1. ISIS PHARMACEUTICALS ISIS-FXIRx Program Update Webcast
December 8, 2014

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

3. Forward Looking Language Statement
This presentation includes forward-looking statements regarding the discovery, development, activity, therapeutic and commercial potential and safety of ISIS-FXIRx 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. 3

4. Participants Dr. Jeffrey Weitz
Professor of Medicine and Biochemistry, McMaster University
Dr. Stan Crooke
CEO and Chairman
Isis Pharmaceuticals
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. Describe ongoing and planned studies
Purpose of Today’s Meeting ISIS-FXIRx: A Potential Breakthrough for Preventing and Treating Thrombosis
Discuss the ISIS-FXIRx Phase 2 Total Knee Arthroplasty (TKA) Study Data
Review the unmet medical needs and therapeutic potential for ISIS-FXIRx
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-FXIRx Phase 2 Clinical Data
Dr. Harry Büller, Professor of Medicine, Dept. of Vascular Medicine, Academic Medical Center, The Netherlands
ISIS-FXIRx 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 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

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

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 10

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 thrombosis1,2
Humans with elevated Factor XI levels have a higher incidence of stroke3
Humans with lower levels of Factor XI have a decreased incidence of venous thrombosis4
Deficiency of Factor XI in humans is not associated with spontaneous bleeding5
In animal models, Factor XI deficiency or inhibition is associated with attenuated thrombosis without increased bleeding6,7
1Meijers 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, 11

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

13. Apixaban (FXa inhibitor)
Antisense Inhibition of Factor XI in Mice Reduces Thrombosis Without Increased Bleeding
Thrombosis
Bleeding
Warfarin 40 80
120
160
0.5 1 2 3 4 5
Warfarin (mg/kg)
(normalized)
0.2
0.4
0.6
0.8
(Blood/grams)
Tail Bleeding
Apixaban (FXa inhibitor) 40 80
120
160
0.5 2 5 10 20
Apixaban (mg/kg)
0.2
0.4
0.6
0.8
Thrombosis
Bleeding
Thrombosis
(normalized)
(Blood/grams)
Tail Bleeding
Factor Xl Antisense 40 80
120
160
1.25
2.5 5 10 20
FXI Antisense (mg/kg)
Thrombosis
(normalized)
-0.2
0.2
0.4
0.6
0.8
Tail Bleeding
(Blood/grams)
Bleeding 13

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

15. ISIS-FXIRx: A Promising New Therapeutic Approach for Thrombosis
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-FXIRx, demonstrated reduction in thrombosis without increased bleeding after surgery
First FXI inhibitor to reduce thrombosis in patients 15

16. ISIS-FXIRx 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

18. ISIS-FXIRx 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-FXIRx and enoxaparin on incidence of venous thromboembolism (VTE) and bleeding
Evaluate other safety outcomes and tolerability of ISIS-FXIRx
Outcomes
VTEs assessed by blinded independent adjudication committee
Bleeding events assessed by blinded independent adjudication committee 18

19. ISIS-FXIRx Phase 2 TKA Study Schema*
*ISIS = ISIS-FXIRx 19

20. ISIS-FXIRx Phase 2 TKA Study – Clinical Characteristics
Enoxaparin 40 mg
(n =72)
ISIS-FXIRx
200 mg
(n = 144)
300 mg
(n = 77)
Mean age – yr
64 ± 9
63 ± 9
63 ± 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
112 ± 31
116 ± 30
Mean factor XI activity (units/ml)
1.23 ± 0.21
1.20 ± 0.20
1.16 ± 0.22
There were no clinically important differences among treatment groups in any of the listed characteristics 20

21. ISIS-FXIRx Phase 2 TKA Study – Patient Disposition
Randomized
n=300
200 mg
n= 147
300 mg
n= 78
40 mg enoxaparin
n= 75
Did not receive drug (3)
Did not receive drug (1)
Did not receive drug (3)
Safety analysis
n= 144
Safety analysis
n= 77
Safety analysis
n= 72
No venography (2)
Non-evaluable exam (3)
Venography not performed in time (5)
No venography (1)
Venography not performed in time (2)
No venography (4)
Non-evaluable exam (2)
PP Efficacy Population
n= 134
PP Efficacy Population
n= 71
PP Efficacy Population
n= 69 21

