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31ST Annual J.P. Morgan Healthcare Conference Stanley T. Crooke, M.D., Ph.D. Chairman of the Board & Chief Executive Officer January 9, 2013
ISIS PHARMACEUTICALS
This presentation includes forward-looking statements regarding Isis Pharmaceuticals’ financial position and outlook, Isis’ business, and the therapeutic and commercial potential of Isis’ technologies and products in development. Any statement describing Isis’ goals, expectations, financial or other projections, intentions or beliefs, including the planned commercialization of KYNAMRO, 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, 2011 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 press release, unless the context requires otherwise, “Isis,” “Company,” “we,” “our,” and “us” refers to Isis Pharmaceuticals and its subsidiaries.
Isis Pharmaceuticals® is a registered trademark of Isis Pharmaceuticals, Inc. Regulus Therapeutics™ is a trademark of Regulus Therapeutics Inc. KYNAMRO™ is a trademark of Genzyme Corporation.
Forward Looking Language Statement
2
Kynamro: Commercialization on the Horizon
Maturing Pipeline Five drugs with launch potential in next five years Nine drugs with Phase 2 or Phase 3 data planned for 2013/early 2014 Two to three Phase 3 programs planned to initiate in 2013/early 2014
Expanding Pipeline Three new drugs in development Growing severe and rare disease program
Antisense Advances Generation 2.0 drugs more potent and better tolerated Generation 2.5 drugs significantly more potent than Generation 2.0
Partnering Success: Significant Interest Continues
2013 Goals
Overview Key Messages
3
Initiated third alliance with Biogen Idec in 2012 – total potential value ~$1.2B Extensive experience in neurology and drug development allows expansion of Isis’
severe disease pipeline
Initiated broad cancer research and development alliance with AstraZeneca worth ~ $1B Significant experience in cancer and broad collaborations allows expansion of Isis’
cancer pipeline
Amended and accelerated ISIS-TTRRx clinical path with GSK TTR Phase 3 program ready to start Fast Track designation for ISIS-TTRRx
Positive clinical data on four drugs ISIS-SMNRx, ISIS-PTP1BRx, ISIS-GCGRRx, ISIS-GCCRRx
Expanded pipeline with three new drugs (28 total) ISIS-PKKRx, ISIS-GSK3Rx, ISIS-AZ1Rx
Successful End for 2012 A Very Busy December
4
Isis’ Clinical-Stage Pipeline January 2013
5
Pipeline Key Indication Drugs Partner Phase I Phase II Phase III Reg & Comm
Cardiovascular Severe HeFHCADCAD
Clotting DisordersSevere & Rare CMV Retinitis
PouchitisHomozygous FHTTR Amyloidosis
Spinal Muscular Atrophy Severe HTGAcromegaly
Cushing's SyndromeMetabolic Diabetes
DiabetesDiabetesObesity
Cancer CancerCancerCancerCancer
Inflammation Inflammation& Other MS
Local FibrosisOcular Disease
Severe Bacterial Infection
ISIS-FXIRx
OGX-011ISIS-EIF4ERx
OGX-427
ISIS-STAT3Rx
ATL1102EXC 001iCo-007
Plazomicin
ISIS-SMNRx
ATL1103
ISIS-FGFR4Rx
ISIS-GCCRRx
ISIS-GCGRRx
ISIS-PTP1BRx
ISIS-TTRRx
KYNAMROTM
ISIS-APOCIIIRx
Vitravene®Alicaforsen
ISIS-CRPRx
ISIS-CRPRx
KYNAMROTM
ISIS-APOCIIIRx
ISIS-GCCRRx
*Named Patient Supply
Isis’ Clinical-Stage Pipeline Isis Wholly Owned Programs
6
Pipeline Key Indication Drugs Partner Phase I Phase II Phase III Reg & Comm
