Interim Results of a Phase 2 Study of ISIS-SMNRx in Children with Spinal Muscular Atrophy Darras, B1; Chiriboga, C2; Swoboda, K3; Iannaccone, S4; Montes, J2; Castro, D4; Holuba, N2; Rausch, N3; Ramos, C3; Visyak, N1; Dunaway, S2; Trussell D3; Pasternak, A1; Neilson, L4; De Vivo, D2; Norris, D5; Bennett, F5; Bishop, K5 1 – Boston Children’s Hospital; 2 – Columbia University Medical Center; 3 – University of Utah; 4 – UT Southwestern Medical Center; 5 – Isis Pharmaceuticals, Inc. ISIS-SMNRx: Modulating Splicing of SMN2 to Increase Normal SMN Protein 2 HO  Uniformly 2’-O-methoxyethyl modified (MOE) antisense drug O  Corrects the splicing disorder in SMN2, resulting in the production of fully functional SMN protein in model systems O S P O O  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* B O OCH3 O O B O OCH3  Has a long half life in CNS tissue (>6 months in animal models) SMN2 Gene SMN2 Gene C to T C to T 1 2a 2b 1 2 3 2 3 4 4 5 5 6 6 7 8 8 SMN2 mRNA Defective Protein, missing exon 7 1 2b 2a 1 22 3 4 6 5 7 8 ISIS-SMNRx 3 4 5 6 7 8 SMN2 mRNA Functional Protein *(Hua et al., Genes Dev., 2010; Passini et al., Sci Transl Med, 2011; Hua et al., Nature, 2011) Clinical Program for ISIS-SMNRx 3  Granted Orphan Drug Status in US and EU and Fast Track Designation in US  Phase 1 Single-dose Study in Children with SMA - completed  Phase 1b/2a Multiple-dose Study in Children with SMA - ongoing  Phase 2 Multiple-dose Study in Infants with SMA - ongoing  Two pivotal, controlled studies planned to start in 2014 - Phase 3 study in Infants with SMA - Phase 3 study in Children with SMA Completed Phase 1 Open-label, Single-dose Study in SMA Patients, Including Long-term Follow-up at 9-14 Months Post-Dose 4  Single dose given intrathecally as an LP bolus injection in male and female Type 2 and Type 3 SMA patients 2-14 years old who were medically stable  No safety or tolerability concerns identified with single doses up to 9 mg  Dose and time dependent Increases in HFMSE scores observed - increase of 5.75 points at 9-14 months in 9 mg group Mean ± SEM 5.75 (p=0.008) 2.5 0.5 -1.7 Phase 2 Multiple-Ascending Dose, Open-Label Study in Medically Stable SMA Patients 2-15 Years of Age (Ongoing)   Objectives:  Evaluate the safety and tolerability of multiple intrathecal doses of ISIS-SMNRx  Evaluate CSF, plasma PK, and clinical outcomes related to SMA (including HMFSE) Status:  3 mg, 6 mg, and 9 mg cohorts completed; 12 mg cohort currently ongoing Cohort Total Dose n 3 mg 9 mg 8 6 mg 18 mg 8 9 mg 18 mg 9 12 mg 36 mg 9 Post-Treatment f/u Period 24 weeks Open Label Screening (≤28 days) Day 1 Dose SUBJECT DEMOGRAPHICS SMA Type Ambulatory/Non-ambulatory Mean age (range) SMN2 Copy # Day 29 f/u & Dose Day 85 f/u & Dose N=25 Type 2 = 10; Type 3 = 15 9/16 7.5 years (2-15) 2 copies = 1; 3 copies = 20; 4 copies = 4 Dose and Time Dependent Increases in HFMSE Scores after Multiple Doses of ISIS-SMNRx * * 3.7 2.3 1.5 Last Dose Study Month Mean + SEM, *p<0.05 compared to BL Increases in HFMSE Scores Observed for Prolonged Time After Last Dose of ISIS-SMNRx in SMA Children  Patients who participated in Phase 2 multi-dose study enrolled in open-label extension study and completed their baseline assessment * 3.2 2.3 1.7 Last Dose *Graph does not include one patient from the 3 mg cohort who underwent spinal surgery between D92 and D169, which caused an immediate 6 point decline in HFMSE. Additional Measurements of Motor Function (6MWT and ULM) Are Consistent With Increases Observed in HMFSE  Six Minute Walk Test (6MWT) Study N Phase 2 9 OLE - Baseline Visit 10 Follow-up from Baseline Baseline (+SEM) Increase from BL (+SEM) 9 months 