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

23. Primary Efficacy Outcome: Reduction in Incidence of VTE Observed in ISIS-FXIRx-treated Patients Compared to Enoxaparin-treated Patients
30.4%
26.9%
4.2%
p<0.001
VTE incidence for enoxaparin-treated patients was within the range reported in previous studies in this patient population 23

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

25. Less Extensive Thrombi in ISIS-FXIRx-treated Patients Compared with Enoxaparin-treated Patients
Enoxaparin
40 mg
(n=69)
ISIS-FXIRx
200 mg
(n=134)
300 mg
(n=71)
Extent of DVT
Total # of DVT / # patients
21/69
36/134
3/71
Bilateral 2
Confluent distal into proximal 6
Isolated proximal, large 1
Isolated proximal, small
Isolated distal, extensive 7 16
Isolated distal, limited 9 12 25

26. Incidence of Clinically Relevant Bleeding Events in ISIS-FXIRx-treated Patients Compared to Enoxaparin-treated Patients
8.3%
2.8%
2.6% 26

27. Incidence of Clinically Relevant Bleeding Events in ISIS-FXIRx-treated Patients Compared to Enoxaparin-treated Patients
Enoxaparin
40 mg
(n=72)
ISIS-FXIRx
200 mg
(n=144)
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. (%)
1 (1.3)
Patients given blood transfusion – no. (%)
23 (31.9)
55 (38.2)
22 (28.6)
*Surgical site hematoma requiring drainage 27

28. ISIS-FXIRx: Safety and Tolerability in Phase 2 Study Was Equivalent to Enoxaparin
ISIS-FXIRx-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-FXIRx: Conclusions from Phase 2 TKA Study
Robust and sustained decrease in Factor XI activity in patients treated with ISIS-FXIRx
Substantially reduced incidence of VTE in patients treated with ISIS- FXIRx compared with enoxaparin treatment
7-fold lower incidence of VTE in patients treated with 300 mg ISIS- FXIRx compared with enoxaparin-treated patients
Numerically fewer bleeding events in ISIS-FXIRx-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-FXIRx
Dr. Jeffrey Weitz
Professor of Medicine and Biochemistry, McMaster University 30

31. Results from Approved Anticoagulant Therapies Evaluated in Phase 3 TKA Studies
Drug
Eliquis1
(apixaban)
Xarelto2 (rivaroxaban)
Pradaxa3 (dabigatran)
Dosing
2.5mg oral bid
10mg oral daily
150mg 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
1.6
2.0
0.9
Rates of Major/CRNM bleeding
3.5%
3.3%
8.1%
Fold reduction in Major/CRNM bleeding vs. Enoxaparin
1.4
0.8
1,2,3 – 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): 31 31

32. Results From ISIS-FXIRx Phase 2 Study – Lowest Reported VTE Incidence And 7-fold Reduction vs. Enoxaparin
Drug
ISIS-FXIRx
(phase 2)
enoxaparin*
Dosing
300mg sub-q weekly
40mg 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
7.0
N/A
Rates of Major/CRNM bleeding
2.6% ‡
8.3% ‡
Fold reduction in Major/CRNM bleeding vs. Enoxaparin
2.7 ‡
‡Safety Set for time period from first study drug administration to end of study
*Enoxaparin results in ISIS-FXIRx Phase 2 study were consistent with previously published data for enoxaparin in this population 32

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

34. Potential Indications for ISIS-FXIRx
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-FXIRx 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-FXIRx 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-FXIRx: 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-FXIRx Program
Additional Phase 2 studies planned to further enhance the profile of ISIS-FXIRx 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. CEO and Chairman, Isis Pharmaceuticals
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-FXIRx may address the limitations of current antithrombotic agents, especially in chronic settings 41

42. ISIS-FXIRx: 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-FXIRx demonstrated decreased thrombosis without increased bleeding after surgery
First FXI inhibitor to decrease thrombosis in patients 42

43. ISIS-FXIRx: 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-FXIRx – Clinical Observations To Date Support Advancement into Phase 3 Development
ISIS-FXIRx has the potential to be a breakthrough therapy despite existing anticoagulants
ISIS-FXIRx is a significant licensing opportunity with high partner interest
Scientific community enthusiastic with ISIS-FXIRx
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) 44

45. Q&A
Dr. Jeffrey Weitz
Professor of Medicine and Biochemistry, McMaster University
Dr. Stan Crooke
CEO and Chairman
Isis Pharmaceuticals
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