timeframe 140

141 Mean Percent Change Lp(a) (± SEM) ISIS-APO(a) Rx Produces Robust and Prolonged Dose-Dependent Reduction in Plasma Lp(a) in Healthy Volunteers Mean % Change in Lp(a) Placebo 0 100mg (n=8) 200mg (n=8) 300mg (n=7) Study Day 141

142 ISIS-APO(a) Rx Phase 1 Safety Summary 142 Well tolerated Low incidence of flu-like symptoms Infrequent, predominantly mild injection site reactions No SAEs No meaningful changes in laboratory values No liver enzyme elevations 142

143 ISIS-APO(a) Rx Phase 2 Planned 12-week Study in Patients with High Lp(a) 143 Randomized, double-blind, placebo-controlled, dose-titration study 2 Cohorts Cohort A: High Lp(a); 1:1 (active : placebo) Cohort B: Very high Lp(a); 4:1 (active : placebo) Objectives Intra-patient dose titration Evaluate activity of ISIS-APO(a) Rx in lowering Lp(a) Evaluate the safety & tolerability of ISIS-APO(a) Rx Phase 2 initiation 1H 2014 Cohorts n A 25 Treatment Period 12 Weeks Post-Treatment f/u Period B 8 28 days R 100 mg 200 mg 300 mg 12 weeks Screening 12 weekly s.c. injections 143

144 ISIS-ANGPTL3 Rx Toward a Better Treatment For Patients with Severe Hyperlipidemia, including Homozygous FH Severe heterozygous FH Severe mixed dyslipidemia

145 ANGPTL3 Target Overview ANGPTL3 is synthesized in liver and secreted ANGPTL3 targeting should provide unique LDL-C and TG lowering profile ANGPTL3 is a genetically validated target for patients with hyperlipidemia Individuals with no/low ANGPTL have good CV health Individual with high ANGPTL have poor CV health 145

146 ISIS-ANGPTL3 Rx Phase 1 (Ongoing) Study Design Double-blind, placebo-controlled, dose-ascending study in healthy volunteers Objectives Evaluate the activity of ISIS-ANGPTL3 Rx on plasma levels of ANGPTL3 and lipoprotein profile Evaluate the safety and tolerability of ISIS-ANGPTL3 Rx Phase 1 initiated in March 2014; data planned YE 2014 Cohorts n 100 mg mg mg mg 8 4 weeks Screening 3:1 R D1 D3 D5 D8 Treatment Period 6 weeks D15 D22 D29 D36 Post-Treatment f/u Period 13 weeks 146

147 Isis Cancer Drugs 147

148 Custirsen (OGX-011) & Apatorsen (OGX-427) Toward a Better Treatment For Patients with Cancer

149 Partnered with: Custirsen & Apatorsen Custirsen SYNERGY - Failed to achieve better survival outcome in Phase 3 study in patients with castration-resistant prostate cancer (CRPC) (first-line combo with docetaxel & prednisone) Two other ongoing Phase 3 studies: AFFINITY (second-line in patients with CRPC) and ESPIRIT (second-line in patients with NSCLC) Apatorsen 6 ongoing Phase 2 studies Metastatic Bladder 2 studies; data from Borealis-1 (overall survival in combo with gemcitabine and cisplatin) expected 2H:2014 Prostate first-line CRPC in combo with Zytiga NSCLC in patients with Stage IV non-squamous Metastatic pancreatic in combo with Abraxane and gemcitabine Phase 2 study in lung cancer planned to start in

150 ISIS-EIF4E Rx Toward a Better Treatment For Patients with Cancer

151 ISIS-EIF4E Rx : Two Phase 2 Studies Non-small Cell Lung Cancer & Castration-resistant Prostate Cancer Randomized controlled trials in combination with chemotherapy Both studies confirmed good target engagement by ISIS-EIF4E Rx Insufficient increases in progression-free survival to support additional investment Ongoing study Investigator-initiated study: Tim Greten, MD at NCI A Phase 1/2 study of ISIS-EIF4E Rx in combination with irinotecan in irinotecan-refractory colorectal cancer 151

152 Isis Gen 2.5 Antisense Cancer Drugs 152

153 Cancer Strategy Why Gen 2.5 Antisense? ISIS-STAT3 Rx and ISIS-AR Rx are Gen 2.5 antisense drugs Gen 2.5 chemistry antisense drugs exhibit greater potency to broaden applicability to different cell types, including tumor cells Gen 2.5 antisense compounds demonstrated markedly superior responses over Gen 2.0 antisense compounds in preclinical cancer models Gen 2.5 superior activity profile has translated into increased activity in human cancer studies 153

154 Gen 2.5 ISIS-STAT3 Rx Has Superior Activity in Tumor Cells Over Gen 2.0 STAT3 Antisense Compound Human STAT3 Protein Level 154

