ISIS PHARMACEUTICALS. ISIS-SMN Rx Investor Event. March 21, Slides available for download at:

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1 ISIS PHARMACEUTICALS ISIS-SMN Rx Investor Event March 21, 2013 Slides available for download at:

2 Forward Looking Language Statement 2 This presentation includes forward-looking statements regarding Isis strategic alliance with Biogen Idec, and the discovery, development, activity, therapeutic and commercial potential and safety of ISIS-SMN Rx. Any statement describing Isis goals, expectations, financial or other projections, intentions or beliefs, including the commercial potential of KYNAMRO, 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, 2012, which is on file with the SEC. Copies of this and other documents are available from the Company. In this press release, unless the context requires otherwise, Isis, Company, we, our, and us refers to Isis Pharmaceuticals and its subsidiaries. Isis Pharmaceuticals is a registered trademark of Isis Pharmaceuticals, Inc. Regulus Therapeutics is a trademark of Regulus Therapeutics Inc. KYNAMRO is a trademark of Genzyme Corporation.

3 Agenda 3 Introduction: Dr. Stan Crooke, CEO & Chairman, Isis Pharmaceuticals Disease Overview and Patient Need: Dr. Richard Finkel, Division Chief, Division of Neurology, Department of Pediatrics, Nemours ISIS-SMN Rx Mechanism of Action: Dr. Frank Bennett, Senior Vice President of Research, Isis Pharmaceuticals AAN Phase 1 Data: Dr. Claudia Chiriboga, Associate Professor of Clinical Neurology & Clinical Pediatrics, Columbia University Medical Center Current Efforts to Support Clinical Development: Dr. Karen Chen, CSO & COO, SMA Foundation Closing Remarks: Dr. Stan Crooke Q&A Panel

4 Participants 4 Richard Dr. Stan Crooke Dr. Richard Finkel Dr. Frank Bennett Dr. Claudia Chiriboga Dr. Karen Chen CEO and Chairman Isis Pharmaceuticals Chief, Division of Neurology Department of Pediatrics, Nemours Children s Hospital Orlando Sr. VP Research Isis Pharmaceuticals Associate Professor of Clinical Neurology & Clinical Pediatrics, Columbia University Medical Center CSO & COO, SMA Foundation

5 ISIS-SMN Rx for Spinal Muscular Atrophy (SMA) Severe Genetic Neuromuscular Disease with No Approved Treatment Partnered with: 5 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

6 Partnered with: ISIS-SMN Rx Well Tolerated in Children with SMA 6 Open-label, single-dose Phase 1 study to evaluate the safety and tolerability of ISIS-SMN Rx in SMA patients 2-14 years of age Type 2 and Type 3 children in the study Intrathecal dosing was well tolerated and no safety concerns were identified Isis first experience in intrathecal dosing in children Feasibility of infrequent dosing demonstrated Drug concentrations in CSF and plasma consistent with preclinical data and support infrequent dosing, ie. every 6 to 9 months. Improvement in Hammersmith scores observed at highest dose in a number of children Hammersmith Muscle Function Expanded Scoring used to assess responses on 33 motor function tasks Multiple-dose Phase 1b/2a study underway Safety study designed to support registration-directed clinical study in type 2/type 3 patients to start in 2014

7 Disease Overview and Patient Need 7 Picture Richard Finkel, M.D. Chief, Division of Neurology Department of Pediatrics, Nemours Children s Hospital Orlando

8 Overview of Spinal Muscular Atrophy Richard S. Finkel, MD Nemours Children s Hospital University of Central Florida College of Medicine 8

9 Objectives 1. Overview of SMA - clinical features and management 2. Discuss the mechanism of disease in SMA and targeted treatment opportunities 3. Review specific studies in SMA performed to date and future treatment opportunities 4. Discuss clinical trial designs for SMA 9

10 SMA, Type I Infantile form: Werdnig-Hoffmann Disease Floppy baby, never sits without support Mild or no contractures Diagnosis usually by 6M Areflexic Tongue fasiculations Death from respiratory failure or infection by age two years 10

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13 13 Survival of SMA-I Zerres and Rudnick-Schoneborn, Arch Neurol 1995; 52:518-2 Retrospective, , Germany. No gender differences seen