230.8 m (31.4 m) 22.7 m (12.3 m) 12-16 months 207.7 m (36.3 m) 24.4 m (9.4 m)  Upper-limb Module (ULM) Study N Phase 2 10 OLE - Baseline Visit 7 Follow-up from Baseline Baseline (+SEM) Increase from BL (+SEM) 9 months 10.5 m (1.0 m) 2.3 m (0.9 m) 11-16 months 9.7 m (1.1 m) 3.1 m (1.4 m) 8 SMN Protein Increased >2 Fold in CSF of SMA Children After Single Doses of 9 mg of ISIS-SMNRx  In multi-dose study, SMN protein increase of 115% (p=0.004, n=9) observed at 3 months  In single-dose study, SMN protein increase of 160% (p=0.09, n=6) observed at ~ 1 year ISIS-SMNRx Safety and Tolerability Profile in SMA Children Supportive of Continued Development  Exposure to ISIS-SMNRx  56 children dosed, doses up to 12 mg  Total of 183 intrathecal (IT) injections  Safety and tolerability  No ISIS-SMNRx-related serious adverse events (SAEs)  Most adverse events mild or moderate in severity and considered not related to drug  No study drug related changes in CSF safety labs or neurological exams  No change in safety profile with repeated doses (most children have received 3-5 injections)  The LP injection procedure in children with SMA has been well tolerated and shown to be feasible Summary of Results to Date in Studies in Children with SMA 11  ISIS-SMNRx has been well tolerated when given as multiple doses up to 12 mg - no safety or tolerability concerns have been identified  CSF and drug concentrations are dose-dependent and consistent with predictions; CSF half-life is about 4-6 months - Observations support infrequent administration  Dose and time dependent increase in HFMSE scores observed (even 8-13 months after last dose)  Additional secondary endpoints (6 MWT, ULM) supportive, although open-label study and small numbers limit interpretation  Treatment with ISIS-SMNRx increased CSF SMN protein levels - Observation supports biological mechanism and is consistent with preclinical and clinical data  These data inform the design of a planned Phase 3 registrationenabling study in children with SMA ISIS-SMNRx Phase 3 Study in SMA Infants – ENDEAR (ongoing)  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  13 month study duration  Evaluate the efficacy and safety of ISIS-SMNRx  Primary efficacy endpoint is time to death/permanent ventilation  Additional efficacy endpoints include CHOP INTEND and motor milestones  Study initiated August 2014 Study Complete 2:1 Cohorts Sham control 12 mg ISIS-SMNRx ≤21 days Screening R 2 months 11 months 4 Induction Doses Maintenance Dose Every 4 Months M13 Last Visit OLE ISIS-SMNRx Phase 3 Study in SMA Children - CHERISH  A Phase 3, Randomized, Double-blind, Sham-Procedure Controlled Study in Children with SMA  Global study in ~120 SMA children with SMA  15 month study duration  Determine the efficacy and safety of ISIS-SMNRx  Primary endpoint is change in Hammersmith motor function score  Planned 2014 initiation Cohorts Sham control 12 mg ISIS-SMNRx Study Complete 2:1 ≤28 days Screening R 3 Induction Doses Maintenance Dose 6 Months Later M15 Last Visit OLE Acknowledgements 14 University of Utah Sandra Reyna Ai Sakonju Abby Smart Michael Worman Columbia University Jose Garcia Jonathan Marra Douglas Sproule Louis Weimer Boston Children’s Hospital Robert Graham Wendy Liew Rebecca Parad Elizabeth Shriber Peter Kang UT Southwestern Stephanie Trest Margaret Cowie ISIS 396443-CS2 DSMB Walter Bradley, Chairperson Anne Connolly Patricia Dickson Stephen Reingold Isis Pharmaceuticals Katie Alexander Matt Buck Shannon Fine Katherine Kwoh Laury Mignon Dan Schulz Mason Yamashita Dawn McGuire Biogen Idec SMA Foundation Families of SMA The patients and families who participated in the study