155 ISIS-STAT3 Rx A Gen 2.5 Antisense Drug for The Treatment of Patients with Cancer

156 STAT3 as a Tumor Target STAT3 Pathway Partnered with: Receptor-mediated activation of tyrosine kinases leads to activation of STAT3 Mutations in STAT3 and other regulatory genes result in constitutively active STAT3, which promote tumor growth Ideal target for antisense drug (undruggable by small molecules or antibodies) From Yu et al

157 ISIS-STAT3 Rx Phase 1/2 (Ongoing) Study in Patients with Advanced Cancers Partnered with: Phase 1 ascending study in patients with advanced cancer completed; data presented at ASCO 2014 Phase 2 expansion (3 mg/kg dose) in lymphoma, including diffuse large B-cell lymphoma Objectives: Determine response rate in diffuse large B cell lymphoma Determine level of target engagement via tumor biopsy Identify biomarkers that can predict response Evaluate the safety and tolerability of ISIS-STAT3 Rx Decision on next stage of development planned for Q Screening Treatment Period (until progression) PET/CT for response Pre-dose biopsy for biomarker D1 D3 D5 D8 D15 D22 D29 D36 D43 D50 Post-dose biopsy for biomarker 157

158 ISIS-STAT3 Rx Phase 1/2 (Ongoing) Study in Patients with Advanced Hepatocellular Carcinoma Open-label, multicenter study in 24 patients with advanced HCC Partnered with: Study divided into dose-ascending phase and dose-expansion phase Objectives: Assess preliminary anti-tumor activity of ISIS-STAT3 Rx Evaluate the safety, tolerability and pharmacokinetics of ISIS-STAT3 Rx Dose-ascending phase completed Planned Phase 2 expansion study to begin shortly Screening Treatment Period (until progression or unacceptable tox) D1 D4 D8 D11 D15 D22 D1 D8 D15 D22 Cycle 1 Subsequent Cycles 158

159 Partnered with: ISIS-STAT3 Rx Clinical Program Advancing in Patients with DLBCL and HCC Encouraging durable partial responses observed in patients with DLBCL Expansion cohort in DLBCL and Phase 1/2 in HCC ongoing Acceptable, manageable safety profile AstraZeneca is planning for a potential Phase 3 study initiation in DLBCL in

160 ISIS-AR RX A Gen 2.5 Antisense Drug for the Treatment for Patients with Castration Resistant Prostate Cancer

161 ISIS-AR Rx Has Potential to Provide Benefit in All Androgen Receptor (AR) Resistance Settings Partnered with: Multiple AR-mediated resistance mechanisms in CRPC Amplified AR Mutated AR Ligand-Independent AR Spliced AR Tumour Androgen Synthesis ISIS-AR Rx targets mrna which is not susceptible to traditional AR-mediated resistance mechanisms 161

162 Tumor Weight (g) Tumor Volume (mm 3 ) Partnered with: ISIS-AR RX Second Gen 2.5 Antisense Drug to Enter Clinic ISIS-AR Rx demonstrated significant antitumor activity in prostate cancer model with mutated AR PBS mpk/QDx * *p=0.027 by Two-way RMANOVA followed by Bonferroni's post-hoc Days Post Tumor Implantation * In animal prostate cancer model Tumor weight reduction: ~50% 15 doses for 3 weeks 0.0 PBS Treatment mpk/QDx5 *p=0.018 by t-test 162

163 ISIS-AR Rx Phase 1/2 Study in Patients With Advanced Solid Tumors (AZ Study) Partnered with: An open-label, dose-ascending study in patients with advanced solid tumors where the androgen receptor pathway is a potential factor 2 cohorts Cohort 1: dose ascending in patients with advanced cancer Cohort 2: expansion in patients who have received a 2nd generation anti-hormonal therapy but have not responded or have relapsed Objectives: Provide early signal of clinical activity Optimize dosing schedule Evaluate safety and tolerability in patients with cancer Planned 1 st patient dose May 2014 Screening Treatment Period (until progression or unacceptable tox) D1 D4 D8 D11 D15 D22 Cycle 1 D1 D8 D15 D22 Subsequent Cycles 163

164 Isis Leads the Industry in Severe & Rare Disease Pipeline

165 Two New Antisense Drugs Entering the Clinic

166 ISIS-PKK Rx Toward a Better Treatment for Patients with Hereditary Angioedema

167 A Wholly Owned Program ISIS-PKK Rx for Hereditary Angioedema Approximately 15-20K Patients in US and EU Hereditary Angioedema (HAE) is a potentially life threatening immune disease Characterized by low levels or dysfunction of the C1 inhibitor protein HAE patients have attacks that are often disabling and sometimes fatal, and characterized by rapid and painful swelling in the hands, feet, limbs, face, abdomen, larynx and trachea ISIS-PKK Rx reduces Prekallikrein (PKK), a clinically validated target PKK disrupts the kinin contact cascade that triggers HAE attacks The role of kinins in HAE has been established by acute treatments used after an attack has already occurred Current prophylactic treatments (e.g., androgens, C-1 inhibitor replacement) are either inadequate or very difficult to use Unmet need: Up to 80% of patients are not using IV prophylaxis and would use a s.c. prophylactic if effective and available 167

