Isis Pharmaceuticals. ISIS-APO(a) Rx and ISIS-APO(a)-L Rx Clinical Data

Transcription

1 Isis Pharmaceuticals ISIS-APO(a) Rx and ISIS-APO(a)-L Rx Clinical Data November 8, 2015

2 Forward Looking Language This presentation includes forward-looking statements regarding Isis business, the business of Akcea Therapeutics, the therapeutic and commercial potential of Isis LICA technology, the discovery, development, activity, therapeutic and commercial potential and safety of ISIS-APO(a) Rx and ISIS-APO(a)- L Rx for the treatment of lipid disorders. 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, 2014, 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. 2

3 Agenda Welcome and Introductions Stanley Crooke M.D., Ph.D., Chairman of the Board & Chief Executive Officer at Isis Pharmaceuticals ISIS-APO(a) Rx Lp(a) Need and ISIS-APO(a) Rx Phase 2 Data Sotirios Tsimikas, M.D., Professor of Medicine & Director of Vascular Medicine, UCSD, Vice President of Clinical Development and Leader of the Cardiovascular Franchise, Isis Pharmaceuticals ISIS-APO(a)-L Rx Phase 1/2a Data Richard Geary, Ph.D., Senior Vice President, Development, Isis Pharmaceuticals Patients with High Lp(a): A Clinical Perspective Patrick Moriarty, M.D., Associate Professor, Department of Internal Medicine, University of Kansas Medical Center ISIS-APO(a)-L Rx Development Plan and Commercial Opportunity Paula Soteropoulos, Chief Executive Officer at Akcea Therapeutics LICA Platform and Strategy Richard Geary, Ph.D., Senior Vice President, Development, Isis Pharmaceuticals Closing Remarks and Q&A Stanley Crooke M.D., Ph.D., Chairman of the Board & Chief Executive Officer at Isis Pharmaceuticals 3

4 Targeting Lp(a): A Compelling Opportunity Isis and Akcea have the first and only program to selectively and robustly reduce Lp(a) in patients by inhibiting apo(a) Reducing high Lp(a) is one of the next frontiers in the treatment of cardiovascular disease As demonstrated by ISIS-APO(a)-L Rx, Isis advanced LIgand Conjugated Antisense (LICA) technology represents a quantum leap in the performance of Isis antisense drugs Commercial opportunities to treat patients with high Lp(a) who also have: Near-term: recurrent cardiovascular events Mid-term: calcific aortic valve stenosis Long-term: elevated cardiovascular risk 4

5 Targeting Lp(a): A Compelling Opportunity Isis and Akcea have the first and only program to selectively and robustly reduce Lp(a) in patients by inhibiting apo(a) Reducing high Lp(a) is one of the next frontiers in the treatment of cardiovascular disease As demonstrated by ISIS-APO(a)-L Rx, Isis advanced LIgand Conjugated Antisense (LICA) technology represents a quantum leap in the performance of Isis antisense drugs Commercial opportunities to treat patients with high Lp(a) who also have: Near-term: recurrent cardiovascular events Mid-term: calcific aortic valve stenosis Long-term: elevated cardiovascular risk 5

6 Isis LICA Technology is a Major Advance >30-fold Increase in Potency in Humans Compared to the Non-LICA Drug Dose-dependent, predictable, substantial reductions Good tolerability profile: no ISRs or FLS in current experience Supports dosing flexibility: weekly, monthly, quarterly, or less frequently Isis, through Akcea, is developing ISIS-APO(a)-L Rx for all indications >30-fold More Potent in Humans Regimen Non-LICA ISIS-APO(a) Rx LICA ISIS-APO(a)-L Rx Weekly Dose ED mg (1.5 ml) 4.5 mg (0.05 ml) 6

