The product of years of basic research at Isis ANTISENSE...ANTISENSE years of basic research at Isis...

Technology Today

The product of 25 A N T I S E N S E

years of basic research at Isis

Isis 2014 R&D Day

May 22, 2014

2

Introduction

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

3

Forward Looking Language Statement

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 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.

Isis Pharmaceuticals® and Vitravene® are registered trademarks of Isis Pharmaceuticals, Inc. Regulus Therapeutics™ is a trademark

of Regulus Therapeutics Inc. KYNAMRO® is a registered trademark of Genzyme Corporation.

4

Participants

Dr. Stan Crooke

CEO and Chairman

Isis Pharmaceuticals

Dr. Frank Bennett

SVP Research


Dr. Sanjay Bhanot

VP Clinical Development

& Translational Medicine


Dr. Richard Geary

SVP Development


Dr. Jeffrey Weitz

Professor, Division of Hematology &

Thromboembolism,

Dept. of Medicine

McMaster University

5

Agenda

Introduction

Dr. Stan Crooke, CEO & Chairman, Isis Pharmaceuticals

ISIS-SMNRx

Dr. Frank Bennett, SVP Research, Isis Pharmaceuticals

ISIS-TTRRx and ISIS-APOCIIIRx

Dr. Richard Geary, SVP Development, Isis Pharmaceuticals

Diabetes Franchise

Dr. Sanjay Bhanot, VP Clinical Development & Translational Medicine, Isis Pharmaceuticals

ISIS-FXIRx

Dr. Sanjay Bhanot, VP Clinical Development & Translational Medicine , Isis Pharmaceuticals

ISIS-FXIRx Phase 2 Study Update

Dr. Jeffrey Weitz, Professor, Division of Hematology & Thromboembolism, McMaster University

Pipeline Overview

Dr. Richard Geary, SVP Development, Isis Pharmaceuticals

Isis’ Future: Focused on Value


Concluding Remarks


Q & A

Why Antisense Technology? Advantages

Uniquely specific and

broadly applicable

Almost universal applicability

Dramatically reduced cost and

increased success in R&D

Chemistry, manufacturing,

formulation, analytical methods

Broad versatility: toxic RNA, splicing, direct

protein down regulation

SubQ, IV, intrathecal, intraocular,

intradermal, inhalation, enema, oral

Only direct route from genes to drugs

Virtually no undruggable targets

Efficient discovery and early development

Investment amortized across the entire pipeline

Multiple antisense mechanisms

Multiple routes of delivery

Demonstrated clinical activity in multiple

tissues Broad clinical activity

6



broadly applicable


















7



broadly applicable


















8



broadly applicable


















9



broadly applicable


















10





broadly applicable
















11



broadly applicable


















12



broadly applicable


















13

Isis Antisense Technology is a Proven, Efficient

Platform for Creating New Drugs

• Successful – 3 commercialized drugs

Approved January 2013

Named Patient Supply

Approved 1998

14




• Efficient – 1 drug per 12 Isis employees

Traditional Pharma

1 drug / ~1,000 employees

ISIS

1 drug / 12 employees

15




• Efficient – 1 drug / 12 Isis employee

• Robust – multiple mechanisms

• Single-stranded antisense drugs can effectively target RNAs in

cytoplasm AND nucleus of the cell

RNase H

Antisense

mRNA for disease-causing

protein

Reduces target RNA &

prevents production of

protein

Increases production of

therapeutic protein DMPKRx

RNase H

Removes toxic RNA

16

Example: ISIS-APOCIIIRx Example: ISIS-SMNRx Example: ISIS-DMPKRx






• Robust – multiple routes of delivery

17






• Robust – multiple routes of delivery

• Robust – broad clinical activity in multiple tissues

18

Isis’ Current Pipeline is Broad, Diverse and Mature

19

ISIS-GCCRRx Cushing’s Syndrome

ISIS-PKKRx Hereditary Angioedema

ISIS-APO(a)Rx Very High Lp(a)