14 Evolving Natural History death Death or Vent 16+ hours/day 14

15 Supportive Management of SMA-I: Medical and Ethical Issues Nutrition support Respiratory support Preventative care - immunizations Physical Therapy Orthopedic management 15

16 SMA, Type II Late Infantile (Intermediate) Form Diagnosis 6 to 12 months Floppy infant with delayed motor milestones, hand tremor, fasiculations in 2/3, absent DTRs in 70% Sits, but never walks unaided; plateau in function Scoliosis Restrictive lung disease Variable longevity infancy to adulthood (68% >25 yr) 16

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19 19 Type II: Survival Zerres et al. J Neurol Sci 1997;146:67-72

20 SMA, Type III Juvenile Form: Kugelberg-Welander Disease Early motor development is normal Ambulates Fails to keep up with peers in activities, trouble with stairs Diagnosis > 1 Yr Muscle aching Proximal weakness, areflexia Neurogenic EMG CK may be elevated Normal life expectancy Stair climbers walk into 30s-40s 20

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22 Supportive Management of SMA, Type II and Type III Medical and Ethical Issues Nutritional support Pulmonary support Scoliosis surgery Anticipate independent function at home and at school. Early use of power wheelchair Pregnancy 22

23 SMN GENE AND TARGETED CLINICAL TRIAL STRATEGIES

24 Structure of SMN Gene Region on 5q cen p44 c NAIP c SMN2 H4F5 c H4F5 t SMN1 NAIP t p44 t tel RNA 1 2a 2b L. Medne NSGC C T 2 exon base pair differences between SMN1 and SMN2 24

25 SMN Protein Full-length protein is produced normally from SMN1. SMN protein functions as part of an oligomeric complex, the spliceosome, important in RNA processing. 90% of SMN2 undergoes alternative splicing leading to truncated SMN protein that lacks exon 7 ( 7SMN) Gene SMN2 SMN1 90% 10% Transcript 1 2a 2b a 2b a 2b Protein unstable stable stable 25 L. Medne NSGC 2002

26 SMA subtypes and OMs SMA Type Characteristics Age Primary OM Secondary OMs M F S H H M T T P F T Q O L I Never sits < 6M Mortality Time to 16 hr/day vent support II Sits, never walks 6-18M Motor function scale III walks >18M motor function scale IV walks adult 6 minute walk test? MFS: motor function scale HHM: hand-held myometry TT: timed testing of 10m, Gowers, 4 step climb, 6 minute walk test PFT: pulmonary function testing of FVC QOL: quality of life measure

27 Clinical Trial Design for Type I 1. Primary outcome measure: Time to death or equivalent (16+ hrs/day vent support) 2. Secondary outcome measures: A. Motor Scale: CHOP INTEND. TIMPSI B. Biomarkers: SMN protein, full-length transcript C. PRO no; QOL scale? D. Pulmonary measure? Not practical E. CMAP = yes; MUNE = not practical 3. Duration: 12 to 18 months 27

28 HFMSE Hammersmith Functional Motor Scale for SMA Expanded version Observed response Assessed on 33 motor function tasks, each scored on a scale from 0 to 2 Can be assessed in patients with SMA Type II and III, > 2 years old minutes to complete Series of observed functional tasks, ordered by increasing difficulty/decreasing function in patents with SMA: Chair sitting Long sitting One hand to head in sitting Two hands to head in sitting Supine to side lying Rolls prone to supine over R Rolls prone to supine over L Rolls supine to prone over R Rolls supine to prone over L Sitting to lying Props on forearms Lifts head from prone Prop on extended arms Lying to sitting Four-point kneeling Crawling Lifts head from supine Supported standing Stand unsupported Stepping Right hip flexion in supine Left hip flexion in supine High kneeling to right half kneel High kneeling to left half kneel High kneeling to standing, leading with L leg (thru R kneel) High kneeling to standing, leading with R leg (thru L kneel) Stand to sitting on the floor Squat Jumps 12 inches forward Ascends 4 stairs with railing Descends 4 stairs with railing Ascends 4 stairs without arm support Descends 4 stairs without arm support 28 Validation of the Expanded Hammersmith Functional Motor Scale in spinal muscular atrophy type II and III. Glanzman AM, O'Hagen JM, McDermott MP, Martens WB, Flickinger J, Riley S, Quigley J, Montes J, Dunaway S, Deng L, Chung WK, Tawil R, Darras BT, De Vivo DC, Kaufmann P, Finkel RS; Pediatric Neuromuscular Clinical Research Network for Spinal Muscular Atrophy (PNCR); Muscle Study Group (MSG). J Child Neurol Dec;26(12):