Cardiovascular Severe HeFHCADCAD
Clotting DisordersSevere & Rare CMV Retinitis
PouchitisHomozygous FHTTR Amyloidosis
Spinal Muscular Atrophy Severe HTGAcromegaly
Cushing's SyndromeMetabolic Diabetes
DiabetesDiabetesObesity
Cancer CancerCancerCancerCancer
Inflammation Inflammation& Other MS
Local FibrosisOcular Disease
Severe Bacterial Infection
ISIS-FXIRx
OGX-011ISIS-EIF4ERx
OGX-427
ISIS-STAT3Rx
ATL1102EXC 001iCo-007
Plazomicin
ISIS-SMNRx
ATL1103
ISIS-FGFR4Rx
ISIS-GCCRRx
ISIS-GCGRRx
ISIS-PTP1BRx
ISIS-TTRRx
KYNAMROTM
ISIS-APOCIIIRx
Vitravene®Alicaforsen
ISIS-CRPRx
ISIS-CRPRx
KYNAMROTM
ISIS-APOCIIIRx
ISIS-GCCRRx
Isis’ Pre-clinical Stage Pipeline January 2013
7
Pipeline Key Indication Drugs Preclinical Phase I Phase II Phase III Reg & Comm
Cardiovascular CADClotting Disorders
Severe & Rare AAT Liver DiseaseHereditary Angioedema
Metabolic NASHCancer Cancer
Inflammation Anemia of Inflammation& Other Antiviral
ISIS-APOARx
ISIS-FVIIRx
ISIS-AATRx
ISIS-DGAT2Rx
XEN701
ISIS-GSK3Rx
ISIS-AZ1Rx
ISIS-PKKRx
Pipeline Key Indication Drugs Preclinical Phase I Phase II Phase III Reg & Comm
Cardiovascular CADClotting Disorders
Severe & Rare AAT Liver DiseaseHereditary Angioedema
Metabolic NASHCancer Cancer
Inflammation Anemia of Inflammation& Other Antiviral
ISIS-APOARx
ISIS-FVIIRx
ISIS-AATRx
ISIS-DGAT2Rx
XEN701
ISIS-GSK3Rx
ISIS-AZ1Rx
ISIS-PKKRx
Isis’ Pre-clinical Stage Pipeline January 2013
8
New Development Candidates
Pipeline Key Indication Drugs Preclinical Phase I Phase II Phase III Reg & Comm
Cardiovascular CADClotting Disorders
Severe & Rare AAT Liver DiseaseHereditary Angioedema
Metabolic NASHCancer Cancer
Inflammation Anemia of Inflammation& Other Antiviral
ISIS-APOARx
ISIS-FVIIRx
ISIS-AATRx
ISIS-DGAT2Rx
XEN701
ISIS-GSK3Rx
ISIS-AZ1Rx
ISIS-PKKRx
Isis’ Pre-clinical Stage Pipeline Isis Wholly-owned Programs
9
FDA Advisory Committee recommended approval — Jan 29 PDUFA date
Preparing for commercial launch Focus on improving disease awareness and treatment of homozygous
FH patients
Re-examination of CHMP opinion requested by Genzyme; anticipate new opinion in 2Q 2013
Investing in the future – FOCUS FH study in severe FH patients ongoing (under SPA); projected completion in 2014
KYNAMROTM (mipomersen sodium) On the Threshold of Commercialization
10
Potential Drug Launches Through 2017
Drug Indication/Market Economics
ISIS-TTRRx
Familial Amyloid Polyneuropathy (FAP) ~10,000 patients
License fee, sales milestone payments and double-digit royalties
ISIS-SMNRx Spinal muscular atrophy (SMA) ~35,000 patients worldwide
License fee, milestone payments and double-digit royalties
ISIS-APOCIIIRx
Severe triglyceridemia (>880 mg/dL) at increased risk of recurrent pancreatitis ~200,000 patients in US & EU
Isis Owned
OGX-011 Castration-resistant prostate cancer (1st line) ~315,000 patients in US/EU
Milestone payments and single-digit royalties
EXC 001 Anti-scarring treatment estimated to be multibillion dollar market
Milestone and other payments and single-digit royalties
11
ISIS-TTRRx for Transthyretin (TTR) Amyloidosis A Fatal Genetic Disease Affecting ~50K Patients Worldwide
12
Partnered with:
Amyloid
Image from Benson MD, Kincaid JC. The molecular biology and clinical features of amyloid neuropathy. Muscle Nerve. 2007;36:411-423.
