Phase 3 APPROACH Study Top-line Results

Transcription

1 Phase 3 APPROACH Study Top-line Results March 2017

2 Ionis and Akcea Participants Dr. Stanley Crooke CEO and Chairman Ionis Pharmaceuticals Dr. Louis St. L. O'Dea CMO Akcea Therapeutics Paula Soteropoulos President and CEO Akcea Therapeutics 2

3 Forward Looking Language Statement This presentation includes forward-looking statements regarding the business of Ionis Pharmaceuticals and Akcea Therapeutics, a subsidiary of Ionis, and the therapeutic and commercial potential of volanesorsen and other products in development. Any statement describing the companies' goals, expectations, financial or other projections, intentions or beliefs, including the commercial potential of volanesorsen, SPINRAZA, IONIS-TTR Rx, and other of the companies' drugs in development 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. The companies 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 the companies forward-looking statements reflect the good faith judgment of their management, these statements are based only on facts and factors currently known by the companies. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning the companies programs are described in additional detail in Ionis annual report on Form 10-K for the year ended December 31, 2016, which is on file with the SEC. Copies of this and other documents are available at In this presentation, unless the context requires otherwise, Ionis, Akcea, Company, Companies we, our, and us refers to Ionis Pharmaceuticals and/or Akcea Therapeutics. Ionis Pharmaceuticals is a trademark of Ionis Pharmaceuticals, Inc. Akcea Therapeutics is a trademark of Ionis Pharmaceuticals, Inc. SPINRAZA TM is a trademark of Biogen. 3

4 Agenda for Today s Presentation Topics Speakers Welcome and Introductions Dr. Stanley Crooke FCS: The Unmet Medical Need Volanesorsen: Phase 3 APPROACH Top-line Results Volanesorsen: Clinical Program Summary Dr. Louis St. L. O'Dea Commercialization Preparations and Next Steps Paula Soteropoulos Conclusion Dr. Stanley Crooke Q&A Dr. Stanley Crooke 4

5 Familial Chylomicronemia Syndrome (FCS) A severe, rare genetic disease affecting 3,000 5,000 patients Extremely elevated triglyceride levels Life-threatening disease with multiple, severe, daily and chronic manifestations No effective treatment currently available 5

6 Volanesorsen Achieved Primary Endpoint in the APPROACH Study Volanesorsen-treated patients achieved robust triglyceride reductions 77% mean reduction in TGs from baseline vs. 18% mean increase with placebo (p<0.0001) 1712 mg/dl mean absolute reduction in TGs vs. 92 mg/dl increase with placebo 50% of patients achieved TGs below 500 mg/dl TG-lowering effect sustained over the 52-week study period Volanesorsen-treated patients achieved additional therapeutic benefits Decreased incidence of pancreatitis attacks Reduced frequency and intensity of abdominal pain We believe the efficacy and safety data demonstrate a favorable risk:benefit profile for patients with FCS 6

7 Dr. Louis St. L. O'Dea, Chief Medical Officer, Akcea Therapeutics FCS: The Unmet Medical Need Volanesorsen: Phase 3 APPROACH Top-line Results Volanesorsen: Clinical Program Summary 7

8 FCS is a Life-threatening Disease with Multiple Severe Daily and Chronic Manifestations Physical complications Recurrent abdominal pain Recurrent acute pancreatitis Pancreatic failure Insulin-resistance/ diabetes Unnecessary surgery Other physical and metabolic symptoms Hematological manifestations Hyperviscosity Thrombocytosis Thrombocytopenia Neurological symptoms Cognitive impairment Memory loss Mild dementia Confusion Fatigue Affects 3,000 5,000 Patients Globally 8 $ Emotional burden Anxiety Depression Guilt Social isolation Severe dietary restrictions <10-20 g of total fat daily Financial burden Days missed from work ER/ICU visits Lengthy hospitalization Permanent disability

9 FCS Natural History: New Insights From the SMASH Initiative at ECOGENE and the IN-FOCUS Survey IN-FOCUS 1 Investigation of Findings and Observations Captured in Burden of Illness Survey in FCS Patients Documented and quantified experience of patients and burden of disease >140 patients (not in volanesorsen studies) from multiple countries SMASH Initiative 2 Set up to understand the natural history and burden of FCS Systematic review of medical files and hospitalizations of 87 FCS patients Includes medical records that go back for up to 20 years, from 1997 to present Quantifying medical burden of disease and identifying previously unreported manifestations of high triglycerides 1. IN-FOCUS Quantitative Study, Ref: European Atherosclerosis Society Congress June 1, Plenary session 4: Future therapeutic challenges. Specific talk title: Lessons Learned from Emerging Therapies for Severe HTG by Dr. Daniel Gaudet 9

