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ISIS-FXI Rx Program Update Webcast December 8, 2014 ISIS PHARMACEUTICALS.

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Presentation on theme: "ISIS-FXI Rx Program Update Webcast December 8, 2014 ISIS PHARMACEUTICALS."— Presentation transcript:

1 ISIS-FXI Rx Program Update Webcast December 8, 2014 ISIS PHARMACEUTICALS

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

3 This presentation includes forward-looking statements regarding the discovery, development, activity, therapeutic and commercial potential and safety of ISIS-FXI Rx and the discovery, development and therapeutic potential of an antisense drug for the treatment of clotting 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, 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. Forward Looking Language Statement 3

4 Participants Dr. Stan Crooke CEO and Chairman Isis Pharmaceuticals Dr. Jeffrey Weitz Professor of Medicine and Biochemistry, McMaster University Dr. Harry Büller Professor of Medicine Dept. of Vascular Medicine Academic Medical Center The Netherlands Dr. Sanjay Bhanot VP Clinical Development & Translational Medicine Isis Pharmaceuticals 4

5 Purpose of Today’s Meeting ISIS-FXI Rx : A Potential Breakthrough for Preventing and Treating Thrombosis Discuss the ISIS-FXI Rx Phase 2 Total Knee Arthroplasty (TKA) Study Data Review the unmet medical needs and therapeutic potential for ISIS-FXI Rx Describe ongoing and planned studies 5

6 Agenda Introduction  Dr. Stan Crooke, CEO & Chairman, Isis Pharmaceuticals Why is a Better Anti-thrombotic Needed?  Dr. Jeffrey Weitz, Professor of Medicine and Biochemistry, McMaster University ISIS-FXI Rx Phase 2 Clinical Data  Dr. Harry Büller, Professor of Medicine, Dept. of Vascular Medicine, Academic Medical Center, The Netherlands ISIS-FXI Rx A Potential Breakthrough with Broad Commercial Opportunities  Dr. Jeffrey Weitz, Professor Medicine and Biochemistry, McMaster University Next Steps  Dr. Sanjay Bhanot, VP Clinical Development, Isis Pharmaceuticals Closing Remarks and Q&A  Dr. Stan Crooke, CEO & Chairman, Isis Pharmaceuticals 6

7 Why We Need Better Antithrombotic Drugs Dr. Jeffrey Weitz Professor of Medicine and Biochemistry, McMaster University 7

8 Thrombosis: A Significant Unmet Medical Need Thrombosis (heart attacks, strokes, pulmonary embolism) is still the leading cause of morbidity and mortality worldwide Although effective for many, not all patients benefit from currently available anticoagulants Currently marketed antithrombotic drugs cannot be used in all patient populations There is a significant need for a drug that can provide antithrombotic benefit without an unacceptable bleeding risk 8 8

9 Current Anticoagulants Parenteral Heparin LMWH Fondaparinux Bivalirudin Oral Warfarin Dabigatran Rivaroxaban Apixaban Therapeutic Options for Treatment & Prevention of Thrombosis 9

10 Limitations of Current Anticoagulants 10 Limitations of current anticoagulants:  Despite the benefit of existing anticoagulants, there is a risk of bleeding with therapeutic use Limits ability to give an effective dose in patients at higher risk of bleeding  Drug-drug interactions  Warfarin and heparin require routine monitoring  Anticoagulants are discontinued prior to surgical procedures, which can place patients at risk of thrombosis These limitations limit the use of current anticoagulants in a variety of different therapeutic settings, including  Patients with atrial fibrillation and high risk of bleeding (e.g., atrial fibrillation in patients with coronary disease and end-stage kidney disease)  Prevention of secondary events in patients with cardiac diseases Prevention of recurrent ischemia in stabilized acute coronary syndrome patients Mechanical heart valves