TTR amyloidosis is a rare genetic disease that results in progressive neurodegeneration and death TTR mutations cause the tetrameric TTR protein to be unstable TTR monomers accumulate, creating plaques in peripheral nerves, heart & other organs
as amyloid deposits, causing cell death Familial Amyloid Polyneuropathy (FAP) with ~10K patients worldwide
Age of onset : 30-50 years Life expectancy after diagnosis: 9-11 years
Familial Amyloid Cardiomyopathy (FAC) with ~40K patients worldwide Age of onset: 60-70 years Life expectancy after diagnosis: 5-6 years
Treatment options are limited. Liver transplant is the most
common treatment
ISIS-TTRRx: Phase 1 Healthy Volunteers Dose-Dependent Prolonged Reduction of Plasma TTR
13
ISIS-TTRRx produced robust and highly statistically significant reductions in TTR levels with good tolerability Sustained reductions in TTR with many subjects achieving >80%
reduction (several subjects reaching undetectable levels) at highest doses No SAEs, no clinically significant increases in liver enzymes or other
lab chemistries Very low
incidence of flu-like symptoms and mild injection site reactions
Partnered with:
ISIS-TTRRx Phase 3 Program Ready to Initiate
14
Randomized Double-blind Placebo-controlled Phase 2/3 Study in Patients with Familial Amyloid Polyneuropathy
Approximately 200 FAP patients at about 20 global sites to receive 300 mg ISIS-TTRRx or placebo (2:1)
Study Objectives
Evaluate efficacy of ISIS-TTRRx as measured by neurological dysfunction and quality of life
Data planned for 2015
Screening & Baseline
Assessments
Post-Treatment f/u Period
6 months R 2:1
1 month
End of Treatment Efficacy
Assessments
Treatment Period
15 months
s.c. dosing (D1, D3, D5) followed by once weekly s.c. dosing
Partnered with:
Potential regulatory filing and commercial launch within the next five years
Initial focus in patients with FAP
Possibility for orphan pricing
Potential “best in class” treatment for all forms of TTR amyloidosis
Reduces all forms of TTR (mutant & normal)
Convenient once-weekly, at-home, self-administered s.c. dosing
Development plan for cardiomyopathy in process
Attractive economics
$80M in upfront payments and pre-licensing milestones
License fee, regulatory and sales milestones
Double-digit royalties
ISIS-TTRRx Rapid Path to Market
15
Partnered with:
ISIS-SMNRx for Spinal Muscular Atrophy (SMA) Severe Genetic Neuromuscular Disease Affecting Children
16
SMA is a rare disease that affects approximately 30-35K children in United States, Europe and Japan
Number one genetic cause of death in infants
Characterized by progressive muscle atrophy and loss of motor function
Caused by genetic defects in the SMN1 gene that result in the lack of functional SMN protein
No currently approved therapies for SMA
Partnered with:
ISIS-SMNRx Modulating RNA Processing to Positively Impact Disease
A related gene, SMN2, normally produces only a small amount of functional SMN protein because of inappropriate RNA processing
ISIS-SMNRx increases the production of functional SMN protein by promoting appropriate RNA processing
Partnered with:
17
SMN-2 Gene
1 2 3 4 5 6 8 SMN-2 mRNA
1 2 3 4 5 6 7 8
C to T
ISIS-SMNRx keeps exon 7 in the RNA and leads to the production of functional SMN protein.
7
ASO
SMN-2 Gene
5 1 2 3 4 6 8 SMN-2 mRNA
1 2 3 4 5 6 7 8
C to T
SMN2 gene does not normally produce enough SMN protein to compensate for loss of SMN1 gene in patients with SMA. Splicing mechanism removes exon 7 resulting
in a shortened defective SMN protein.