29 Hammersmith Scores are Stable Over Time in Natural History Studies SMA CARNI-VAL Trial (Swoboda et al., 2010) - MHFMS Placebo control group: All subjects (N=31; 2-8 yrs) <3 yrs old 3-8 yrs old 3 month change from BL Not reported month change from BL PNCR Natural History Study (Kaufmann et al, 2011) HFMSE in 45 Type 2/3 SMA patients 2-45 years old 2 months 4 months 6 months 9 months 12 months Change

30 DRUG MECHANISM SMA TYPE I II III IV Hydroxyurea R R, O Na Phenylbutyrate R,O R, O SMN2 transcript modulation increase exon 7 inclusion Valproate R, O R,O R, O Isis oligonucleotide Quinazalone Riluzole Excitotoxic R,O R Gabapentin R R L-Carnitine Mitochondrial R O Trophos R Albuterol Muscle anabolic R, O 30 P = Pilot O = open-label R = randomized placebo blinded CT

31 Trichostatin A and Sodium Butyrate have Modest Effects in SMA Mouse Model, Systemic ISIS SMN Rx Has Profound Effects on Survival Single ICV dose doubles survival in SMA model Trichostatin A (HDAC Inhibitor) Sodium Butyrate (HDAC Inhibitor) Avila et al. J. Clin. Inves. 117: 659, 2007 Chang et al., PNAS 98: Systemic Dosing of ISIS SMN Rx Untreated SMA mice ISIS SMN Rx 40 µg x 2 ISIS SMN Rx 80 µg x 2 ISIS SMN Rx 160 µg x 2 Heterozygous mice Hua et al. Nature 478:123, 2011 Single ICV Dose of ISIS SMN Rx Untreated Control oligo 4 µg ISIS SMN Rx 2 µg ISIS SMN Rx 4 µg ISIS SMN Rx 8 µg Passini et al. Science Trans. Med. 3:72ra18, Based upon results with experimental HDAC inhibitors, such as trichostatin A and sodium butyrate, FDA approved HDAC inhibitors phenylbutryate and valproic acid were evaluated in SMA patients

32 Conclusions Clinical trials can be performed in all types of SMA To date, no published intervention studies have shown clinical benefit Several trials have shown improvement in smn Natural history data is critical to designing effective clinical trials. Defines effect size and power calculation, sample size 32

33 Conclusions - 2 Multicenter clinical trials are necessary and requires Harmonization of Outcome Measures Standards of Care Effective coordination of Clinicians Advocacy groups Industry Regulatory agencies and especially patients Better animal models, biomarkers are needed.

34 ISIS-SMN Rx Mechanism of Action 34 Frank Bennett, Ph.D. Senior VP of Research Isis Pharmaceuticals

35 Therapeutic Antisense Strategy for the Treatment of Spinal Muscular Atrophy 35 Spinal Muscular Atrophy (SMA) is caused by loss of a gene called SMN-1 Humans have a second copy of the gene that produces a defective protein due to an RNA splicing defect SMN-2 Gene SMN-1 Gene C to T 1 2a 2b a 2b a 2b SMN-2 mrna Defective Protein, missing exon 7 Gene missing, so no Protein Our antisense drug corrects the splicing disorder resulting in the production of a functional protein in animal models of disease SMN-2 Gene SMN-1 Gene C to T 1 2a 2b a 2b ASO 1 2a 2b SMN-2 mrna Functional Protein Gene missing, so no Protein

36 36 ISIS-SMN Rx Increased Survival & Muscle Function in a Severe SMA Mouse Model

37 ISIS-SMN Rx Increases SMN2 Exon 7 and Increases Production of SMN Protein In Mouse Spinal Cord Tissue 37 SMN Targeting ASO Promotes a Dose Dependent Increase in SMN2 Splicing µg/day Mouse # % incl SMN Protein Expression is Increased in Spinal Cord Motor Neurons Following Treatment of Mice With ISIS-SMN Rx 0 µg 10 µg 50 µg