7 Isis LICA Technology is a Major Advance Realizing Value Today: 8 LICA Drugs in Isis Pipeline Isis initial LICA represents a dramatic advancement for Isis pipeline for liver targets Cardiovascular Drugs Indication Partner ISIS-APO(a)-L Rx High Lp(a) Isis/Akcea ISIS-AGT-L Rx Treatment-Resistant Hypertension Isis ISIS-ANGPTL3-L Rx Hyperlipidemia Isis/Akcea ISIS-APOCIII-L Rx Severely High TGs Isis/Akcea Severe and Rare Drugs Indication Partner ISIS-GHR-L Rx Acromegaly Isis ISIS-TMPRSS6-L Rx β-thalassemia Isis Other Drugs Indication Partner ISIS-GSK4-L Rx Ocular Disease GSK ISIS-GSK6-L Rx Antiviral GSK 7

8 Why is Lowering Lp(a) Important? Sotirios (Sam) Tsimikas, M.D. Professor of Medicine & Director of Vascular Medicine, UCSD Vice President of Clinical Development and Leader of the Cardiovascular Franchise, Isis Pharmaceuticals

9 Targeting Apo(a) to Reduce Lp(a) The Next Frontier in Cardiovascular Disease Management 9 Apo(a) is a liver-derived protein linked to an LDL Lp(a) is a genetically determined, independent driver for many cardiovascular diseases Antisense is the only technology shown to selectively and robustly reduce Lp(a) levels Apo(a) + LDL = Lp(a) Schematic of Lp(a) (Koschinsky & Marcovina (2004) Curr Opin Lipol. 15: ) 9

10 IMPROVE-IT Study Demonstrated That Aggressive LDL-C Lowering Does Not Eliminate All Cardiovascular Disease Risk Even if LDL-C is controlled, many patients still have significant cardiovascular risk due to other untreated risk factors, including high Lp(a) 40 IMPROVE-IT Study* 34.7% 32.7% CV event (%) Continued risk: due to untreated risk factors 0 LDL-C=70 mg/dl Simvastatin N=9077 a LDL-C=53 mg/dl Ezetimibe + Simvastatin N=9077 *Cannon et al. (2015) NEJM. 372:

11 Strong Evidence Demonstrates High Lp(a) is a Key Driver of Cardiovascular Disease Linear relationship between Lp(a) levels and cardiovascular risk Even modest increases in Lp(a) lead to meaningful cardiovascular risk Similar to the risk associated with LDL-C and triglycerides 11

12 High Lp(a) is Recognized by the Medical Community as a Key Driver of Cardiovascular Disease That Needs to be Addressed Elevated levels are associated with increased risk for premature ASCVD, and are largely genetically determined Lp(a) measurement should be considered in people with high CVD risk or a strong family history of premature atherothrombotic disease Lp(a) is an independent, additive contributor to CV risk A very strong family history of vascular events, or the presence of vascular disease, should lead to assessments Report on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Disease in Adults: Full Panel Report Supplement 2 Reiner, et al. (2011) Eur Heart J. 32: Davidson et al., (2011) J Clin Lipidol. 5:

13 Compelling Results from ISIS-APO(a) Rx Phase 2 Study Data on ISIS-APO(a) Rx Presented Nov. 8, 2015 at the American Heart Association Meeting by Joseph Witztum, M.D., Distinguished Professor of Medicine and Director of the Atherosclerosis Research Group, University of California, San Diego

14 ISIS-APO(a) Rx Phase 2 Study in Patients with High Lp(a) Randomized, double-blind, placebo-controlled, dose-titration study 2 Cohorts Cohort A: High Lp(a) ( 50 (125 nmol/l) and < 175 mg/dl (438 nmol/l)) Cohort B: Very high Lp(a) ( 175 mg/dl) Intra-patient dose titration (100mg-300mg) Objectives Evaluate activity of ISIS-APO(a) Rx in lowering Lp(a) Evaluate the safety & tolerability of ISIS-APO(a) Rx Rapid enrollment Cohorts PBO (n) ISIS- APO(a) Rx (n) A Treatment Period Once weekly s.c. injections Post-Treatment f/u Period B days R 12 weeks 16 weeks Screening 14