ISIS-ANGPTL3Rx Hyperlipidemia

ISIS-FGFR4Rx Obesity

ISIS-HBVRx HBV

RG-101 HCV

KYNAMRO® Homozygous FH

Alicaforsen* Pouchitis

Vitravene® CMV Retinitis

Commercialized

Phase 2

Cardiovascular Severe & Rare Metabolic Cancer Other

Phase 1

ISIS-SMNRx Spinal Muscular Atrophy

ISIS-APOCIIIRx FCS

ISIS-APOCIIIRx Severely High TGs

ATL1103 Acromegaly

ISIS-FXIRx Clotting Disorders

ISIS-CRPRx CAD

ISIS-GCGRRx Diabetes

ISIS-GCCRRx Diabetes

ISIS-PTP1BRx Diabetes

ISIS-EIF4ERx Cancer

Apatorsen

(OGX-427) Cancer

ISIS-STAT3Rx Cancer

Plazomicin Severe Bacterial Infection

EXC 001

(PF-06473871) Scarring

iCo-007 Diabetic Macular Edema

ATL1102 Multiple Sclerosis

ISIS-TTRRx TTR Amyloidosis

KYNAMRO® Severe HeFH

Custirsen

(OGX-011)

Prostate / Lung

Cancer

Phase 3 ISIS-DMPKRx Myotonic Dystrophy 1

ISIS-HTTRx Huntington Disease

RG-012 Alport Syndrome

ISIS-FVIIRx Clotting Disorders

ISIS-DGAT2Rx NASH

ISIS-ARRx Cancer

ISIS-GSK4Rx Ocular Disease

Preclinical

* Named Patient Supply 19

7 6

7 8

7

14 2

7

1

3

2010 2014 (Projected)

Regulatory/Commercialization

Maturing Pipeline Many Shots on Goal: Increasing Value, Decreasing Risk

20

Phase 3

Phase 2

Phase 1

Preclinical

Programs in pipeline: 24 38

Biogen Idec

Focus: ISIS-SMNRx

Upfront, Milestones

and Licensing Fees: $298M

21

Biogen Idec

Focus: ISIS-DMPKRx

Upfront, Milestones


Biogen Idec

Focus: 3 Neurological

Disease Targets

Upfront, Milestones

and Licensing Fees: >$660M

Biogen Idec

Focus:

Neurological

Disease Strategic

Relationship

Upfront, Milestones

and Licensing Fees: >$3B

AstraZeneca

Focus: Cancer

Upfront, Milestones

and Licensing Fees: >$1.2B

Roche

Focus: Huntington’s

Disease

Upfront, Milestones


GSK

Focus: Rare and Infectious

Diseases

Upfront, Milestones

and Licensing Fees: ~$1.5B Revenue

Potential to

Earn >$6B

Pharmaceutical Companies Are Excited About the Potential for Antisense Drugs to Provide Benefits to Patients Partnerships Provide Significant Reliable Revenue Stream

Near-term Drivers of Value 6 Drugs with Potential to File for Commercialization by 2018

ISIS-APOCIIIRx

FCS: 3,000-5,000 WW

Severe TG: ~50,000 in US/EU

Ph

as

e 3

Mid

-20

14

ISIS-TTRRx

FAP: ~10,000 WW

FAC: ~40,000 WW

Ph

as

e 3

on

go

ing

Custirsen (OGX-011) • Initial Phase 3 data negative

• Additional Phase 3 studies

in CRPC and NSCLC

enrolling

Ph

as

e 3

da

ta 2

01

4

EXC 001

Anti-scarring drug with

potential for multibillion

dollar market

Ph

as

e 2

co

mp

leti

ng

22

22

ISIS-SMNRx

SMA: ~35,000 US, EU &

Japan

Ph

as

e 3

Mid

-20

14

ISIS-STAT3Rx

A Gen 2.5 Antisense Drug

Ph

as

e 3

2

01

5 (

Po

ten

tial)

• Phase 2 expansion

study in DLBCL

• Ongoing Phase 1/2

study in HCC

ISIS-SMNRx

For Infants and Children with Spinal

Muscular Atrophy

Frank Bennett, Ph.D. Senior Vice President, Research

ISIS-SMNRx for Spinal Muscular Atrophy (SMA) Severe Genetic Neuromuscular Disease Affecting Children

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

24

25

Broad Phenotypic Spectrum of SMA

Type 1 60%

Type 2 27%

Type 3 12%

Type 4 1%

Type 1 14%

Type 2 51%

Type 3 35%

Type 4 <1%

Incidence of SMA Types

Prevalence of SMA Types

ISIS-SMNRx – Splicing Mechanism

26

ISIS-SMNRx Clinical Studies Design

27

Phase 1 Open-label Study

Childhood SMA (Type 2 and 3)