168 A Wholly Owned Program ISIS-PKK Rx for HAE Prophylaxis for patients with frequent HAE attacks ISIS-PKK Rx : potential best-in-class treatment for HAE Targeted, mechanism-based therapy that could prevent attacks by altering the cause of the disease Antisense reduction in PKK prevented or ameliorated tissue swelling in animal models of HAE Convenient, at-home self-administered subcutaneous injections Infrequent, low-volume injections Improved tolerability and safety compared to existing prophylactic treatments Rapid path to proof-of-concept study Phase 1 study in healthy volunteers has already begun Planned clinical study in HAE patients in 2H

169 ISIS-DMPK Rx A Gen 2.5 Antisense Drug for Patients with Myotonic Dystrophy 1 (DM1)

170 DM1 Disease Overview RNA-caused Disease Uniquely Suited to Antisense Therapy Autosomal dominant genetic disease that causes Severe muscle problems that include weakness (myopathy), trouble relaxing muscles (myotonia) and muscle wasting Affects other body functions, including the heart and gastrointestinal system DM1 is caused by production of toxic RNA in the cell nucleus Caused by expanded CUG repeat in 3 -UTR of Dystrophia Myotonica-Protein Kinase (DMPK) Repeat length ranges from 50 to 3000 repeats & correlates to disease severity DM1 often affects an entire family: anticipation can occur with each generation getting a more severe form of the disease due to expansion of repeat Affects 40,000 patients in US: 150,000 patients in US, EU and Japan

171 ISIS-DMPK Rx Reducing Toxic RNA to Positively Affect Disease ISIS-DMPK Rx targets the DMPK transcript to decrease the level of this toxic RNA, restoring normal cellular function Phase 1 study in healthy volunteers Planned for mid year 2014 initiation Phase 2 study in DM1 patients planned to initiate in 2H

172 Growing Pipeline Multiple Phase 1 Assets Advancing in the Clinic ISIS-ANGPTL3 Rx Hyperlipidemia ISIS-PKK Rx Hereditary Angioedema ISIS-DMPK Rx Myotonic Dystrophy 1 (DM1) Phase 1 Healthy Volunteers Phase 1 Healthy Volunteers Phase 1 Healthy Volunteers Phase 1/2 HAE Patients Phase 1 Data YE2014 Phase 1/2 DM1 Patients ISIS-HBV Rx HBV ISIS-AR Rx Cancer Phase 1 Healthy Volunteers Phase 2 Chronic HBV Patients Phase 1/2 Cancer Patients Completed study On-going study Planned study Severe & Rare Cardiovascular Cancer Other 172

173 Phase 2 or 3 Study Initiation Advancing the Pipeline Multiple Phase 2 and 3 Data Read Outs & Planned Study Initiations in OGX-011 Prostate cancer ISIS-EIF4E Rx Prostate/Lung Cancer ISIS-STAT3 Rx Lymphoma HCC ico-007 Diabetic macular edema ISIS-SMN Rx Spinal Muscular Atrophy ISIS-CRP Rx Atrial Fibrillation OGX-427 Bladder cancer ISIS-FXI Rx Thrombosis in Knee replacement ISIS-GCGR Rx Type 2 Diabetes ISIS-PTP1B Rx Type 2 Diabetes Phase 3 data Phase 2 or 3 Data Release Phase 2 data Phase 2 or 3 Study Initiation ISIS-SMN Rx Infant SMA study ISIS-SMN Rx Childhood SMA study ISIS-APOCIII Rx FCS study ISIS-APOCIII Rx TG >880 mg/dl Plazomicin MDR study ISIS-APO(a) Rx High Lp(a) study ISIS-GCCR Rx Cushings study Phase 3 initiation Phase 2 initiation 173

174 Isis Future: Focused on Value Stan Crooke, M.D., Ph.D. CEO and Chairman

175 What Has Isis Accomplished Over the Last 25 Years? Created the third platform for drug discovery Only direct route from gene to patients Used efficiency of antisense to build a broad and mature pipeline of 32 first-in-class or best-in-class drugs Controlled the technology through innovation and IP strategy Employed a novel partnering strategy to fully exploit the breadth and potential of antisense technology Enhanced long-term innovation through maintaining a small innovation-centered organization 175