15 Substantial Reductions of Lp(a) in Patients with High Levels Mean reduction of 71%, up to 94% reduction Equally effective regardless of starting Lp(a) levels Generally well tolerated; no safety issues observed; no-drug related SAEs Lp(a), mean % reduction from baseline (± SEM) Placebo Cohort A Cohort B *** *** *** *** *** ***p (ANOVA) for both cohorts vs. placebo /99/ET Lp(a), mean % reduction from baseline (± SEM) Baseline Lp(a) (mg/dl) Lp(a) Lp(a) 175 Study Day 15

16 Compelling Results from ISIS-APO(a)-L Rx Phase 1/2a Study Richard Geary, Ph.D. Senior Vice President, Development, Isis Pharmaceuticals Data on ISIS-APO(a)-L Rx Presented Nov. 8, 2015 at the American Heart Association Meeting by Joseph Witztum, M.D., Distinguished Professor of Medicine and Director of the Atherosclerosis Research Group, University of California, San Diego v

17 ISIS-APO(a)-L Rx Phase 1/2a Study Design Single and Multiple Ascending Dose Study in Subjects with High Lp(a) Cohorts Single Dose Study PBO (n) ISIS- APO(a)-L Rx (n) 10 mg* mg* mg mg 2 6 *only 30 days follow-up period Screening up to 28 days 3:1 R D1 1 SC Dose Post-Treatment f/u Period 90 days Multiple Dose Study Cohorts PBO (n) ISIS- APO(a)-L Rx (n) 4:1 Post-Treatment f/u Period 10 mg mg mg 2 8 Screening up to 28 days R D1 D3 D5 D8 D15 D22 6 SC Doses over 4 Weeks 13 weeks 17

18 Predictable and Dose-dependent Reduction in Lp(a) After a Single Dose of ISIS-APO(a)-L Rx Dose (n) Volume (ml) Mean Reduction (% ± SEM) Max Reduction (%) 10 mg (3) 20 mg (3) 40 mg (3) 80 mg (6) ± ± ± ± % max reduction in Lp(a) 30 days after a single dose 18

19 Significant and Sustained Reduction in Lp(a) After a Single Dose of ISIS-APO(a)-L Rx Mean reduction of 79%, up to 97% reduction Enhanced potency enables flexible dosing schedule: weekly, monthly, quarterly, or less frequently 20 Placebo ISIS-APO(a)-L Rx (80 mg) Lp(a), mean % reduction from baseline (± SEM) ** * ** ** ** * * * Wilcoxon Rank Sum Test *p 0.05 vs Placebo **p 0.01 vs Placebo Single injection (D1) Study Day 19

20 Significant Reduction in Lp(a) After Multiple Doses of ISIS-APO(a)-L Rx Up to 99% reduction, with mean reduction of 92% at 40 mg Equally effective regardless of starting Lp(a) levels Lp(a), mean % reduction from baseline (± SEM) Placebo ISIS-APO(a)-L Rx (20 mg) * *** Wilcoxon Rank Sum Test *p 0.05 vs Placebo ***p vs Placebo *** *** *** ISIS-APO(a)-L Rx (10 mg) ISIS-APO(a)-L Rx (40 mg) *** *** *** *** *** *** *** *** *** ISIS-APO(a)-L Rx Injection Study Day 20

21 Phase 1/2a Study of ISIS-APO(a)-L Rx Demonstrates Good Tolerability and Safety Profile 21 No tolerability or safety issues No injection site reactions or flu-like symptoms 159 injections 21

22 ISIS-APO(a)-L Rx is a Major Advance >30-fold Increase in Potency In Humans Compared to the Non-LICA Drug Dose-dependent, durable, statistically significant reductions in Lp(a) Good tolerability profile: no ISRs or FLS in current experience Supports dosing flexibility: weekly, monthly, quarterly, or less frequently Supports rapid development in high unmet need patient populations 22

23 Patients with High Lp(a): A Clinical Perspective Patrick Moriarty, M.D. Associate Professor, Department of Internal Medicine, University of Kansas Medical Center