ISIS-SMNRx Phase 1 Single-Dose Study in SMA Patients (Dosing Completed)
18
Open-label, single-dose study to evaluate the safety and tolerability of ISIS-SMNRx in SMA patients 2-14 years of age
Intrathecal dosing was well tolerated
Feasibility of infrequent dosing demonstrated
Improvements in muscle function observed in a number of children
Abstract accepted for a special presentation at the American Academy of Neurology meeting in March 2013
Screening (≤28 days)
Post-Treatment In-Patient f/u Period
Day 1 Single Dose
24 hours Open Label
•4 weeks post dose (1 mg & 3 mg) •12 weeks post dose (6 mg & 9 mg)
Post-Treatment Evaluation Period
Cohorts n
1 mg 6
3 mg 6
6 mg 6
9 mg 10
Partnered with:
ISIS-SMNRx Phase 1b/2a Multiple-Dose Study in SMA Patients (Ongoing)
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Open-label, intrathecal, dose escalation study in SMA patients 2-15 years of age
Objectives Evaluate the safety and tolerability of multiple doses of ISIS-SMNRx Evaluate biomarkers and clinical outcomes related to SMA Determine dose and dose interval for Phase 3 study Determine appropriate Phase 3 endpoints
Data planned for late 2013/early 2014
Screening (≤28 days)
Post-Treatment In-Patient f/u Period
Day 1 Dose
3 mg, 6 mg, 9mg cohorts
24 hours Open Label
Cohorts n
3 mg 8
6 mg 8
9 mg 8 Day 29 f/u & Dose
3 mg & 6 mg cohorts
Day 85 f/u & Dose
3 mg, 6 mg, 9mg cohorts
24 weeks
Post-Treatment f/u Period
19
Partnered with:
ISIS-SMNRx Rapid Path to Market
20
Potential regulatory filing and commercial launch within the next five years
Granted Orphan Drug Status in US and EU and Fast Track Designation in US
Two pivotal studies planned to start in 2013/early 2014
Infant onset Phase 2/3 study
Childhood onset Phase 2/3 study
Attractive economics
$74M in upfront payment and pre-licensing milestones
$225M in license fee and milestone payments
Double-digit royalties
Partnered with:
ISIS-APOCIIIRx for Severe Hypertriglyceridemia An Isis-owned Rare-disease Opportunity
21
More than 200K patients in US and EU with severe hypertriglyceridemia (HTG) (triglycerides of >880 mg/dL)
Significant risk of developing recurring pancreatitis, often requiring multiple hospitalizations and may require surgery
High risk for cardiovascular disease
Standard therapies, including niacin, fibrates and fish oil are inadequate
Potential for broader utility in cardiovascular disease and metabolic syndrome, including diabetes
ISIS-APOCIIIRx Phase 1 in Healthy Volunteers Dose-Dependent Reduction in Fasting and Diet-Induced Triglycerides
* * * Fasting TGs increase due to high-fat diet
22
Safety Summary No SAEs, no clinically significant increases in liver
enzymes or other lab chemistries
No flu-like symptoms and very low incidence of mild injection site reactions
Screening &
Diet Run-in
Post-Treatment f/u Period
12 weeks R
Treatment Period 13 Weeks
ISIS-APOCIIIRx Two Phase 2 Studies Planned to Complete in 2013
23
Severely Elevated Triglyceride Study, ~100 Patients with Triglycerides between 440-2000 mg/dL (Ongoing) Study designed to demonstrate that ISIS-APOCIIIRx can decrease triglycerides and apoC-III in
patients with severely elevated triglycerides Doses: 100, 200, or 300 mg/wk Data planned for mid 2013
Moderate Elevated Triglyceride in Type II Diabetics Study, ~25 Patients with Uncontrolled