176 Basic Antisense Research at Isis: The Impact More than 100-fold improvement in potency More than 100-fold improvement in safety Substantial advances in tolerability 1000-fold improvement in therapeutic index Activity in multiple organs in animals and humans Nearly all routes of delivery Multiple mechanisms of action Broad applicability to many diseases Precision dosing Extraordinary improvements in drug discovery and development efficiency Dominant evergreen patent estate

177 Basic Antisense Research at Isis: The Impact More than 100-fold improvement in potency More than 100-fold improvement in safety Substantial advances in tolerability Activity in multiple organs in animals and humans Nearly all routes of delivery Multiple mechanisms of action Very broad utility Broad applicability to many diseases Precision dosing Extraordinary improvements in drug discovery and development efficiency Dominant evergreen patent estate 177

178 Basic Antisense Research at Isis: The Impact More than 100-fold improvement in potency More than 100-fold improvement in safety Substantial advances in tolerability Activity in multiple organs in animals and humans Nearly all routes of delivery Multiple mechanisms of action Broad applicability to many diseases Precision dosing Extraordinary improvements in drug discovery and development efficiency Broad, mature and enlarging pipeline Dominant evergreen patent estate 178

179 Basic Antisense Research at Isis: The Impact More than 100-fold improvement in potency More than 100-fold improvement in safety Substantial advances in tolerability Activity in multiple organs in animals and humans Nearly all routes of delivery Multiple mechanisms of action Broad applicability to many diseases Precision dosing Extraordinary improvements in drug discovery and development efficiency Dominant evergreen patent estate Continue control 179

180 The Future: Focus on Value Broad, Robust and Mature Pipeline Phase 2 Phase 1 Commercialized ISIS-SMN Rx ISIS-APOCIII Rx Spinal Muscular Atrophy FCS ISIS-GCCR Rx ISIS-PKK Rx Cushing s Syndrome Hereditary Angioedema KYNAMRO Homozygous FH ISIS-APOCIII Rx Severely High TGs ISIS-APO(a) Rx Very High Lp(a) Alicaforsen* Pouchitis ATL1103 Acromegaly ISIS-ANGPTL3 Rx Hyperlipidemia Vitravene CMV Retinitis ISIS-FXI Rx Clotting Disorders ISIS-FGFR4 Rx Obesity * Named Patient Supply ISIS-CRP Rx ISIS-GCGR Rx CAD Diabetes ISIS-HBV Rx RG-101 HBV HCV ISIS-TTR Rx KYNAMRO Custirsen (OGX-011) ISIS-GCCR Rx Diabetes ISIS-PTP1B Rx Diabetes 180 Phase 3 ISIS-EIF4E Rx Cancer ISIS-DMPK Rx Myotonic Dystrophy 1 Apatorsen TTR Amyloidosis Cancer (OGX-427) ISIS-HTT Rx Huntington Disease Severe HeFH Prostate / Lung Cancer ISIS-STAT3 Rx Plazomicin EXC 001 (PF ) ico-007 Cancer Severe Bacterial Infection Scarring Diabetic Macular Edema RG-012 ISIS-FVII Rx ISIS-DGAT2 Rx ISIS-AR Rx Preclinical Alport Syndrome Clotting Disorders NASH Cancer ATL1102 Multiple Sclerosis ISIS-GSK4 Rx Ocular Disease Severe & Rare Cardiovascular Metabolic Cancer Other 180

181 The Future: Focus on Value Broad, Robust and Mature Pipeline Phase 2 Phase 1 Commercialized ISIS-SMN Rx ISIS-APOCIII Rx Spinal Muscular Atrophy FCS ISIS-GCCR Rx ISIS-PKK Rx Cushing s Syndrome Hereditary Angioedema KYNAMRO Homozygous FH ISIS-APOCIII Rx Severely High TGs ISIS-APO(a) Rx Very High Lp(a) Alicaforsen* Pouchitis ATL1103 Acromegaly ISIS-ANGPTL3 Rx Hyperlipidemia Vitravene CMV Retinitis ISIS-FXI Rx Clotting Disorders ISIS-FGFR4 Rx Obesity * Named Patient Supply ISIS-CRP Rx ISIS-GCGR Rx CAD Diabetes ISIS-HBV Rx RG-101 HBV HCV ISIS-TTR Rx KYNAMRO Custirsen (OGX-011) ISIS-GCCR Rx Diabetes ISIS-PTP1B Rx Diabetes 181 Phase 3 ISIS-EIF4E Rx Cancer ISIS-DMPK Rx Myotonic Dystrophy 1 Apatorsen TTR Amyloidosis Cancer (OGX-427) ISIS-HTT Rx Huntington Disease Severe HeFH Prostate / Lung Cancer ISIS-STAT3 Rx Plazomicin EXC 001 (PF ) ico-007 Cancer Severe Bacterial Infection Scarring Diabetic Macular Edema RG-012 ISIS-FVII Rx ISIS-DGAT2 Rx ISIS-AR Rx Preclinical Alport Syndrome Clotting Disorders NASH Cancer ATL1102 Multiple Sclerosis ISIS-GSK4 Rx Ocular Disease Severe & Rare Cardiovascular Metabolic Cancer Other 181