11 Factor XI is a Genetically Validated Target in Humans Factor XI contributes to thrombosis in humans  Humans with Factor XI levels in the upper 10% have an increased risk of venous and arterial thrombosis 1,2  Humans with elevated Factor XI levels have a higher incidence of stroke 3  Humans with lower levels of Factor XI have a decreased incidence of venous thrombosis 4 Deficiency of Factor XI in humans is not associated with spontaneous bleeding 5 In animal models, Factor XI deficiency or inhibition is associated with attenuated thrombosis without increased bleeding 6, Meijers et al. (2000) NEJM. 342, Doggen et al. (2006) Blood. 108, Siegerink et al. (2014) J Thromb Haemost. 12, Salomon et al. (2011) J Thromb Haemost. 105, Duga, S. & Salomon, O. (2013) Semin Thromb Hemost. 39, van Montfoort et al. (2014) Arterioscler Thromb Vasc Biol. 34, Zhang et al. (2010) Blood. 116,

12 Platelet Activated Platelet Vascular Injury (TF/Collagen Exposure VII VIIa X Xa Prothrombin Thrombin Fibrinogen Fibrin Polymer Extrinsic Pathway XII XIIa XI XIa IX IXa VIII VIIIa X Intrinsic Pathway Collagen / Tissue Factor Endothelium ISIS-FXI Rx Inhibiting Factor XI Activity Reduces Clot Propagation, but NOT Clot Initiation Therefore, Risk of Bleeding is Low Common Pathway 12

13 Antisense Inhibition of Factor XI in Mice Reduces Thrombosis Without Increased Bleeding Factor Xl Antisense FXI Antisense (mg/kg) Thrombosis (normalized) Tail Bleeding (Blood/grams) Thrombosis Bleeding Apixaban (FXa inhibitor) Apixaban (mg/kg) Thrombosis Bleeding Thrombosis Bleeding Warfarin Warfarin (mg/kg) Thrombosis (normalized) Tail Bleeding (Blood/grams) Thrombosis (normalized) Tail Bleeding (Blood/grams) 13

14 Phase 1 Study: ISIS-FXI Rx Produced Dose-dependent and Sustained Reductions in Factor XI Activity in Healthy Subjects 14 ISIS-FXI Rx -treated subjects had no increase in spontaneous bleeding compared with placebo-treated subjects 14

15 ISIS-FXI Rx : A Promising New Therapeutic Approach for Thrombosis 15 High unmet medical need for safer antithrombotic agents  Lack of clear dissociation between antithrombotic effect and bleeding risk, drug-drug interactions and other issues limit the use of current anticoagulants in various therapeutic settings Inhibition of Factor XI may provide, for the first time, the ability to dissociate the antithrombotic effect from bleeding risk  Genetic validation in humans with FXI deficiency  Preclinical data demonstrated that Factor XI reduction is associated with decreased thrombosis without increased bleeding  Clinical data with a second generation antisense inhibitor of Factor XI, ISIS-FXI Rx, demonstrated reduction in thrombosis without increased bleeding after surgery ■ First FXI inhibitor to reduce thrombosis in patients

16 ISIS-FXI Rx Phase 2 Clinical Data Dr. Harry Büller Professor of Medicine Dept. of Vascular Medicine Academic Medical Center The Netherlands 16

17 Factor XI Antisense Oligonucleotide for Prevention of Venous Thrombosis Harry R. Büller, M.D., Claudette Bethune,Ph.D., Sanjay Bhanot, M.D., Ph.D, David Gailani, M.D., Brett P. Monia, Ph.D.,Gary E. Raskob, Ph.D., Annelise Segers, M.D., Peter Verhamme, M.D., and Jeffrey I. Weitz, M.D. Published online on December 7, 2014 at 17

18 ISIS-FXI Rx Phase 2 Study Six-week Study in Total Knee Replacement Open-label, randomized, active comparator-controlled study in ~300 patients undergoing knee replacement surgery Objectives  Compare the effects of ISIS-FXI Rx and enoxaparin on incidence of venous thromboembolism (VTE) and bleeding  Evaluate other safety outcomes and tolerability of ISIS-FXI Rx Outcomes  VTEs assessed by blinded independent adjudication committee  Bleeding events assessed by blinded independent adjudication committee 18