Glucose Levels and Triglycerides between 200-500 mg/dL (Ongoing) Study designed to demonstrate that ISIS-APOCIIIRx can decrease triglycerides and apoC-III in
type II diabetes patients with moderately elevated triglycerides Exploring multiple measures of insulin sensitivity Dose: 300 mg/wk Data planned for late 2013
≤8 weeks Weekly dosing
End of Treatment Efficacy
Assessments
ISIS-APOCIIIRx Rapid Path to Market
Potential regulatory filing and commercial launch within next five years
Phase 3 study in patients with severe hypertriglyceridemia (TG > 880 mg/dL) Planned to begin late 2013/ early 2014
Isis wholly owned program
24
Advancing the Pipeline Numerous Drugs with Phase 2 or Phase 3 Data Potentially in 2013/Early 2014
25
Drug Indication Studies Study Phase
OGX-011 Cancer Prostate Cancer Phase 3
ISIS-FXIRx Thrombosis Total Knee Replacement Phase 2
ISIS-CRPRx Inflammation Cardiovascular Disease
Endotoxin RA Atrial Fibrilation
Phase 2
ISIS-EIF4ERx Cancer Lung Cancer Prostate Cancer Phase 2
ISIS-APOCIIIRx Severe Hypertriglyceridemia (HTG)
Severe HTG Moderate HTG Phase 2
ISIS-SMNRx Spinal Muscular Atrophy (SMA) SMA (childhood onset) Phase 2
ISIS-STAT3Rx Cancer Lymphoma Phase 2
OGX-427 Cancer Prostate Cancer Phase 2
iCo-007 Ocular Diabetic Macular Edema Phase 2
Advancing the Pipeline Numerous Drugs with Phase 2 and Phase 3 Studies Potential to Start in 2013/Early 2014
26
Drug Indication(s) Studies Planned Study
ISIS-TTRRx Familial Amyloid Polyneuropathy (FAP) FAP Phase 2/3
ISIS-APOCIIIRx Hypertriglyceridemia (HTG) Severe HTG Phase 3
ISIS-SMNRx Spinal Muscular Atrophy (SMA) SMA (infantile onset) Phase 2/3
ISIS-GCCRRx Cushing's Syndrome Type 2 Diabetes
Cushing's Syndrome Type 2 Diabetes
Phase 2 Phase 2
ISIS-GCGRRx Type 2 Diabetes Type 2 Diabetes Phase 2
ISIS-PTP1BRx Type 2 Diabetes Type 2 Diabetes Phase 2
ISIS-STAT3Rx Cancer Cancer Phase 2
2013 Partnering Opportunities Unpartnered Drugs with Phase 2 Efficacy Data Planned in 2013/Early 2014
27
Drug Indication(s) Studies
ISIS-APOCIIIRx Severe Hypertriglyceridemia (HTG)
Severe HTG Moderate HTG
ISIS-FXIRx Thrombosis Total Knee Replacement
ISIS-CRPRx Inflammation Cardiovascular Disease
Endotoxin, RA Atrial Fibrilation
ISIS-EIF4ERx Cancer Lung Cancer Prostate Cancer
ISIS-FXIRx for Thrombotic Disorders Potential Multibillion Dollar Commercial Opportunity
28
Thrombosis, a major component of cardiovascular disease, is one of the leading causes of death in the western world The formation or presence of a blood clot can occur suddenly and result in death
Current treatments to prevent blood clots often result in an unacceptably high risk of bleeding which can also result in death
There is significant need for a treatment to prevent blood clots, with less bleeding, in diseases where warfarin and Factor Xa and Factor IIa are currently used Acute Coronary Syndromes (ACS)
Stroke Prevention
Venous Thromboembolism (VTE), including Pulmonary Embolism (PE) and Deep Vein Thrombosis (DVT)
Potential significant near-term licensing opportunity
Factor Xl ASO
0 20 40 60 80
100 120 140 160
1.25 2.5 5 10 20 40 FXI ASO (mg/kg)
Thro
mbo
sis
(n
orm
aliz
ed)
-0.2
0
0.2
0.4
0.6
0.8
Tail
Ble
edin
g
(Blo
od/g
ram
s) Thrombosis Bleeding
Factor Xa Small Molecule
0 20 40 60 80
100 120 140 160
0.5 2 5 10 20
Apixaban (mg/kg)
Thro
mbo
sis
(n
orm
aliz
ed)
0
0.2
0.4
0.6
0.8 Ta
il B
leed
ing
(B
lood
/gra
ms)
Thrombosis Bleeding
