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ISIS-FXIRx Program Update
WebcastDecember 8, 2014
ISIS PHARMACEUTICALS
Introduction
Stan Crooke, M.D., Ph.D.CEO and Chairman, Isis Pharmaceuticals
2
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
3
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
4
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
5
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
6
Why We Need Better Antithrombotic Drugs
Dr. Jeffrey Weitz
Professor of Medicine and Biochemistry, McMaster University
7
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
Current Anticoagulants
ParenteralHeparinLMWH
FondaparinuxBivalirudin
OralWarfarin
DabigatranRivaroxaban
Apixaban
Therapeutic Options for Treatment & Prevention of Thrombosis
9
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
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
11
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
12
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
)
13
Phase 1 Study: ISIS-FXIRx Produced Dose-dependent and Sustained Reductions in Factor XI Activity in Healthy Subjects
14
ISIS-FXIRx-treated subjects had no increase in spontaneous bleeding compared with placebo-treated subjects
14
ISIS-FXIRx: 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-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
Professor of MedicineDept. of Vascular MedicineAcademic Medical CenterThe Netherlands
16
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/
17
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
18
19
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
20
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
Safety analysisn= 77
Safety analysisn= 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
Treatment With ISIS-FXIRx Produced Dose-dependent and Sustained Decrease in Factor XI Activity
22
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)
24
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
25
Incidence of Clinically Relevant Bleeding Events in ISIS-FXIRx-treated Patients Compared to Enoxaparin-treated Patients
26
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)
27
*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
2828
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
Therapeutic Opportunity for ISIS-FXIRx
Dr. Jeffrey Weitz
Professor of Medicine and Biochemistry, McMaster University
30
Results from Approved Anticoagulant Therapies Evaluated in Phase 3 TKA Studies
31
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
33
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
35
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
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
VP Clinical Development & Translational MedicineIsis Pharmaceuticals
38
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
Closing Remarks
Stan Crooke, M.D., Ph.D.CEO and Chairman, Isis Pharmaceuticals
40
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
4141
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
4343
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
44
Q&A
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
45
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