10 IN-FOCUS: Quantifying the Severity and Frequency of the Disease Burden 1 1. IN-FOCUS Quantitative Study: Interim analysis based on 60 US respondents 10

11 IN-FOCUS: Quantifying the Severity and Frequency of the Disease Burden 1 1. IN-FOCUS Quantitative Study: Interim analysis based on 60 US respondents 11

12 SMASH Initiative: Natural History Study Documenting the Clinical Burden of FCS Clinical Manifestation of FCS n = 57 History of acute pancreatitis (%) 83 History of recurrent acute pancreatitis (%) 52 Acute pancreatitis events (# of events/pt) Lipemia retinalis (%) 54 Eruptive xanthomata (%) 27 12

13 SMASH Initiative: FCS is Associated with Substantial Variability in Platelet Counts SMASH Initiative natural history study in FCS patients demonstrates variability in platelet counts that may result in thrombocytosis and thrombocytopenia A large proportion of patients with FCS have experienced low platelet counts Fluctuations in triglycerides can be associated with fluctuations in platelet counts in FCS patients 13

14 SMASH Initiative: Natural History of FCS Demonstrates Significant Platelet Variability Platelet Variability in FCS Patients Platelet count (x 10 3 /µl) Thrombocytosis Thrombocytopenia Patients 14

15 SMASH Initiative: Thrombocytopenia Experienced by 55% of FCS Patients Thrombocytopenia (platelet count) n (%) Thrombocytosis (platelet count) n (%) 100, ,000/µL 31 (35.6) 450, ,000/µL 6 (6.9) 50,000 99,000/µL 15 (17.2) 600, ,000/µL 4 (4.6) < 50,000/µL 2 (2.4) 900,000m 1,000,000/µL 1 (1.1) Total 48 (55.2) Total 11 (12.6) 15

16 SMASH Initiative: Fluctuations in Platelet Counts can be Associated with Triglyceride Fluctuations in FCS Patients Patient 1 Patient 2 Platelet count (x 10 3 /µl) Platelet count (x 10 3 /µl) Triglycerides (mg/dl) Triglycerides (mg/dl) 4 years 20 years 16

17 SMASH Initiative: FCS Natural History Demonstrates Association Between Triglyceride and Platelet Levels Patients with FCS have variable platelet counts from well above normal to as low as 42,000/µL >55% of FCS patients have presented with at least one episode of thrombocytopenia Evidence that, in some patients, substantial variations in triglycerides can be associated with substantial variations in platelet counts 17

18 FCS: A Severe, Rare Genetic Disease Severe, rare genetic disease characterized by extremely elevated levels of triglycerides Life-threatening disease with multiple, severe, daily and chronic manifestations Natural history demonstrates association between triglyceride and platelet counts No effective treatment currently available 18

19 ApoC-III: Genetically Validated Target For Severe Triglyceride-Driven Diseases Volanesorsen targets ApoC-III to lower triglycerides ApoC-III is a key regulator of triglyceride clearance Reducing ApoC-III levels with volanesorsen shown to robustly lower triglyceride levels in multiple clinical studies in patients with a wide range of incoming triglyceride levels 19

20 APPROACH Phase 3 Study in Patients with FCS Global study in 67* patients Randomized, double-blind, placebo-controlled studies Primary efficacy endpoint: Percent change in fasting triglycerides from baseline after 3 months of dosing 1:1 R Primary endpoint: 3 months dosing OLE or 13-week f/u 6 weeks Screening and Diet stabilization 52 weekly SC injections *1 patient uncompliant with visit schedule, never dosed 20

21 Volanesorsen: Baseline Patient Demographics in Phase 3 APPROACH Study Relevant Baseline Demographics Placebo (n = 33) Volanesorsentreated (n = 33) Gender- % M/F 42.4/ /51.5 Age (years) - mean (range) 46 (20-68) 47 (22 75) Triglycerides - mean* History of acute pancreatitis n (%) 26 (78.8%) 24 (72.7%) Platelet count (x 10 3 /µl) mean (range) 228 ( ) 215 ( ) * Upper limit of normal is 150 mg/dl 21