Thrombosis Bleeding
Warfarin
0 20 40 60 80
100 120 140 160
0.5 1 2 3 4 5
Warfarin (mg/kg)
Thro
mbo
sis
(n
orm
aliz
ed)
0
0.2
0.4
0.6
0.8
Tail
Ble
edin
g
(Blo
od/g
ram
s)
ISIS-FXIRx demonstrated potent antithrombotic activity with no increase in bleeding compared to standard anti-clotting agents, including low-molecular weight heparin,
warfarin and Factor Xa inhibitors (all of which increased bleeding)
ISIS-FXIRx Preclinical Data Efficacy without Increased Bleeding
29
In Phase 1 study, ISIS-FXIRx demonstrated robust, sustained and dose-dependent reduction in FXI activity without increases in bleeding or bruising Maximum reduction achieved with 200 mg and 300 mg doses
No clinically significant increases in liver enzymes or other lab chemistries
Very low incidence of flu-like symptoms and mild injection site reactions
ISIS-FXIRx Profile of a Potential Best-in-Class Antithrombotic Agent
30
ISIS-FXIRx Phase 2 Study (Ongoing)
31
Open-label, Randomized, Active Comparator-Controlled, Multicenter (Canada and Eastern Europe) Study in Patients Undergoing Total Knee Arthroplasty (TKA)
Objectives Evaluate the safety and efficacy, including incidence of bleeding and VTE
and compare to enoxaparin
Data planned for 2013
Cohorts ISIS-FXIRx
n
100mg 100
200mg 100
300mg 100
*For the comparator arm, patients will be treated with enoxaparin (40 mg, s.c.) on the evening before surgery, the day after surgery and for 8 additional days
Screening wk1 wk2 wk3
12 wks 3:1 R
Surgery Treatment
8-12 d
Bilateral Venography
3 wks 3 wks
Post-Treatment f/u Period
ISIS-CRPRx – Targeting C-Reactive Protein (CRP) Potential Multibillion Dollar Commercial Opportunity
32
CRP is elevated in many inflammatory diseases and diseases with inflammatory components, such as Acute Coronary Syndrome (ACS) Atrial Fibrillation (AF) Rheumatoid Arthritis (RA) Chronic Kidney Disease (CKD) End Stage Renal Disease (ESRD) Organ Transplant
Elevated CRP levels are associated with increased disease burden
CRP is a complex glycoprotein, making it difficult to specifically target with small molecule drugs
Large commercial opportunity Potential broad applications in a number of diseases exacerbated by inflammation Market for inflammatory disease estimated to be > $20B
Potential significant near-term licensing opportunity
ISIS-CRPRx The First Selective CRP Lowering Drug in Man
33
Subjects with elevated CRP levels had a median reduction of >70% compared to baseline
ISIS-CRPRx was well tolerated at doses up to 600 mg/week
No SAEs, no clinically significant increases in liver enzymes or other lab chemistries
Very low incidence of flu-like symptoms and mild injection site reactions
ISIS-CRPRx Lowers CRP in Healthy Volunteers
Phase 1 clinical study demonstrated that ISIS-CRPRx produced statistically significant reductions in CRP
ISIS-CRPRx – Multiple Clinical Readouts in 2013 Designed to Produce Compelling Data Showing Therapeutic Benefit of Reducing CRP
Endotoxin Challenge Study in ~30 Healthy Volunteers (Completed) Study designed to demonstrate that ISIS-CRPRx can blunt acute severe
increases in CRP Exploring other key inflammatory mediators such as TNF-α, IL-1β, IL-6
and complement Data planned for 1H 2013
Phase 2 Study in ~ 50 Patients with Rheumatoid Arthritis (Ongoing) Study designed to demonstrate benefit of lowering CRP in patients with
chronically elevated CRP levels Data planned for mid 2013