38 Systemic ISIS SMN Rx Has Profound Effects on Survival 38 Single ICV dose doubles survival in SMA model Systemic Dosing of ISIS- SMN Rx Untreated SMA mice ISIS SMN Rx 40 µg x 2 ISIS SMN Rx 80 µg x 2 ISIS SMN Rx 160 µg x 2 Heterozygous mice Single ICV Dose of ISIS-SMN Rx Untreated Control oligo 4 µg ISIS SMN Rx 2 µg ISIS SMN Rx 4 µg ISIS SMN Rx 8 µg Hua et al. Nature 478:123, 2011 Passini et al. Science Trans. Med. 3:72ra18, 2011 ISIS-SMN Rx works both within CNS and in peripheral tissues to increase survival in severe SMA mouse models Severe SMA mice have pathologies in peripheral tissues that impact survival (e.g. cardiomyopathy) These pathologies rarely occur in SMA patients

39 Comparison of Neuromuscular Junction in Normal and SMA Mice 39 Normal Neuromuscular Junction Neuromuscular Junction in SMA Mice

40 ISIS-SMN Rx Preserves Neuron and Muscle Function in a Mouse Model of SMA 40 SMN Targeting ASO Preserves Neuromuscular Junctions SMN Targeting ASO Maintains Muscle Fiber Size

41 ISIS-SMN Rx Has a Prolonged Half-Life in CNS Tissues in Preclinical Studies 41 Metabolite findings Only N-1

42 A Single Intrathecal Bolus Injection in Non-Human Primates Resulted in Accumulation of Antisense Oligonucleotides in Motor Neurons and Glia Throughout the Spinal Cord 42 Active Tissue Concentration is 1 to 10 µg/gm tissue Single dose mg 12 μg/g 16 μg/g 18 μg/g

43 Conclusions on ISIS-SMN Rx Preclinical Findings 43 ISIS-SMN Rx is first drug designed to correct genetic defect in SMA in clinical trials in SMA patients Well characterized mechanism of action in animal models Strong preclinical data package support testing in patients Long half-life in CNS tissues in animals supports potential for infrequent (every 6 to 9 months) intrathecal injections

44 ISIS-SMN Rx : A Consortium of Collaborators and Supporters 44 Collaborators Cold Spring Harbor Labs Dr. Adrian Krainer Dr. Yimin Hua

45 AAN Presentation: ISIS-SMN Rx Phase 1 in Children with SMA 45 Claudia Chiriboga, M.D., M.P.H. Associate Professor of Clinical Neurology & Clinical Pediatrics, Columbia University Medical Center

46 Results of an Open-Label, Escalating Dose Study to Assess the Safety, Tolerability, and Dose Range Finding of a Single Intrathecal Dose of ISIS-SMN Rx in Patients with Spinal Muscular Atrophy Chiriboga, Claudia 1 ; Swoboda, Kathryn 2 ; Darras, Basil 3 ; Iannaccone, Susan 4 ; Montes, Jacqueline 1 ; Rausch, Nicole 2 ; Parad, Rebecca 3 ; Johnson, Shanda 4 ; De Vivo, Darryl 1 ; Norris, Dan 5 ; Alexander, Katie 5 ; Bennett, C. Frank 5 ; Bishop, Kathie 5 1 Columbia University Medical Center; 2 University of Utah; 3 Boston Children s Hospital; 4 UT Southwestern Medical Center; 5 Isis Pharmaceuticals, Inc.

47 SMA: Leading Genetic Cause of Mortality in Infants and Toddlers 47 Severe neuromuscular disease, characterized by : - Loss of spinal cord motor neurons, muscle atrophy, and loss of motor function - Estimated to be 30,000+ patients in US, Europe, Japan Disease is due to loss or mutation in the SMN1 gene (autosomal recessive inheritance) Humans have a second gene, SMN2, which is improperly spliced resulting in expression of mostly (~90%) truncated, defective protein Variable copy number of SMN2 generally correlates with SMA disease severity, due to variability in amount of effective SMN protein produced