■ Single IT dose (1, 3, 6 or 9 mg)

■ 28 patients: 15 Type 2 and 13 Type 3, 2 – 14 years of age

Phase 2 Open-label Studies

Childhood SMA (Type 2 and 3)

■ Three (3 or 6 mg) or two (9mg) IT doses over three months

■ 25 patients: 10 Type 2 and 15 Type 3, 2 -15 years of age

■ 12 mg dose cohort ongoing

Infant SMA (Type 1)

■ Three IT doses (6 or 12 mg) over three months

■ 15 Type 1 patients: < 7 months of age

– All but one patient in the per protocol efficacy population had 2 copies of SMN2

■ Additional patients currently enrolling in 12 mg cohort

ISIS-SMNRx: What Have We Learned?

28

Magnitude of effect

ISIS-SMNRx has shown both dose and time dependent effects on motor

function

Effects have been consistent from

Mouse to human

Infant to children (Type 1 to Type 2/3)

Study to study

Effects on multiple measures of activity observed

Increases in SMN protein levels in CSF consistent with drug

mechanism

ISIS-SMNRx has been well tolerated to date

Some patients have been treated for over 2 years

44 doses in 15 infants and 138 doses in 54 children as of April 7

ISIS-SMNRx: Demonstrated Activity in Mice

and Multiple Types of SMA Patients

30

ISIS-SMNRx Increases SMN2 Splicing, Increases Production of SMN

Protein In Mouse Spinal Cord Tissue and Human CSF

33 36 34 35

10 10 9 9 32 31 33 25 67 75 62 63 87 84 89 85 96 97 97 97 95 97 97 96 % incl

150 mg/day

29 32 30 31

100

25 28 26 27

50

21 24 29 23

25

17 20 18 19

10

13 16 14 15

0

6 7 8

6 8

Mouse #

SMN Targeting ASO Promotes a Dose Dependent Increase in SMN2 Splicing

SMN Protein in mouse CSF

(Mean ± SD) 3.5 fold Increase

Study Timing Change in CSF SMN

Protein

Phase 1 9-14

months

160% increase (2.6

fold)

Phase 2 3 months 115% increase (2.1

fold)

Increases in CSF SMN Protein in SMA

Children with A Single 9 mg Dose

3.5 Fold Increase in Protein Achieved >90% Corrected Splicing

ISIS-SMNRx Preserves Neuron and Muscle

Function in a Transgenic Mouse Model of SMA

ISIS-SMNRx Treatment Preserves Neuromuscular Junctions

ISIS-SMNRx Treatment Maintains Muscle Fiber Size and Muscle Strength

31

ISIS-SMNRx: Infant Data Summary

Death/Permanent Ventilation (>16 hours/day ventilation continuously for >2 weeks, in

the absence of an acute reversible illness)

Natural History of Infantile-onset Type 1 SMA

(Finkel et al., under review)

With 2 copies SMN2:

Median age at endpoint = 10.5 months

At 18 months, 85% meet endpoint

3 SMN2 copies

2 SMN2 copies

33

Isis Phase 2 infant SMA study

well matched

Comparable patient population

Comparable standard of care

Contemporaneous

Similar physicians

Similar sites

Pro

babili

ty o

f E

ndpoin

t-F

ree

Su

rviv

al

Age (Months) 10.5

months

1 Per protocol efficacy population = patients who receive 3 initial loading doses and Day 92 evaluation 2 ≥16 hours hours/day of ventilation continuously for >2 weeks, in the absence of an acute reversible illness

Efficacy

Population1

12 mg Cohort

Efficacy

Population1

6 mg Cohort

2

Accidental Death

Patients in 12 mg

cohort started

study~ 6 months

after patients in 6

mg cohort

Median age at event or April 7

= 14 months

Median age at event or April 7

= 9.6 months

Median Age of SMA Infants in 6 mg Cohort of ISIS-SMNRx

Phase 2 Infant Study Greater Than That Observed in

Finkel et al., Natural History Study (Patient Status as of April 7, 2014)

