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

ISIS-FXIRx Program Update

WebcastDecember 8, 2014

ISIS PHARMACEUTICALS

Introduction

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

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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.

Forward Looking Language Statement

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Participants

Dr. Stan Crooke

CEO and ChairmanIsis Pharmaceuticals

Dr. Jeffrey Weitz

Professor of Medicine and Biochemistry, McMaster University

Dr. Harry Büller

Professor of MedicineDept. of Vascular MedicineAcademic Medical CenterThe Netherlands

Dr. Sanjay Bhanot

VP Clinical Development & Translational MedicineIsis Pharmaceuticals

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Purpose of Today’s MeetingISIS-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

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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 Dr. Stan Crooke, CEO & Chairman, Isis Pharmaceuticals

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Why We Need Better Antithrombotic Drugs

Dr. Jeffrey Weitz


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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

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Current Anticoagulants

ParenteralHeparinLMWH

FondaparinuxBivalirudin

OralWarfarin

DabigatranRivaroxaban

Apixaban

Therapeutic Options for Treatment & Prevention of Thrombosis

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Limitations of Current Anticoagulants

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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

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

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1Meijers et al. (2000) NEJM. 342,696-701. 2Doggen et al. (2006) Blood. 108, 4045-4051. 3Siegerink et al. (2014) J Thromb Haemost. 12, 606-613. 4Salomon et al. (2011) J Thromb Haemost. 105, 269-273. 5Duga, S. & Salomon, O. (2013) Semin Thromb Hemost. 39, 621-631. 6van Montfoort et al. (2014) Arterioscler Thromb Vasc Biol. 34, 1668-1673. 7Zhang et al. (2010) Blood. 116, 4684-4692.

PlateletActivated Platelet

Vascular Injury(TF/Collagen Exposure

VII

VIIa

X Xa

ProthrombinThrombin

FibrinogenFibrin

Fibrin Polymer

Extrinsic Pathway

XII XIIa

XI XIa

IX IXa

VIII VIIIa X

IntrinsicPathway

Collagen / Tissue Factor

Endothelium

ISIS-FXIRx

Inhibiting Factor XI Activity Reduces Clot Propagation, but NOT Clot Initiation Therefore, Risk of Bleeding is Low

Common Pathway

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Antisense Inhibition of Factor XI in Mice Reduces Thrombosis Without Increased Bleeding

Factor Xl Antisense

0

40

80

120

160

1.25 2.5 5 10 20 40

FXI Antisense (mg/kg)

Th

rom

bo

sis

(n

orm

aliz

ed)

-0.2

0

0.2

0.4

0.6

0.8

Tail

Ble

edin

g(B

loo

d/g

ram

s)

Thrombosis Bleeding

Apixaban (FXa inhibitor)

0

40

80

120

160

0.5 2 5 10 20

Apixaban (mg/kg)

0

0.2

0.4

0.6

0.8Thrombosis Bleeding

Thrombosis Bleeding

Warfarin

0

40

80

120

160

0.5 1 2 3 4 5

Warfarin (mg/kg)

Th

rom

bo

sis

(n

orm

aliz

ed

)

0

0.2

0.4

0.6

0.8

Tail

Ble

ed

ing

(Blo

od

/gra

ms

)

Th

rom

bo

sis

(n

orm

aliz

ed

)

Tail

Ble

ed

ing

(Blo

od

/gra

ms

)

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Phase 1 Study: ISIS-FXIRx Produced Dose-dependent and Sustained Reductions in Factor XI Activity in Healthy Subjects

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ISIS-FXIRx-treated subjects had no increase in spontaneous bleeding compared with placebo-treated subjects

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ISIS-FXIRx: A Promising New Therapeutic Approach for Thrombosis

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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

ISIS-FXIRx Phase 2 Clinical Data

Dr. Harry Büller


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Factor XI Antisense Oligonucleotide for Prevention of Venous ThrombosisHarry 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 http://www.nejm.org/

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http://www.nejm.org/

ISIS-FXIRx Phase 2 StudySix-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

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ISIS-FXIRx Phase 2 TKA Study Schema

19*ISIS 416858 = ISIS-FXIRx

*

There were no clinically important differences among treatment groups in any of the listed characteristics

ISIS-FXIRx Phase 2 TKA Study – Clinical Characteristics

Enoxaparin 40 mg

(n =72)