48 ISIS-SMN Rx : Modulating Splicing of SMN2 to Increase Normal SMN Protein 48 Uniformly 2 -O-methoxyethyl modified (MOE) antisense drug Corrects the splicing disorder in SMN2, resulting in the production of fully functional SMN protein in model systems In mild and severe mouse models of SMA provides a phenotypic and pathological benefit when delivered centrally* Distributes broadly to spinal cord motor neurons after intrathecal delivery in monkeys* Has a long half life in CNS tissue (>6 months in animal models) HO O B O O S P O O O O OCH 3 B O OCH 3 SMN2 Gene SMN2 Gene C to T 1 2a 2b C to T 1 2a 2b SMN2 mrna Defective Protein, missing exon 7 ISIS-SMN Rx SMN2 mrna Functional Protein *(Hua et al., Genes Dev., 2010; Passini et al., Sci Transl Med, 2011; Hua et al., Nature, 2011)

49 Phase 1 Open-label, Single-dose Study in Medically Stable SMA Patients 2-14 Years of Age 49 Objective: To evaluate the safety, tolerability, and pharmacokinetics of a single dose of ISIS-SMN Rx administered intrathecally to patients with Spinal Muscular Atrophy Single dose given intrathecally as an LP bolus injection in male and female SMA patients 2-14 years old who are medically stable Primary endpoints: - Safety/tolerability - CSF and plasma drug level pharmacokinetics Exploratory efficacy endpoints included to gain experience with these endpoints Cohorts n 1 mg 6 3 mg 6 6 mg 6 9 mg 10 Screening ( 28 days) Open label Post-Treatment In-Patient f/u Period Day 1 Single Dose 24 hours Post-Treatment Evaluation Period 4 weeks post dose (1 mg & 3 mg) 12 weeks post dose (6 mg & 9 mg)

50 Key Study Outcomes 50 Safety and Tolerability Assessments - Adverse events - Neurological examinations - CSF laboratory tests (cell count, protein, glucose, cytokines) - Vital signs - Clinical laboratory tests (serum chemistry, hematology, coagulation, urinalysis) - Physical examinations and weight - ECGs - Use of concomitant medications Pharmacokinetic Measures - Plasma levels of drug (over 24 hours post-dosing & at 7 days post-dose) - CSF levels of drug (at 7 days post-dose) Exploratory Endpoints - Hammersmith Motor Function Scale Expanded - Neuromuscular Electrophysiology CMAP/MUNE

51 Subject Demographics 51 A total of 28 patients enrolled; all completed the study Demographics Gender - Female 61%, Male 39% Race - 82% White, 7% Asian, 4% Black, 4% >One race, 4% Other Age (years) - Mean = 6.1, Range = 2-14 Weight (kgs) - Mean = 23.6, Range = SMA Disease Characteristics SMA Type 2 = 15; SMA Type 3 = 13 Non-ambulatory = 18; Ambulatory = 10 SMN2 Copy# 3 = 25; Copy# 4 = 2; Copy# 5 = 1

52 Safety and Tolerability Results 52 ISIS-SMN Rx was well tolerated, with no significant safety findings when given as a single dose up to 9 mg - No SAEs or potential Dose Limiting Toxicities - Adverse Events all mild (67/72 AEs) or moderate (5/72 AEs) in severity - Adverse Events were not related to dose level (see next slide) - No drug-related changes on neurological exams - No changes in CSF safety labs or CSF cytokines (IL6, TNF-alpha, MCP1) compared to pre-dose (at 7 days post-dose for Cohorts 1-3; for Cohort 4 at 7 or 28 days post-dose) The LP injection procedure in SMA children was also well tolerated and was shown to be feasible Data suggest that LP tolerability is improved with use of a smaller LP needle (i.e. 24G or 25G)

53 Treatment-emergent Adverse Events 53 Adverse events listed are those that occurred with a frequency >5% (in >1 subject); None of these AEs were considered to be study-drug related Adverse Event Term All ISIS-SMN Rx N= 28 % Subjects (n) # Subjects by Dose Group N = 6, 6, 6, 10 1mg, 3mg, 6 mg, 9 mg Headache 39% (11) 4, 0, 3, 4 Post-LP Syndrome* 21% (6) 1, 2, 2, 1 Back pain 18% (5) 2, 2, 0, 1 Pyrexia 14% (4) 1, 0, 1, 2 Constipation 11% (3) 2, 1, 0, 0 Nausea 11% (3) 1, 2, 0, 0 Vomiting 11% (3) 1, 2, 0, 0 Upper respiratory infection 11% (3) 0, 1, 1, 1 Puncture Site Pain 7% (2) 1, 0, 0, 1 Pharyngitis streptococcal 7% (2) 0, 0, 0, 2 *Post-LP headache rate of 6 events/55 LPs = 11% is consistent with expected rate in children