182 Antisense: A Solution Need Opportunity 182

183 The Need Declining Productivity of Drug Discovery Research and development efficiency: The number of new drugs approved by the US Food and Drug Administrator per billion dollars (inflation adjusted) spent on research and development (R&D) from 1950 to Scannell et al Nature Rev Drug Discov. 183

184 The Opportunity: The Redefinition of Disease into Actionable Molecular Terms Antisense: Direct from Gene to Treatment Utilize molecular pathological methods to genetically validate targets Focus on factors in or causes of cellular dysfunction or dysregulation Develop treatment based on molecular targets and identifying the patients most likely to respond to altering that molecular target 184

185 The Opportunity: Examples of Current Diagnostic Classifications Congestive heart failure First Use 1550 B.C. Definition Increased abdominal girth associated with weak pulse Psoriasis 1684 A dry, itching scab Asthma 1819 Paroxysmal dyspnea Cancer Ancient Greece Crab-like invasive tissue 1867 Histological description of carcinomas 185

186 The Opportunity: Evolution in the Definitions of Diseases Example: Psoriasis Qu, Xiaoyan, et al. Drug Discovery Today Integrative clinical transcriptomics analyses for new therapeutic intervention strategies: a psoriasis case study. 186

187 The Opportunity: Today s Molecular Target Identification Analyses for new therapeutic intervention strategies: a psoriasis case study 22% Undruggable Molecular pathologic methods enable us to: Genetically identify and validate targets in humans Genetically identify patient subpopulations Focus on key molecular pathways Qu, Xiaoyan, et al. Drug Discovery Today Integrative clinical transcriptomics analyses for new therapeutic intervention strategies: a psoriasis case study. 187

188 The Opportunity: The Future of Antisense: Creating the Highest Value Medicines for Patients with the Greatest Need Meeting the productivity needs of the industry Exploiting the opportunities presented by molecular medicine Creating drugs to novel, genetically identified targets Developing drugs to treat patients most sensitive to treatment and most likely to achieve greatest benefit Pursuing the most direct development paths 188

189 Isis Strategy

190 Strategy (1 of 2) Broadly exploit antisense technology Undruggable targets Multiple targets Multiple tissues Multiple routes of administration Multiple mechanisms Focus on creating the highest value medicines Genetically, epigenetically or functionally defined rare diseases Genetically or functionally defined subpopulations of traditionally defined diseases First-in-class or best-in-class Staged development

191 Strategy (2 of 2) Continue to advance antisense technology Utilize advanced screening to enhance drug performance Expand into new routes of delivery (e.g., oral) Design more potent chemical classes Create chemical solutions to enhance delivery to specific tissues Exploit new molecular mechanisms Apply molecular insights to make more potent and specific antisense drugs Control technology Focus on innovation and evergreening IP strategy Add 3 to 5 new development candidates per year to pipeline

192 The Future: Focus on Value Targets Diseases and subdividing diseases Making better antisense drugs Advanced screening Advanced chemistry RNA-caused diseases Maturing pipeline

193 The Future: Focus on Value Undruggable Targets Multi-gene families PTP-1B, STAT-3 Proteins difficult or impossible to address with small molecules or antibodies ApoB-100, clusterin, Factor XI, CRP Diseases associated with toxic or mis-spliced RNA ISIS-SMN Rx, ISIS-DMPK Rx, Targets that take advantage of antisense tissue specificity ISIS-GCCR Rx

194 The Future: Focus on Value Genetically or Functionally Defined Subpopulations of Traditionally Defined Diseases Subdivide lipid opportunities Severely elevated LDL-C: KYNAMRO (HoFH, severe HeFH) Severely high TGs: ISIS-APOCIII Rx (FCS, >880 mg/dl) Very high Lp(a) MACE and aortic stenosis: ISIS-APO(a) Rx HoFH and severe HeFH: ISIS-ANGPTL3 Rx Subdivide diabetes Severe diabetes: ISIS-GCGR Rx Glucocorticoid related problems: ISIS-GCCR Rx (Cushing s, obesity associated diabetes, iatrogenic diabetes)

195 Continue to Advance Antisense Technology Newer Gen 2.0 Antisense Drugs are More Potent and Better Tolerated Newer Gen 2.0 antisense drugs are more potent than KYNAMRO Newer Gen 2.0 antisense drugs have fewer and more mild injection site reactions Potency derived from target protein reduction after 4 Weeks of Treatment with 200 mg. Compared to KYNAMRO Phase 1 Studies. 195