22 Platelet Variability in Placebo-treated Patients Similar to that Observed in SMASH Initiative Platelet Variability in Placebo Cohort Over Study Period (n = 33) Thrombocytosis Platelet count (x 10 3 /µl) Thrombocytopenia Patients 22

23 Volanesorsen Met the Primary Endpoint of the APPROACH Study in Patients With FCS Triglycerides Month 3 Mean % Change from Baseline % Mean Reduction in Triglycerides at 3 Months Placebo (n = 33) +18% Volanesorsen (n = 33) Triglycerides Month 3 Mean Absolute Change from Baseline (mg/dl) 1712 mg/dl Absolute Reduction in Triglycerides at 3 Months % 400 Volanesorsen (n = 33) mg/dl p = p < Robust, statistically significant reductions continued over 12 months 23

24 Majority of Volanesorsen-treated Patients Achieved Triglyceride Levels Below Accepted Risk Thresholds Placebo* n = 31 n (%) Volanesorsen* n = 30 n (%) P value TG <1000 mg/dl 4 (12.9) 24 (80.0) p < TG <750 mg/dl 3 (9.7) 23 (76.7) p = TG <500 mg/dl 0 (0.0) 15 (50.0) p < *Data includes all patients with triglycerides 750 mg/dl at baseline 24

25 Reduced Frequency of Pancreatitis Attacks Statically significant decrease in pancreatitis attacks in patients with documented high frequency of pre-study attacks Positive trend in APPROACH in reduction of pancreatitis attacks (4 events with placebo, 1 event with volanesorsen) Across the Phase 3 program, statistically significant reduction in pancreatitis attacks 25

26 Statistically Significant Decrease in Pancreatitis Attacks In Patients With High Frequency of Pre-study Attacks Placebo n = 33 Volanesorsen n = 33 Patients Events Patients Events Patients with Multiple Adjudicated Events in Past 5 Years Events during Study p-value p =

27 Phase 3 Program: Lower Incidence of Pancreatitis in Treated Patients Compared to Placebo Incidence of Pancreatitis Placebo Volanesorsen APPROACH (n) # of Pancreatitis Events 4 1 COMPASS (n) # of Pancreatitis Events 6 0 COMPASS + APPROACH (n) # of Pancreatitis Events 10 1 (p = 0.007) Data include results from 52-week treatment period and 28 days after treatment (p = 0.01) 27

28 Reduced Frequency and Intensity of Patientreported Abdominal Pain in Patients Reporting Pre-study Pain Average Maximum Pain Intensity Intensity p = 0.03 Placebo (n = 10) Volanesorsen (n = 7) week Study Run-in 52-week Treatment Period Frequency of Pain Frequency 10 of Moderate to Severe Pain Worst Pain Intensity Frequency Frequency Intensity to 3 4 to 12 7 to 12 Study Months 0 0 to 3 4 to 12 7 to 12 Study Months 0 0 to 3 4 to 12 7 to 12 Study Months 28

29 Volanesorsen: Safety and Tolerability Observed in APPROACH Study No treatment-related liver AEs No increase in liver fat No treatment-related renal AEs Most common AEs were injection site reactions (ISRs), mostly mild 5 early terminations due to ISRs Declines in platelet counts observed in many patients Generally well-managed with dose adjustment 5 early terminations due to declines in platelet counts No terminations in the last 6 months of the study after platelet monitoring fully implemented 14 treatment-emergent SAEs 8 with volanesorsen, 2 considered related or possibly related Infrequent serious platelet events (grade 4 thrombocytopenia), which resolved without complication after cessation of dosing 6 with placebo 29

30 Volanesorsen: Two Positive Phase 3 Studies Volanesorsen Phase 3 Clinical Experience Phase 3 in 113 patients with severely elevated TGs Phase 3 in 66 patients with FCS Placebo Volanesorsen Treatment Placebo Volanesorsen Treatment n = 38 n = 75 n = 33 n = 33 FCS OLE Study 30