24 Case Presentation from Dr. Moriarty s Clinic of a Patient with Recurrent MACE with High Lp(a) 49 year old non-obese Male with the following risk factors: Low HDL-C Strong family history of CAD with his father with MI in late 40 s 1 brother and 2 cousins with premature CAD Age 41 Presented with a ST-segment elevation myocardial infarction (acute coronary syndrome) Received 2 stents in LAD artery 44 CAD progression Required coronary bypass surgery with four grafts Developed acute coronary syndrome Required 2 stents in his bypass grafts Developed 3 rd acute coronary syndrome Received another stent in his bypass grafts (total 5) Referred to clinic, at this point he was on rosuvastatin (20 mg) with: Total cholesterol = 117 mg/dl, LDL-C = 75 mg/dl, HDL-C = 31 mg/dl, non- HDL-C = 85 mg/dl, TG = 93 mg/dl Lp(a) = 177 mg/dl Placed on niaspan (2000 mg/day) Started apheresis, post apheresis: LDL-C = 25 mg/dl, Lp(a) = 30 mg/dl No further events on apheresis 24

25 Developing ISIS-APO(a)-L Rx For Patients With Significant Unmet Cardiovascular Need Paula Soteropoulos Chief Executive Office, Akcea Therapeutics

26 ISIS-APO(a)-L Rx Opportunity to Treat Patients w/ High Lp(a) Development Plan Our Commercial Approach 26

27 ISIS-APO(a)-L Rx Opportunity VALUE CREATION Recurrent Cardiovascular Events, with Very High Lp(a) Calcific Aortic Valve Stenosis, with High Lp(a) Lp(a)-driven CVD Risk NEAR TERM MID TERM LONG TERM Patient Burden Acute morbidity & mortality Aggressive morbidity, mortality risk Lifetime risk Development & Regulatory Path Orphan/rare; no outcomes; experience w/ LDL & Trigs Clinical endpoint using valve echo imaging Secondary prevention outcomes study US Disease Prevalence 10,000 s 100,000 s 1,000,000 s 27

28 ISIS-APO(a)-L Rx Opportunity VALUE CREATION Recurrent Cardiovascular Events, with Very High Lp(a) NEAR TERM Patient Burden Acute morbidity & mortality Sudden, recurrent, unpredictable; MI, strokes, multiple revascularization procedures Current Care Development & Regulatory Path US Disease Prevalence No specific or apheresis in extreme cases Orphan/rare; no outcomes; experience w/ LDL & Trigs 10,000 s 28

29 ISIS-APO(a)-L Rx Opportunity VALUE CREATION Recurrent Cardiovascular Events, with Very High Lp(a) Calcific Aortic Valve Stenosis, with High Lp(a) NEAR TERM MID TERM Patient Burden Acute morbidity & mortality Aggressive morbidity, mortality risk Sudden, recurrent, unpredictable; MI, strokes, multiple revascularization procedures Shortness of breath, fatigue, limits mobility/daily activities; risk of heart failure; elevated Lp(a) accelerates mild to severe progression w/in few years Current care No specific or apheresis in extreme cases Watch & wait until valve replacement surgery Development & regulatory path Orphan/rare; no outcomes; experience w/ LDL & Trigs Clinical endpoint using valve echo imaging US Disease Prevalence 10,000 s 100,000 s 29

30 Mid-Term Indication: Calcific Aortic Valve Stenosis with High Lp(a) Calcific Aortic Valve Stenosis, with High Lp(a) Progressive calcification & restriction of aortic valve supplying oxygenated blood to the rest of the body With time, shortness of breath, fatigue, limits mobility and daily activities Untreated, severe cases have 2-yr mortality of 50-60%, 3 yr survival of <30% 1 Currently, no treatment beyond monitoring progression, until symptoms require valve replacement surgery Elevated Lp(a) leads to faster progression of aortic stenosis & the need for valve replacement Image courtesy Mayo Foundation 1 Spaccarotella et al. (2011) Circ J. 75:

31 ISIS-APO(a)-L Rx Opportunity VALUE CREATION Recurrent Cardiovascular Events, with Very High Lp(a) Calcific Aortic Valve Stenosis, with High Lp(a) Lp(a)-driven CVD Risk NEAR TERM MID TERM LONG TERM Patient Burden Acute morbidity & mortality Aggressive morbidity, mortality risk Lifetime risk Sudden, recurrent, unpredictable; MI, strokes, multiple revascularization procedures Shortness of breath, fatigue, limits mobility/daily activities; risk of heart failure; elevated Lp(a) accelerates mild to severe progression w/in few years Unexpected events if all other CV risk factors controlled Current Care No specific or apheresis in extreme cases Watch & wait until valve replacement surgery Currently no specific treatment Development & Regulatory Path Orphan/rare; no outcomes; experience w/ LDL & Trigs Clinical endpoint using valve echo imaging Secondary prevention outcomes study US Disease Prevalence 10,000 s 100,000 s 1,000,000 s 31

32 Long-Term: Broad Populations At Risk of Lp(a)-driven CVD Lp(a)-driven CVD Risk 1 Millions of patients globally well-controlled on lipid-lowering therapy still at risk of CVD 2 ~20% of general population have Lp(a) levels placing them at CVD risk (>50mg/dL) 3 ISIS-APO(a)-L Rx 1st & only drug to specifically target & robustly lower Lp(a) 32

33 ISIS-APO(a)-L Rx Development Plan One drug, all indications Develop ISIS-APO(a)-L Rx for all populations Rapid & efficient development plan Rapid completion of Phase 2b program to refine dose and gain experience in calcific aortic stenosis Two Phase 3 studies on track On track to initiate two Phase 3 studies targeting late 2017/early 2018 Recurrent Cardiovascular Events with Very High Lp(a) Calcific Aortic Valve Stenosis with High Lp(a) Dosing Flexibility Developing plan to initiate secondary prevention outcomes trial for millions of patients with elevated Lp(a) Progressing towards broad opportunity Study both weekly and monthly dosing 33

34 Differentiated Commercial Strategy EXPAND Expand on core commercial foundation from volanesorsen FOCUS Expertise and excellence in cardiometabolic diseases with a focus on lipids LEVERAGE Common key thought leader base across pipeline EFFICIENCY Strategy consistent across rare and broad disease approach where there is no effective treatment today. 34

35 Commercial Strategy into Commercial Sales EDUCATE on burden of disease impact of high Lp(a) PARTNER with to drive broad lipid screening of Lp(a) DRIVE urgency to intervene early to diagnose and treat high Lp(a) SELL, pulling through via highly educated sales force, market access & support team 35

36 Efficiency & Leverage Across Advanced, Transformative Lipid & Cardiovascular Pipeline Target Franchise Product Candidate Disease Type Disease Stage of Development Preclin. Phase 1 Phase 2 Phase 3 Approved Volanesorsen Rare FCS FPL APOCIII Triglycerides APOCIII-L Rx Broader Cardiometabolic Severe High Triglycerides (SHTG) High Triglycerides with Type 2 Diabetes Rare Recurring CVD with High Lp(a) APO(a) Lp(a) APO(a)-L Rx Broader Cardiovascular Calcific Aortic Valve Stenosis with High Lp(a) CVD with High Lp(a) ANGPTL3 ANGPTL3-L Rx Rare and Broader Cardiometabolic Mixed Dyslipidemias 36

37 LICA Technology and Strategy Richard Geary, Ph.D., Senior Vice President, Development, Isis Pharmaceuticals

38 LICA is a Game Changing Advance in the Potency of Isis Antisense Drugs 1 >30-fold more potent in humans as demonstrated by Isis first LICA drug 2 Ultra-low dose volume, easy to administer 3 Flexible dosing: weekly, monthly, quarterly or less frequently 4 Good tolerability observed in clinical studies 38

39 ISIS-APO(a)-L Rx is >30-fold More Potent in Humans Isis LICA technology significantly increases drug potency by enhancing drug delivery to target tissue ISIS-APO(a)-L Rx is >30-fold more potent than the Non-LICA drug in humans Regimen Non-LICA ISIS-APO(a) Rx LICA ISIS-APO(a)-L Rx Weekly Dose ED mg (1.5 ml) 4.5 mg (0.05 ml) 39