ISIS-FXIRx

200 mg(n = 144)

ISIS-FXIRx

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

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ISIS-FXIRx Phase 2 TKA Study – Patient Disposition

• Did not receive drug (3)

Randomizedn=300

200 mgn= 147

300 mgn= 78

40 mg enoxaparinn= 75

Safety analysisn= 144



PP Efficacy Population

n= 134


n= 71


n= 69

• No venography (2)• Non-evaluable exam

(3)• Venography not

performed in time (5)


• No venography (4)• Non-evaluable exam

(2)


• No venography (1)• Venography not

performed in time (2)

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Treatment With ISIS-FXIRx Produced Dose-dependent and Sustained Decrease in Factor XI Activity

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ISIS-FXIRxTxEnox

Tx

Surgery (day 36)

Primary Efficacy Outcome: Reduction in Incidence of VTE Observed in ISIS-FXIRx-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 23

30.4%

26.9%

4.2%p<0.001

Secondary Efficacy Outcome: Reduction in Components of Deep Vein Thrombosis

Enoxaparin 40 mg(n=69)

ISIS-FXIRx

200 mg(n=134)

ISIS-FXIRx

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)

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Enoxaparin

40 mg(n=69)

ISIS-FXIRx 200 mg

(n=134)

ISIS-FXIRx

300 mg (n=71)

Extent of DVT

Total # of DVT / # patients

21/69

36/134

3/71

Bilateral 2 2 0

Confluent distal into proximal

2 6 0

Isolated proximal, large 1 0 0

Isolated proximal, small 0 0 1

Isolated distal, extensive 7 16 0

Isolated distal, limited 9 12 2

Less Extensive Thrombi in ISIS-FXIRx-treated Patients Compared with Enoxaparin-treated Patients

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Incidence of Clinically Relevant Bleeding Events in ISIS-FXIRx-treated Patients Compared to Enoxaparin-treated Patients

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8.3%

2.8% 2.6%

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)

ISIS-FXIRx

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) 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)

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*Surgical site hematoma requiring drainage

ISIS-FXIRx: Safety and Tolerability in Phase 2 Study Was Equivalent to Enoxaparin

Safety

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

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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

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Therapeutic Opportunity for ISIS-FXIRx

Dr. Jeffrey Weitz


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Results from Approved Anticoagulant Therapies Evaluated in Phase 3 TKA Studies

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DrugEliquis1

(apixaban)

Xarelto2 (rivaroxaba

n)

Pradaxa3 (dabigatra

n)

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

deathvs. 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. Enoxaparin1.4 0.8 0.8

1,2,3 – Phase 3 studies selected based on similar patient population and study design: [1] Lancet. 2010 Mar 6;375(9717):807-15. [2] N Engl J Med. 2008 Jun 26;358(26):2776-86 [3] J Thromb Haemost. 2007 Nov;5(11):2178-85. 31

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

deathvs. Enoxaparin

7.0 N/A

Rates of Major/CRNM bleeding 2.6% ‡ 8.3% ‡

Fold reduction in Major/CRNM bleeding

vs. Enoxaparin2.7 ‡ N/A

*Enoxaparin results in ISIS-FXIRx 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

ISIS-FXIRx: Data to Date Suggest Potential For Best-in-Class Profile for a Novel Anticoagulant

DrugArterial

ThombosisVenous

Thombosis

Low Bleeding

Risk

No Drug-drug

Interactions

No RoutineMonitoring

Antidote Available

ISIS-FXIRx Yes Yes Yes Yes Yes Yes

Warfarin Yes Yes No No No Yes

Heparin Yes Yes No Yes No Yes

Factor Xa Inhibitors No Yes No No Yes No

ThrombinInhibitors

No Yes No No Yes No

Efficacy Parameters Safety Parameters

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Potential to stay on ISIS-FXIRx during surgical procedure

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

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

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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

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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 valves37

Next Steps

Dr. Sanjay Bhanot


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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

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Closing Remarks

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

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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

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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

4242

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

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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)

ISIS-FXIRx – Clinical Observations To Date Support Advancement into Phase 3 Development

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Q&A

Dr. Stan Crooke

CEO and ChairmanIsis Pharmaceuticals

Dr. Jeffrey Weitz


Dr. Harry Büller


Dr. Sanjay Bhanot


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Documents

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