19 19 ISIS-FXI Rx Phase 2 TKA Study Schema 19 *ISIS = ISIS-FXI Rx *

20 There were no clinically important differences among treatment groups in any of the listed characteristics ISIS-FXI Rx Phase 2 TKA Study – Clinical Characteristics Enoxaparin 40 mg (n =72) ISIS-FXI Rx 200 mg (n = 144) ISIS-FXI Rx 300 mg (n = 77) Mean age – yr64 ± 963 ± 963 ± 8 Female – no. (%)60 (83%)118 (82%)60 (78%) Mean Weight, kg (range)87 (52, 132)89 (52,124)90 (52,130) Creatinine clearance (ml/min)111 ± ± ± 30 Mean factor XI activity (units/ml) 1.23 ± ± ±

21 ISIS-FXI Rx Phase 2 TKA Study – Patient Disposition Did not receive drug (3) Randomized n= mg n= mg n= mg enoxaparin n= 75 Safety analysis n= 144 Safety analysis n= 77 Safety analysis n= 72 PP Efficacy Population n= 134 PP Efficacy Population n= 71 PP Efficacy Population n= 69 No venography (2) Non-evaluable exam (3) Venography not performed in time (5) Did not receive drug (1) No venography (4) Non-evaluable exam (2) Did not receive drug (3) No venography (1) Venography not performed in time (2) 21

22 Treatment With ISIS-FXI Rx Produced Dose-dependent and Sustained Decrease in Factor XI Activity 22 ISIS-FXI Rx Tx Enox Tx Surgery (day 36)

23 Primary Efficacy Outcome: Reduction in Incidence of VTE Observed in ISIS-FXI Rx -treated Patients Compared to Enoxaparin-treated Patients VTE incidence for enoxaparin-treated patients was within the range reported in previous studies in this patient population % 26.9% 4.2% p<0.001

24 Secondary Efficacy Outcome: Reduction in Components of Deep Vein Thrombosis Enoxaparin 40 mg (n=69) ISIS-FXI Rx 200 mg (n=134) ISIS-FXI Rx 300 mg (n=71) COMPONENTS Symptomatic VTE – no. (%)1 (1.4)2 (1.5)0 Asymptomatic DVT – no. (%)20 (29.0)34 (25.4)3 (4.2) Proximal DVT– no. (%)4 (5.8)7 (5.2)1 (1.4) Distal DVT – no. (%)17 (24.6)29 (21.6)2 (2.8) 24

25 Enoxaparin 40 mg (n=69) ISIS-FXI Rx 200 mg (n=134) ISIS-FXI Rx 300 mg (n=71) Extent of DVT Total # of DVT / # patients 21/69 36/134 3/71 Bilateral 220 Confluent distal into proximal 260 Isolated proximal, large 100 Isolated proximal, small 001 Isolated distal, extensive 7160 Isolated distal, limited 9122 Less Extensive Thrombi in ISIS-FXI Rx -treated Patients Compared with Enoxaparin-treated Patients 25

26 Incidence of Clinically Relevant Bleeding Events in ISIS-FXI Rx - treated Patients Compared to Enoxaparin-treated Patients % 2.8% 2.6%

27 Incidence of Clinically Relevant Bleeding Events in ISIS-FXI Rx - treated Patients Compared to Enoxaparin-treated Patients Enoxaparin 40 mg (n=72) ISIS-FXI Rx 200 mg (n=144) ISIS-FXI Rx 300 mg (n=77) Major or Clinically Relevant Non-major (CRNM) Bleeding no. (%) 6 (8.3)4 (2.8)2 (2.6) Major Bleeding– no. (%)0 (0) 1 (1.3)* CRNM bleeding– no. (%)6 (8.3)4 (2.8)1 (1.3) Patients given blood transfusion – no. (%) 23 (31.9)55 (38.2)22 (28.6) 27 *Surgical site hematoma requiring drainage

28 ISIS-FXI Rx : Safety and Tolerability in Phase 2 Study Was Equivalent to Enoxaparin Safety ISIS-FXI Rx -treated patients had numerically lower incidence of clinically relevant bleeding events compared with enoxaparin No drug-related SAEs No observed differences in other safety outcomes compared with enoxaparin group Tolerability Well tolerated No flu-like symptoms The most common adverse event was infrequent (6.6%), mild injection site reactions 28