31 Phase 3 Program: Volanesorsen Demonstrated Consistent, Robust TG-lowering Volanesorsen-treated COMPASS All Patients (n = 75) COMPASS FCS Subset (n = 5) APPROACH (n = 33) Mean % Change in TGs from Baseline -71% -73% -77% (p < ) (p < ) Mean Absolute Change in TGs from Baseline -869 mg/dl mg/dl mg/dl Achieved TGs <500 mg/dl (%) 59 (82%)* 3 (60%) 15 (50.0%)** *n = 72; Data includes all patients with triglycerides 500 mg/dl at baseline **n = 30; Data includes all patients with triglycerides 750 mg/dl at baseline 31

32 Overall Clinical Experience Phase 1 Study Phase 2 Program Phase 3 in 113 patients with severely elevated TGs Phase 3 in 66 patients with FCS Phase 2 studies: Monotherapy, Add-on to Fibrates, High TGs with T2D, FCS Placebo Volanesorsen Treatment n = 29 n = 74 Placebo Volanesorsen Treatment n = 38 n = 75 Placebo FCS OLE Study Volanesorsen Treatment n = 33 n = 33 Overall Clinical Experience Volanesorsen-treated (all) n = 232 Volanesorsen-treated (FCS) n = 66 32

33 Overall Clinical Experience in Patients with FCS: Consistent, Substantial TG-lowering Triglycerides in Patients with FCS Phase 2 (n = 3) COMPASS (n = 5) APPROACH (n = 33) Mean % Change from Baseline -69% -73% -77% (p < ) Mean Absolute Change from Baseline mg/dl mg/dl mg/dl Achieved TGs <500 mg/dl (%) 3 (100%) 3 (60%) 15 (50.0%)* *n = 30; Data includes all patients with triglycerides 750 mg/dl at baseline 33

34 Overall Clinical Experience: Positive Effects in Multiple Disease Manifestations Across Several Studies Decreased triglycerides sustained through treatment period 1,2,3 Decreased incidence of pancreatitis attacks 2,3 Decreased incidence and severity of abdominal pain 3 Improved glucose control, insulin sensitivity 1 1) Phase 2 Program Results; 2) Phase 3 COMPASS Results; 3) Phase 3 APPROACH Results 34

35 Overall Clinical Experience: Volanesorsen Safety and Tolerability 1 No treatment-related liver AEs No treatment-related renal AEs Most common AEs were injection site reactions (ISRs), mostly mild Declines in platelet counts observed in many patients Generally well-managed with monitoring and dose adjustment 5 treatment-related or possibly treatment-related SAEs No deaths Infrequent serious platelet events (grade 4 thrombocytopenia), which resolved without complication after cessation of dosing 1. Results from Phase 1 study, Phase 2 Program, Phase 3 COMPASS study and Phase 3 APPROACH study 35

36 Overall Clinical Experience: Platelet Findings 178 individuals have been treated with 300mg of volanesorsen, including 66 FCS patients, with some treated for over 2 years 3 patients (all with FCS) experienced a serious platelet event (grade 4 thrombocytopenia); all patients recovered with cessation of dosing Measuring platelet counts is routine and can be done by any lab Monitoring platelet counts is part of our clinical program 36

37 Volanesorsen: Potentially the First Drug for Patients with FCS 1 Robust and sustained triglyceride lowering Decreased incidence of pancreatitis attacks Additional positive patient benefits in other endpoints including pain Consistent positive results across multiple clinical studies We believe the efficacy and safety data from volanesorsen studies demonstrate a favorable risk:benefit profile for patients with FCS 1. Results from Phase 1 study, Phase 2 Program, Phase 3 COMPASS study and Phase 3 APPROACH study 37

38 Paula Soteropoulos, President and Chief Executive Officer, Akcea Therapeutics Commercialization Preparations and Next Steps 38

39 Volanesorsen: Next Steps Prepare regulatory dossiers for 2017 regulatory submissions in US, EU and Canada Present full APPROACH results at an upcoming scientific conference Complete initial build out of commercial infrastructure for potential launch in

40 Making Significant Progress on Finding and Supporting Patients Disease education, simplifying diagnosis, and disease support Defining and quantifying burden of disease Finding patients through field, congress interactions and electronic medical record searches Our pre-launch patient database tracker is growing, focused in US, EU, Canada Independent patient-driven advocacy and awareness groups formed and active 40