54 CSF and Plasma Drug Levels Are Measurable, Only Moderately Variable, and Dose-dependent 54 CSF Drug Levels at 7 Days Post-Dose (Mean + SD) Plasma Drug Levels over 24 Hours Post- Dose (Mean + SD) CSF and plasma drug levels were reasonably consistent with predicted values from monkey nonclinical studies

55 Exploratory Outcome Measure Hammersmith Motor Function Scale Expanded 55 Mean + SEM At Day 85, mean change from baseline=3.1 points (p=0.02); % change=17.6% 6/10 subjects with change 4 points (3/6 were 5 years old)

56 Neuromuscular Electrophysiology 56 CMAP and multipoint incremental MUNE performed in highest dose group at Baseline and Day 85 Primary purpose was to determine feasibility of this method in SMA patients for potential use in later studies Performed on right ulnar nerve innervated Abductor Digiti Minimi (ADM) Variable Change (n=8) CMAP (mv) MUNE SMUP (μv) Modified figure from Anatomic Guide for the Electromyographer Charles C. Thomas, Publisher, 1980, p4. Electrophysiology measurements in highest dose at 3 months demonstrate stable CMAP with potential increase in MUNE

57 Conclusions and Implications 57 ISIS-SMN Rx was well tolerated at all dose levels - no safety or tolerability concerns were identified The LP injection procedure was shown to be feasible in SMA children CSF and plasma drug concentrations were dose-dependant - Observations were consistent with preclinical data, thus support infrequent administration (i.e. every 6-9 months) Improvement in HFMSE scores observed at the highest dose level - Interpret with caution due to open-label nature of the study and small number of subjects Electrophysiology measurements in highest dose cohort at 3 months demonstrated increase in MUNE with stable CMAP Ongoing multiple-dose study with additional endpoints and longer follow-up will provide more data on safety and potential efficacy Controlled Phase 2/3 registration-enabling studies in infants and children with SMA are being planned

58 Acknowledgements 58 Columbia University Sally Dunaway Nicole Holuba Jonathan Marra Douglas Sproule Louis Weimer University of Utah Heather Allen Sandra Reyna Ai Sakonju Abby Smart Donata Viazzo-Trussel Boston Children s Hospital Peter Kang Wendy Liew Jennifer Markowitz Amy Pasternak Elizabeth Shriber UT Southwestern Diana Castro Muna Khan Leslie Nelson ISIS CS1 DSMB Walter Bradley, Chairperson Anne McConnell Patricia Dickson Stephen Reingold Isis Pharmaceuticals Matt Buck Shannon Fine John Grundy Steve Hughes Katherine Kwoh Dan Schulz Mason Yamashita Dawn McGuire Biogen Idec SMA Foundation Families of SMA The patients and families who participated in the study

59 Current Efforts to Support Clinical Development 59 Picture Karen Chen, Ph.D. CSO & COO SMA Foundation

60 Closing Remarks 60 Stan Crooke, M.D., Ph.D. Isis CEO and Chairman

61 Partnered with: ISIS-SMN Rx Rapid Path to Market 61 Granted Orphan Drug Status in US and EU and Fast Track Designation in US Phase 1b/2a multiple-dose study ongoing in children with SMA Two pivotal studies planned to start in 2013/early 2014 Infant onset Phase 2/3 study Primary endpoints: Survival and time to progression to permanent ventilation reviewed and supported by US and EU regulators Childhood onset Phase 2/3 study Primary endpoint: Hammersmith Muscle Function Expanded Score reviewed and supported by US and EU regulators Potential regulatory filing and commercial launch within the next five years

62 Q&A 62 Richard Dr. Stan Crooke Dr. Richard Finkel Dr. Frank Bennett Dr. Claudia Chiriboga Dr. Karen Chen CEO and Chairman Isis Pharmaceuticals Chief, Division of Neurology Department of Pediatrics, Nemours Children s Hospital Orlando Sr. VP Research Isis Pharmaceuticals Associate Professor of Clinical Neurology & Clinical Pediatrics, Columbia University Medical Center CSO & COO, SMA Foundation