Phase 2 Study in ~ 20 Patients with Atrial Fibrillation (Planned Start 1H 2013) Study designed to demonstrate CRP reduction has a positive effect on the
duration and frequency of atrial fibrillation events Data planned for 1H 2014
34
Isis’ Severe and Rare Disease Pipeline Expanding One the of Largest Severe and Rare Disease Programs in Biotech
35
Pipeline Key Indication Drugs Preclinical Phase I Phase II Phase III Reg & Comm
Severe & Rare CMV RetinitisPouchitis
Homozygous FHTTR Amyloidosis
Spinal Muscular Atrophy Severe HTG
Cushing's SyndromeAcromegaly
AAT Liver Disease
ISIS-SMNRx
ISIS-GCCRRx
ATL1103
ISIS-TTRRx
KYNAMROTM
ISIS-APOCIIIRx
Vitravene®Alicaforsen
ISIS-AATRx
*Named Patient Supply
Isis’ Severe and Rare Disease Pipeline Expanding One the of Largest Severe and Rare Disease Programs in Biotech
36 36
Pipeline Key Indication Drugs Preclinical Phase I Phase II Phase III Reg & Comm
Severe & Rare CMV RetinitisPouchitis
Homozygous FHTTR Amyloidosis
Spinal Muscular Atrophy Severe HTG
Cushing's SyndromeAcromegaly
AAT Liver DiseaseHereditary Angioedema
ISIS-SMNRx
ISIS-GCCRRx
ATL1103
ISIS-TTRRx
KYNAMROTM
ISIS-APOCIIIRx
Vitravene®Alicaforsen
ISIS-AATRx
ISIS-PKKRx
*Named Patient Supply
Hereditary Angiodedema (HAE) is a potentially life threatening immune disease Characterized by low levels or dysfunction of the C1 inhibitor protein HAE patients have attacks of rapid and painful swelling in the hands, feet,
limbs, face, abdomen, larynx and trachea
Current prophylactic treatments (androgens) are either inadequate or very difficult to use Example: Cinryze IV 3x/week administered in the hospital setting
Average cost $300,000 per patient for Cinryze prophylaxis
Unmet need: Up to 80% of patients are not using IV prophylaxis and would use a s.c. prophylactic if effective and available
ISIS-PKKRx for Hereditary Angioedema Approximately 15-20K Patients in US and EU
37
Prekallikrein (PKK) is the precursor of plasma kallikrein, a serine protease that activates kinins. PKK is cleaved to produce kallikrein by Factor XIIa
ISIS-PKKRx A Clinically Validated Target
38
PKK disrupts the kinin contact cascade that results in Hereditary Angioedema (HAE) attacks
The role of kinins in HAE has been established by acute treatments used after an attack has already occurred
ISIS-PKKRx will be used as prophylaxis for patients with frequent HAE attacks in a convenient once weekly subcutaneous injection
New Mechanisms RNA Processing/Splicing Single-stranded RNAi
New Routes of Delivery Intrathecal Intradermal
Better Performance Improved screening produces more potent and better
tolerated 2nd Generation antisense drugs 2.5 Generation antisense drugs even more potent
Advancing Antisense Technology New Mechanisms, New Routes of Delivery, Better Performance
39
Advancing Antisense Technology Improved Screening Generates More Potent Generation 2.0 Antisense Drugs
40
Dose Level (mg) ISIS-APOCIIIRx ISIS-FXIRx ISIS-TTRRx
100 -25% (1.2X) -49% (2X) -23% (1.1X)
200 -71% (1.8X) -71% (1.8X) -53% (1.5X)
300/400 >-78% (>1.5X) >-90% (>1.8X) >-75% (>1.5X)
Greater Reduction of Target Protein after 4 Weeks of Treatment (Fold Improvement vs. Kynamro )
Conclusion: Newer Generation 2.0 antisense drugs are more potent than Kynamro
Advancing Antisense Technology Improved Screening Enhances Tolerability Profile of Gen 2.0 Antisense Drugs