29 ISIS-FXI Rx : Conclusions from Phase 2 TKA Study Robust and sustained decrease in Factor XI activity in patients treated with ISIS-FXI Rx Substantially reduced incidence of VTE in patients treated with ISIS- FXI Rx compared with enoxaparin treatment  7-fold lower incidence of VTE in patients treated with 300 mg ISIS- FXI Rx compared with enoxaparin-treated patients Numerically fewer bleeding events in ISIS-FXI Rx -treated patients than with enoxaparin treatment  Clear dissociation between thrombosis and bleeding for the first time  Enoxaparin efficacy and bleeding rates were within expected ranges in this patient population Safety and tolerability profile supportive of continued clinical development 29

30 Therapeutic Opportunity for ISIS-FXI Rx Dr. Jeffrey Weitz Professor of Medicine and Biochemistry, McMaster University 30

31 Results from Approved Anticoagulant Therapies Evaluated in Phase 3 TKA Studies 31 Drug Eliquis 1 (apixaban) Xarelto 2 (rivaroxaban) Pradaxa 3 (dabigatran) Dosing 2.5mg oral bid10mg oral daily150mg oral daily Rates of VTE and all cause death 15.1%9.6%40.5% Fold reduction in rates of all VTE and all cause death vs. Enoxaparin Rates of Major/CRNM bleeding 3.5%3.3%8.1% Fold reduction in Major/CRNM bleeding vs. Enoxaparin ,2,3 – Phase 3 studies selected based on similar patient population and study design: [1] Lancet Mar 6;375(9717): [2] N Engl J Med Jun 26;358(26): [3] J Thromb Haemost Nov;5(11):

32 Results From ISIS-FXI Rx Phase 2 Study – Lowest Reported VTE Incidence And 7-fold Reduction vs. Enoxaparin Drug ISIS-FXI Rx (phase 2) enoxaparin* Dosing 300mg sub-q weekly40mg sub-q daily Rates of VTE and all cause death 4.2%30.4% Fold reduction in rates of all VTE and all cause death vs. Enoxaparin 7.0N/A Rates of Major/CRNM bleeding 2.6% ‡ 8.3% ‡ Fold reduction in Major/CRNM bleeding vs. Enoxaparin 2.7 ‡ N/A *Enoxaparin results in ISIS-FXI Rx Phase 2 study were consistent with previously published data for enoxaparin in this population 32 ‡ Safety Set for time period from first study drug administration to end of study

33 ISIS-FXI Rx : Data to Date Suggest Potential For Best-in-Class Profile for a Novel Anticoagulant Drug Arterial Thombosis Venous Thombosis Low Bleeding Risk No Drug-drug Interactions No Routine Monitoring Antidote Available ISIS-FXI Rx Yes Warfarin Yes No Yes Heparin Yes NoYesNoYes Factor Xa Inhibitors NoYesNo YesNo Thrombin Inhibitors NoYesNo YesNo Efficacy ParametersSafety Parameters 33 Potential to stay on ISIS-FXI Rx during surgical procedure

34 Potential Indications for ISIS-FXI Rx Initial focus on patients with highest unmet need in therapeutic settings in which current anticoagulants are not used and relatively small studies can be conducted  Patients at high risk for thrombosis and high risk of bleeding (e.g., patients with atrial fibrillation and end-stage kidney disease) Subsequently move into broader indications in which drug profile provides a competitive advantage  Long-term focus: prevention of secondary events in patients with cardiac diseases ■ Prevention of recurrent ischemia in stabilized acute coronary syndrome patients ■ Patients with mechanical heart valves 34

35 Initial Potential Indications for ISIS-FXI Rx Patients with Atrial Fibrillation and End-Stage Renal Disease Atrial fibrillation is an attractive opportunity but comparisons with new anticoagulants would require large trials  AF population with ESRD is a potential “high risk” population that could benefit from reduction in stroke, CV events and access site thrombosis  At least 15% of ESRD patients (~130K) have AF; 25% of strokes in ESRD patients are AF-related and cardiovascular events are the major cause of death 35