196 Continue to Advance Antisense Technology Medicinal Chemistry Objectives Improve potency Improve tolerability Enhance therapeutic index Broaden accessible tissues Lower cost of therapy Enhance patient convenience 196

197 Continue to Advance Antisense Technology More Potent Chemical Classes Gen 2.5 chemistry Activity in less accessible tissues (e.g., tumors, muscle) Lower dosing for targets in more accessible tissues (e.g., liver) LIgand-Conjugated ASOs (LICA) for targeting specific tissues (e.g., liver) 197

198 Continue to Advance Antisense Technology Isis Proprietary Advanced Chemistries Adds stability Improves distribution to tissues Increases potency Increases stability Reduces non-specific toxicities Improves potency and therapeutic index Expands range of targets and tissues 1200 to 3500 mg/week ~100 to 400 mg/week Expect 20 to 80 mg/week 198

199 Continue to Advance Antisense Technology Isis Novel and Proprietary LICA Technology Improves distribution to liver Decreases amount of drug needed to achieve target knockdown in hepatacytes Up to 10x more potent than corresponding Gen 2.0 or Gen 2.5 compound LICA 199

200 mrna (% UTC) SRB mrna (% UTC) mrna (% UTC) SRB mrna (% UTC) Continue to Advance Antisense Technology LICA Improves Potency of Gen 2.0 and Gen 2.5 Antisense Compounds 100 Gen Gen LICA (Mouse) 100 Gen Gen 2.5-LICA Log Dose (mpk) Log Dose (mpk) Antisense compound Projected Dose in Humans (mg/wk) Gen Gen 2.0-LICA 20 Gen Gen 2.5-LICA 2 200

201 The Future: Focus on Value Multiple Tissues, Multiple Routes of Delivery Antisense drugs are proven to work in multiple tissues Antisense drugs can be effectively delivered through multiple routes Demonstrated that oral delivery of antisense drugs is feasible with KYNAMRO Gen 2.5 antisense drugs are more potent and may enable commercial feasibility of oral delivery 201

202 The Future: Focus on Value Example of the Application of Isis Strategy: Rare Disease Program Major programs within Isis R&D spanning a broad range of therapeutic areas 10 rare disease programs currently in development 5-10 new programs to enter development in the next two years Genetically defined targets and diseases Monogenic diseases Gain-of-toxic protein functions Gain-of-toxic RNA functions Loss of function due to altered RNA processing Polygenic diseases

203 Isis Rare Disease Program Relies on a Consortium of Broad Collaborations for Continued Infusion of New Targets National Organization for Rare Disorders (NORD) Rare Diseases Europe (EURORDIS) Canadian Organization for Rare Disorders (CORD) Beijing Genomic Institute (BGI) Illumina Sequencing Centers 100K Genome Project Rare Diseases Clinical Research Network (RDCRN) Canadian Pediatric Genetic Disorders Sequencing Consortium The BRIDGE consortium (NIHR) Rare Disease Organization Genomic Consortium Isis NIH/NCI Patient Advocacy Groups Academic Investigators NINDS The Cancer Genome Atlas Cold Spring Harbor MIT U. of Michigan Garvan Institute U. Of Washington Stanford U. U. Of Queensland Beijing U. UCSD Disease causal information obtained directly from the source Close working relationships established Collaborative working relationships that have led to multiple rare disease clinical programs today MDA AFM Families of SMA Amyloid Foundation 203

204 Isis Rare Disease Strategy Complete development of current antisense drug candidates Continue to mine for antisense opportunities for monogenic disease Near-term 204

205 Isis Rare Disease Strategy Complete development of current antisense drug candidates Continue to mine for antisense opportunities for monogenic disease Continue to mine GWAS and transcriptome data sets for genetically caused rare disease opportunities Identify additional opportunities for polygenic rare diseases and to subset larger polygenic diseases into smaller rare disease opportunities (e.g. familial hypercholesteremia) Near-term Mid-term 205

206 Isis Rare Disease Strategy Complete development of current antisense drug candidates Continue to mine for antisense opportunities for monogenic disease Continue to mine GWAS and transcriptome data sets for genetically caused rare disease opportunities Identify additional opportunities for polygenic rare diseases and to subset larger polygenic diseases into smaller rare disease opportunities (e.g. familial hypercholesteremia) Expand to intermediary metabolic pathways and other pathways which are associated with rare disease opportunities Leverage new RNA biology and genomic methodologies to identify new opportunities for treating rare diseases Near-term Mid-term Long-term 206