41
Parameter ISIS-APOCIIIRx ISIS-FXIRx ISIS-TTRRx
Injection-site Reactions (% SC Injections)
89% fewer ISRs 64% fewer ISRs 65% fewer ISRs
Flu-like Symptoms None reported None reported
None reported
Improvement in Nuisance Side Effects Observed in Newer 2nd Generation Antisense Drugs Compared to Kynamro
Experience with ISIS-STAT3Rx demonstrates: Gen 2.5 drugs are up to 10x more potent than previous
Gen 2.0 drugs
Gen 2.5 drugs have good tolerability with evidence of durable response in patients with diffuse large B-cell lymphoma
Data planned for 2013
Advancing Antisense Technology Improved Potency Demonstrated with Generation 2.5 Antisense Drugs
42
After Treatment (2 mg/kg) Before Treatment
55% response observed in 63 year old female with
diffuse large B-cell lymphoma
Partnered with:
No evidence of chronic systemic inflammation in man
Injection site reactions are now readily managed and declining with patient and physician education and use of a prefilled syringe
Clean carcinogenicity studies No clinically relevant findings
Antisense Technology Lessons Learned from Kynamro Development
43
Partner programs at earlier stages of development in therapeutic areas with higher risk (e.g., neuro and cancer) and where Phase 2 data will not provide a large increase in value
Defer license fees with manageable and relatively inexpensive Phase 2 programs where results will cause significant value inflection
Unique partner strategy for each program to maximize value
Superior down stream economics
Isis controls earlier-stage development
~$2B in cash from partnerships to date
Isis’ Partnering Progress Business Strategy Maximizes Value and Minimizes Risk
44
Isis Financial Position September 30, 2012 (in millions)
45
Revenue Operating Expenses – Pro forma (1)
Loss from Operations – Pro forma (1)
At September 30, 2012
$ 344 201 37 70
170
3 Months Ended, September 30
2012 2011
$ $ 12 38
(26)
21 41
(20)
9 Months Ended, September 30
2012 2011
$ $ 82 118 (36)
67 112 (45)
Cash & Short-term Investments
2¾% Convertible Notes (2)
Deferred Revenue (Long-term Portion) Long-term Financing Liability for Leased Facility (3)
Stockholders’ Equity We expect to end 2012 with more than $300M in cash and a pro forma 2012 NOL in the mid $70M range. (1) Amounts exclude non-cash compensation expense related to equity awards.
(2) Amount represents the principal balance of our 2¾% Convertible Notes. On the balance sheet, the carrying value of these notes is $142.5M because accounting rules required us to record the notes at a discount based on the estimated fair value of similar debt without the conversion feature.
(3) Accounting rules required us to record the cost of our leased facility as a fixed asset with a corresponding liability.
Kynamro commercialization
Positive Phase 2 and Phase 3 data from up to nine programs ISIS-APOCIIIRx, ISIS-FXIRx, ISIS-CRPRx, ISIS-SMNRx, ISIS-STAT3Rx, ISIS-
EIF4ERx, iCo-007, OGX-011, OGX-427
Initiation of two to three Phase 3 studies ISIS-TTRRx, ISIS-SMNRx, ISIS-APOCIIIRx
Initiation of four additional Phase 2 studies ISIS-STAT3Rx, ISIS-GCCRRx, ISIS-GCGRRx, ISIS-PTP1BRx
Additional partnering opportunities with three to four mature programs ISIS-APOCIIIRx, ISIS-FXIRx, ISIS-CRPRx, ISIS-EIF4ERx
Maintain strong financial position
2013 Goals
46
47 47 47
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