36 Long-term Potential Indications for ISIS-FXI Rx Patients with Cardiac Disease Prevention of secondary events in patients with cardiac diseases remains a key long-term potential indication  Coronary syndrome  Atrial fibrillation  Mechanical heart valves For long term prophylaxis, these populations represent a large unmet need, especially since most of the novel oral anticoagulants are not approved in the United States 36

37 ISIS-FXI Rx : Phase 2 Data Support a Potential Breakthrough Therapeutic Opportunity for Thrombosis Lowest reported incidence of VTE and 7-fold reduction vs. enoxaparin in total knee replacement surgery  Without prophylaxis, patients undergoing knee anthroplasty are at high risk for postoperative venous thromboembolism These results support a potential best-in-class profile for a novel anticoagulant Potential in wide array of therapeutic settings where other anticoagulants are not currently used  Atrial fibrillation in patients with end-stage kidney disease  Prevention of secondary events in patients with cardiac diseases ■ Prevention of coronary syndrome ■ Mechanical heart valves 37

38 Next Steps Dr. Sanjay Bhanot VP Clinical Development & Translational Medicine Isis Pharmaceuticals 38

39 Next Steps For ISIS-FXI Rx Program Additional Phase 2 studies planned to further enhance the profile of ISIS-FXI Rx and evaluate potential in populations with greatest unmet need Initial opportunities in areas with a high unmet need in which relatively small studies can be conducted  Atrial fibrillation patients with end-stage kidney disease  Long-term treatment of recurrent VTE Identify best partner for later stage development and commercialization 39

40 Closing Remarks Stan Crooke, M.D., Ph.D. CEO and Chairman, Isis Pharmaceuticals 40

41 Significant Commercial Opportunity for a Safer, More Effective Antithrombotic Despite the benefit of existing anticoagulants, numerous patient settings still require a safer and more effective anticoagulant for chronic use  Potentially unacceptable bleeding risk exists at therapeutically active doses – limits use in a number of patient populations  Routine monitoring is required for heparin and warfarin and no antidote available  Drug-drug interactions are a problem—and many of these patients are taking multiple drugs  Need to discontinue prior to medical procedures to avoid increased bleeding Inhibiting Factor XI activity with ISIS-FXI Rx may address the limitations of current antithrombotic agents, especially in chronic settings 41

42 ISIS-FXI Rx : Potential for An Optimal Antithrombotic Profile Inhibition of Factor XI may provide, for the first time, the ability to dissociate the antithrombotic effect of a drug from bleeding risk  Genetic validation in humans with FXI deficiency showing decreased clotting without increased bleeding  Preclinical data has demonstrated that Factor XI reduction is associated with decreased thrombosis without increased bleeding  Clinical data with ISIS-FXI Rx demonstrated decreased thrombosis without increased bleeding after surgery ■ First FXI inhibitor to decrease thrombosis in patients 42

43 ISIS-FXI Rx : Potential for Significant Commercial Opportunity Significant initial indications in markets where current agents are not approved or have limited use  Patients with atrial fibrillation (AF) at high risk ■ AF patients with end-stage kidney disease ■ AF patients with coronary disease Larger long-term opportunities in broader antithrombotic indications  Prevention of secondary cardiovascular events ■ Prevention of recurrent ischemia in stabilized acute coronary syndrome patients ■ Atrial fibrillation ■ Mechanical heart valves 43

44 ISIS-FXI Rx has the potential to be a breakthrough therapy despite existing anticoagulants ISIS-FXI Rx is a significant licensing opportunity with high partner interest Scientific community enthusiastic with ISIS-FXI Rx  Featured in ASH press briefing (Dec. 7)  Simultaneous NEJM publication (published online Dec. 7, 2014)  ASH Late-breaker presentation (Dec. 9, 7:30 to 9:00 AM PST) ISIS-FXI Rx – Clinical Observations To Date Support Advancement into Phase 3 Development 44

45 Q&A Dr. Stan Crooke CEO and Chairman Isis Pharmaceuticals Dr. Jeffrey Weitz Professor of Medicine and Biochemistry, McMaster University Dr. Harry Büller Professor of Medicine Dept. of Vascular Medicine Academic Medical Center The Netherlands Dr. Sanjay Bhanot VP Clinical Development & Translational Medicine Isis Pharmaceuticals 45


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