40 Enhanced Potency of Isis LICA Technology Enables Ultra-low Doses Weekly Doses ISIS-APO(a)-L Rx 0.1 ml Gen Antisense 1.5 ml sirna GalNAC 2 X 1.25 ml = 2.5 ml + ISIS-APO(a)-L Rx P2 Dose 40

41 Enhanced Potency of Isis LICA Drugs Enables Flexibility in Dosing Schedule Dramatic potency increase supports dosing flexibility of weekly, monthly, quarterly or less frequently Lp(a), mean % change Lp(a) (%Baseline) from baseline (± SEM) Observed Predicted Projected Observed Predicted Projected Study Month Time (Months) ISIS-APO(a)-L Rx injection (80 mg) 41

42 Enhanced Potency of Isis LICA Drugs Enables Flexibility in Dosing Schedule Dramatic potency increase supports dosing flexibility of weekly, monthly, quarterly or less frequently Lp(a), mean % change Lp(a) (%Baseline) from baseline (± SEM) Quarterly dosing: steady state reduction of 80%, maximum reduction of >90% Observed Predicted Projected Observed Predicted Projected Study Month Time (Months) ISIS-APO(a)-L Rx injection (80 mg) Proposed ISIS-APO(a)-L 42 Rx injection

43 Lp(a), mean % change from baseline (± SEM) Lp(a) (%Baseline) Enhanced Potency of Isis LICA Drugs Enables Flexibility in Dosing Schedule Dramatic potency increase supports dosing flexibility of weekly, monthly, quarterly or less frequently Quarterly dosing: steady state reduction of 80%, maximum reduction of >90% Predicted Observed Predicted Projected Study Month Time (Months) Nadir: > -90% Approx. -65% Avg: -80% ISIS-APO(a)-L Rx injection (80 mg) Proposed ISIS-APO(a)-L 43 Rx injection

44 LICA is a Game Changing Advance in the Potency of Isis Antisense Drugs LICA technology significantly increases drug potency by enhancing drug delivery to target tissue ISIS-APO(a)-L Rx, is >30-fold more potent in humans than non- LICA drug LICA drug profile reduces barriers to adherence and compliance: Low volume: multiple options for convenient administration Maximum dosing flexibility: weekly, monthly, quarterly or less frequently Good tolerability profile: no ISRs or FLS observed to date 44

45 Realizing Value Today: 8 LICA Drugs in Isis Pipeline Cardiovascular Drugs Indication Partner ISIS-APO(a)-L Rx High Lp(a) Isis/Akcea Severe and Rare Drugs Indication Partner ISIS-GHR-L Rx Acromegaly Isis ISIS-AGT-L Rx Treatment-Resistant Hypertension Isis ISIS-TMPRSS6-L Rx b-thalassemia Isis ISIS-ANGPTL3-L Rx Hyperlipidemia Isis/Akcea ISIS-APOCIII-L Rx Severely High TGs Isis/Akcea Other Drugs Indication Partner ISIS-GSK4-L Rx Ocular Disease GSK ISIS-GSK6-L Rx Antiviral GSK Isis and Akcea developing three LICA drugs: ISIS-APOCIII-L Rx, ISIS- APO(a)-L Rx and ISIS-ANGPTL3-L Rx All three LICA drugs broaden market opportunity for Akcea s lipid franchise Future drugs for liver targets will incorporate LICA technology 45

46 Closing Remarks Stanley Crooke, M.D., Ph.D. Chairman of the Board & Chief Executive Officer, Isis Pharmaceuticals

47 Targeting Lp(a): A Compelling Opportunity Isis and Akcea have the first and only program to selectively and robustly reduce Lp(a) in patients by inhibiting apo(a) Addressing high Lp(a) will transform the treatment of cardiovascular disease As demonstrated by ISIS-APO(a)-L Rx, Isis advanced LICA technology represents a quantum leap in the performance of Isis antisense drugs Near, mid and long-term commercial opportunities to treat patients with high Lp(a) 47

48 Isis Pharmaceuticals Q & A November 8, 2015