207 The Future: Focus on Value Broad, Robust and Mature Pipeline Phase 2 Phase 1 Commercialized ISIS-SMN Rx ISIS-APOCIII Rx Spinal Muscular Atrophy FCS ISIS-GCCR Rx ISIS-PKK Rx Cushing s Syndrome Hereditary Angioedema KYNAMRO Homozygous FH ISIS-APOCIII Rx Severely High TGs ISIS-APO(a) Rx Very High Lp(a) Alicaforsen* Pouchitis ATL1103 Acromegaly ISIS-ANGPTL3 Rx Hyperlipidemia Vitravene CMV Retinitis ISIS-FXI Rx Clotting Disorders ISIS-FGFR4 Rx Obesity * Named Patient Supply ISIS-CRP Rx ISIS-GCGR Rx CAD Diabetes ISIS-HBV Rx RG-101 HBV HCV ISIS-GCCR Rx ISIS-STAT3 Rx Plazomicin EXC 001 (PF ) ico-007 Diabetes ISIS-PTP1B Rx Diabetes 207 Phase 3 ISIS-EIF4E Rx Cancer ISIS-DMPK Rx Myotonic Dystrophy 1 Apatorsen ISIS-TTR Cancer Rx TTR Amyloidosis (OGX-427) ISIS-HTT Rx Huntington Disease KYNAMRO Custirsen (OGX-011) Severe HeFH Prostate / Lung Cancer Cancer Severe Bacterial Infection Scarring Diabetic Macular Edema RG-012 ISIS-FVII Rx ISIS-DGAT2 Rx ISIS-AR Rx Preclinical Alport Syndrome Clotting Disorders NASH Cancer ATL1102 Multiple Sclerosis ISIS-GSK4 Rx Ocular Disease Severe & Rare Cardiovascular Metabolic Cancer Other 207

208 The Future: Focus on Value First-in-class Phase 2 Phase 1 Commercialized ISIS-SMN Rx ISIS-APOCIII Rx Spinal Muscular Atrophy FCS ISIS-GCCR Rx ISIS-PKK Rx Cushing s Syndrome Hereditary Angioedema KYNAMRO Homozygous FH ISIS-APOCIII Rx Severely High TGs ISIS-APO(a) Rx Very High Lp(a) Alicaforsen* Pouchitis ATL1103 Acromegaly ISIS-ANGPTL3 Rx Hyperlipidemia Vitravene CMV Retinitis ISIS-FXI Rx Clotting Disorders ISIS-FGFR4 Rx Obesity * Named Patient Supply ISIS-CRP Rx ISIS-GCGR Rx CAD Diabetes ISIS-HBV Rx RG-101 HBV HCV ISIS-GCCR Rx ISIS-STAT3 Rx Plazomicin EXC 001 (PF ) ico-007 Diabetes ISIS-PTP1B Rx Diabetes 208 Phase 3 ISIS-EIF4E Rx Cancer ISIS-DMPK Rx Myotonic Dystrophy 1 Apatorsen ISIS-TTR Cancer Rx TTR Amyloidosis (OGX-427) ISIS-HTT Rx Huntington Disease KYNAMRO Custirsen (OGX-011) Severe HeFH Prostate / Lung Cancer Cancer Severe Bacterial Infection Scarring Diabetic Macular Edema RG-012 ISIS-FVII Rx ISIS-DGAT2 Rx ISIS-AR Rx Preclinical Alport Syndrome Clotting Disorders NASH Cancer ATL1102 Multiple Sclerosis ISIS-GSK4 Rx Ocular Disease Severe & Rare Cardiovascular Metabolic Cancer Other 208

209 The Future: Focus on Value Potential Best-in-class Phase 2 Phase 1 Commercialized ISIS-SMN Rx ISIS-APOCIII Rx Spinal Muscular Atrophy FCS ISIS-GCCR Rx ISIS-PKK Rx Cushing s Syndrome Hereditary Angioedema KYNAMRO Homozygous FH ISIS-APOCIII Rx Severely High TGs ISIS-APO(a) Rx Very High Lp(a) Alicaforsen* Pouchitis ATL1103 Acromegaly ISIS-ANGPTL3 Rx Hyperlipidemia Vitravene CMV Retinitis ISIS-FXI Rx Clotting Disorders ISIS-FGFR4 Rx Obesity * Named Patient Supply ISIS-CRP Rx ISIS-GCGR Rx CAD Diabetes ISIS-HBV Rx RG-101 HBV HCV ISIS-GCCR Rx ISIS-STAT3 Rx Plazomicin EXC 001 (PF ) ico-007 Diabetes ISIS-PTP1B Rx Diabetes 209 Phase 3 ISIS-EIF4E Rx Cancer ISIS-DMPK Rx Myotonic Dystrophy 1 Apatorsen ISIS-TTR Cancer Rx TTR Amyloidosis (OGX-427) ISIS-HTT Rx Huntington Disease KYNAMRO Custirsen (OGX-011) Severe HeFH Prostate / Lung Cancer Cancer Severe Bacterial Infection Scarring Diabetic Macular Edema RG-012 ISIS-FVII Rx ISIS-DGAT2 Rx ISIS-AR Rx Preclinical Alport Syndrome Clotting Disorders NASH Cancer ATL1102 Multiple Sclerosis ISIS-GSK4 Rx Ocular Disease Severe & Rare Cardiovascular Metabolic Cancer Other 209