41 Finding FCS Patients Through Comprehensive and Multiple Channels Speaker programs 1:1 Medical Affairs clinician engagement Scientific roundtables Expert theaters at key conferences FCS FOCUS Fcsfocus.com website The FCS FOUNDATION Patient advocacy partnership Patient identification Initiatives EMR (Electronic Medical Record) searches Digital initiatives Med Info booth at key conferences Society engagement Registry Sales team 41

42 Quantifying FCS Disease Burden: Substantial Economic Impact on Healthcare Systems 1 Clinical Outcomes in Acute Pancreatitis: Normal vs Severe Triglyceride Levels Triglycerides <150 mg/dl Triglycerides 1000 mg/dl Patients (%) 23% 60% 36% 50% 48% 17% 3% 8% Days n=115 n=25 n=74 n=22 n=115 n=25 n=115 n=25 Need for Intensive Care Pancreatic Necrosis Persistent Organ Failure Mortality 0 n=115 n=25 Median Hospital Stay 1. Nawaz H, et al. Am J Gastroenterol. 2015;110(10):

43 Clinical Outcomes in Acute Pancreatitis: Normal vs Severe Triglyceride Levels a Patients (%) Quantifying FCS Disease Burden: Substantial Economic Impact on Healthcare Systems 1 Hypertriglyceridemia-induced pancreatitis results in longer hospital stays, Triglycerides more days <150 mg/dl in intensive Triglycerides 1000 care mg/dl unit, increased risk of organ damage and higher mortality 23% 60% 36% 50% 48% 17% 3% 8% n=115 n=25 n=74 n=22 n=115 n=25 n=115 n=25 Need for Intensive Care Pancreatic Necrosis 1. Nawaz H, et al. Am J Gastroenterol. 2015;110(10): Persistent Organ Failure Mortality Days n=115 n=25 Median Hospital Stay 43

44 Akcea Pioneering the Understanding of FCS from the Patient s Perspective Investigation of Findings and Observations Captured in Burden of Illness Survey in FCS Patients 44

45 Building Commercial Capabilities Targeting Lipid Specialists Medical and sales force build-out initiated Small focused rare disease salesforce & field support: US, EU, Canada US in place by end 2017; EU, Canada in place early 2018 Focused on lipidologists, specialized endocrinologists and pancreatologists Leveraging the same call points/physicians across our pipeline Lipid Treatment Hubs: ~45 US, ~75 EU; physicians Building a specialized and focused global team centered around hightouch patient and physician support Patient-centered hub & case management including disease education, reimbursement, access, nursing and dietary support, platelet monitoring 45

46 Building High-Touch Patient Support Program for Successful Start & Retention The Core: Dedicated Case Management Highly skilled in relationship building and management with healthcare providers and patients Extensive experience working with healthcare providers, patients, insurers, pharmacy benefit manger, and specialty pharmacies Convenient platelet monitoring routinely measured at any lab or at home Reimbursement Support Specialty Pharmacy Injection Training Platelet Monitoring Dietary Support Persistence & Compliance 46

47 Volanesorsen: On Target, On Track Pivotal Phase 3 study in patients with FCS successfully completed Well along in preparations for regulatory filings and commercial launch Data presentations throughout

48 Dr. Stanley T. Crooke, Chief Executive Officer, Ionis Pharmaceuticals Conclusion Q&A 48

49 Volanesorsen: Potentially the First Drug for Patients with FCS FCS represents a severe, rare genetic disease characterized by severely elevated triglycerides Life-threatening disease with multiple severe daily and chronic symptoms No effective therapeutic options Volanesorsen demonstrated consistent results in multiple studies in patients with FCS Sustained, robust triglyceride lowering Decreased incidence of pancreatitis attacks Additional positive patient benefit in other endpoints, including pain We believe the efficacy and safety data demonstrate a favorable risk:benefit profile for patients with FCS 66 FCS patients treated, some for more than 2 years Akcea preparing for 2017 regulatory submissions and 2018 launch 49

50 Ionis: Near-Term Potentially Transformative Medicines with Significant Commercial Value SPINRAZA Actively launching in US Under Accelerated Assessment in EU Submit additional marketing applications globally Successful launch Volanesorsen Phase 3 COMPASS data Phase 3 APPROACH data in Q1:17 Submit marketing applications globally Successful launch IONIS-TTR Rx Phase 3 NEURO-TTR data in Q2:17 Submit marketing applications globally Successful launch 50

51 Revolutionizing Medicine. Saving Lives. 51