210 The Future: Focus on Value Add 3 to 5 New Drugs to Development Phase 2 Phase 1 Commercialized ISIS-SMN Rx ISIS-APOCIII Rx Spinal Muscular Atrophy FCS ISIS-GCCR Rx ISIS-PKK Rx Cushing s Syndrome Hereditary Angioedema KYNAMRO Homozygous FH ISIS-APOCIII Rx Severely High TGs ISIS-APO(a) Rx Very High Lp(a) Alicaforsen* Pouchitis ATL1103 Acromegaly ISIS-ANGPTL3 Rx Hyperlipidemia Vitravene CMV Retinitis ISIS-FXI Rx Clotting Disorders ISIS-FGFR4 Rx Obesity * Named Patient Supply ISIS-CRP Rx ISIS-GCGR Rx CAD Diabetes ISIS-HBV Rx RG-101 HBV HCV ISIS-GCCR Rx ISIS-STAT3 Rx Plazomicin EXC 001 (PF ) ico-007 Diabetes ISIS-PTP1B Rx Diabetes 210 Phase 3 ISIS-EIF4E Rx Cancer ISIS-DMPK Rx Myotonic Dystrophy 1 Apatorsen ISIS-TTR Cancer Rx TTR Amyloidosis (OGX-427) ISIS-HTT Rx Huntington Disease KYNAMRO Custirsen (OGX-011) Severe HeFH Prostate / Lung Cancer Cancer Severe Bacterial Infection Scarring Diabetic Macular Edema RG-012 ISIS-FVII Rx ISIS-DGAT2 Rx ISIS-AR Rx Preclinical Alport Syndrome Clotting Disorders NASH Cancer ATL1102 Multiple Sclerosis ISIS-GSK4 Rx Ocular Disease Severe & Rare Cardiovascular Metabolic Cancer Other 210

211 Evolution of Isis Pipeline Mature Pipeline: Continuing to Grow and Mature Commercial Phase III 8% (3) 11% (4) Phase III Commercial 20% 15% Phase II 37% (14) Phase I 18% (7) Preclinical 26% (10) Phase II 24% Phase I 20% Preclinical 20% 2014 (projected) 38 Drugs in Development 3 Drugs Commercialized 2020 (projected) 54 Drugs in Development 8 Drugs Commercialized 11 Drugs in Phase 3 211

212 Evolution of Pipeline Growing Focus on Genetically and Functionally Defined Targets Broadly Useful 51% (18) Genetically Defined 23% (8) Functionally Defined 34% (12) Broadly Useful 40% Genetically Defined 28% Functionally Defined 32% 2014 (projected) 38 drugs in development Equal distribution between broadly useful drugs and genetically and functionally defined drugs 2020 (projected) 54 drugs in development Genetically and functionally defined drugs dominate 212

213 Evolution of Pipeline Growing Focus on Undruggable Targets Splicing & noncoding RNA 11% (4) Tissue Selective 11% (4) Druggable 21% (8) Splicing or noncoding RNA 19% Tissue Selective 13% Druggable 17% Diff. to Target Proteins 57% (22) Diff. to Target Proteins 51% 2014 (projected) 38 drugs in development Targets from multigene families, tissue selective targets and targets not druggable by small molecule or antibodies dominate 2020 (projected) 54 drugs in development Expansion of splicing or noncoding RNA targets 213

214 2014 Objectives On Track Together with Genzyme, Isis will continue to support KYNAMRO development, marketing and commercialization activities Mature the pipeline Report Phase 2 data on ISIS-SMN Rx at AAN Report data from up to seven drugs in late-stage development, including Phase 2 data on ISIS-FXI Rx and ISIS-GCGR Rx Initiate up to five Phase 3 studies, including Phase 3 studies on ISIS-APOCIII Rx and ISIS-SMN Rx, Plazomicin Initiate Phase 2 studies on up to three drugs Broaden pipeline by adding up to five new drugs in both partnered and unpartnered programs ISIS-HTT Rx and RG-012 have been added to the pipeline to date Continue to successfully execute business strategy to generate revenue and cash 214

215 Isis Future: Focused on Value 2014 A Unique Moment Antisense technology Proven Broadly applicable Genetic-like specificity Dramatically more efficient than other drug discovery platforms Broad, mature pipeline of 32 potential first-in-class and best-in-class drugs that will continue to grow Opportunities to apply antisense technology continue to expand Genomics Epigenomics RNA functions and targets Unique business strategy coupled to efficiencies of antisense technology 215

216