34

ISIS-SMNRx Increases SMA Infants’ Motor Function;

Increases in CHOP INTEND Scores Observed (Efficacy Population: Data Cut-off April 7)

Increases in CHOP INTEND scores were substantial

Mean change from baseline = 8.3 points for 12 mg

cohort

Increases were observed in majority of patients

6/7 patients in 12 mg dose cohort had

increases ≥5 points

Increases were persistent

Natural History of Infantile-onset Type 1 SMA

(Finkel et al., under review)

Type 1 SMN Natural History

CHOP INTEND scores show steady

decline (1.27 points/yr)

Few patients show increases

Increases are short-lived

Red=12 mg Cohort

Blue=6 mg Cohort

35

Achievement of New Motor Milestones Observed

in Some Infants at Last Non-dosing Visit (Efficacy Population: Data cut-off April 7, 2014) Blue—6 mg, Red—12 mg

Head

control

Unable to maintain upright

Wobbles All the time upright

Sitting Cannot sit Sit with support at

hips

Props Stable sit Pivots

(rotates)

Voluntary

grasp

No grasp Uses whole hand Index finger and

thumb but immature

grasp

Pincer grasp

Ability to

kick (in

supine)

No kicking Kicks horizontally;

legs do not lift

Upward (vertically) Touches leg Touches

toes

Rolling No rolling Rolling to side Prone to supine Supine to

prone

Crawling Does not lift head On elbow On outstretched

hand

Crawling flat

on abdomen

On hands

and knees

Standing Does not support weight

Supports weight Stands with support Stands

unaided

Walking No walking Bouncing Cruising (holding on) Walking

independently

36

ISIS-SMNRx: Childhood Data Summary

Increases in Muscle Function Scores Observed in the Phase 1 Study

up to 14 Months After a Single Dose of ISIS-SMNRx

At Day 85, mean change from baseline = 3.1

points (p=0.02)

6/10 patients with change ≥4 points

Mean + SEM

Mean ± SEM 5.75

(p = 0.008)

2.5

0.5

-1.7

1-3 Months Post Single Dose 9-14 Months Post Single Dose

38

At 9-14 months, mean change from baseline = 5.75

points (p=0.008)

No patients declined

6/8 patients with change ≥ 4 points

Observations on the 9 mg cohort

Dose and Time Dependent Increases in Muscle Function Scores

Replicated in Patients Treated With Multiple Doses of ISIS-SMNRx

*

*

Mean + SEM, *, p<0.05,

compared to BL

3.7

2.3

1.5

Time (months)

39

Results: Additional Measurements of Motor

Function Are Consistent and Encouraging

Results of Six Minute Walk Test (6MWT) and Upper Limb

Module (ULM) test consistent with increases observed in

Hammersmith Functional Motor Scale–Expanded

Mean increase of 22.7 meters (SEM ±12.3) observed at 9 months

in 6MWT in 9 ambulatory patients (mean baseline 230.8 m,

SEM ±31.4)

6MWT measures the distance an ambulatory SMA patient is able to walk over a

total of six minutes on a hard, flat surface

Mean increase of 2.3 points (SEM ±0.9) observed at 9 months in

the ULM test in 10 nonambulatory patients (mean baseline 10.5,

SEM ±1.0)

ULM Test used for SMA patients who were nonambulatory, in which a 9 item scale

is scored as 0, 1 or 2 per item (max score 18)

40

ISIS-SMNRx Lessons Learned Supporting Phase 3

Design and Conduct

Data support selection of the 12mg dose for pivotal studies

Long half-life of ISIS-SMNRx in CNS supports infrequent dosing

Two to three month loading dose schedule followed by infrequent

maintenance administration

In infants with SMA, data support time to death/permanent ventilation

as primary endpoint with motor function (CHOP INTEND, motor

milestones) as secondary endpoints

Regulatory agencies agreement

In children with SMA, data support change from baseline in

Hammersmith motor function scale as the primary endpoint in pivotal

study

Regulatory agencies agreement

41

Isis successfully matched patients in Phase 2 infant study to

those in Finkel et al. natural history study

Similar patient population, sites, and standard of care

In studies conducted, ISIS-SMNRx has been active and well

tolerated

Early and aggressive treatment with ISIS-SMNRx and supportive

care are vital in this rapidly progressive disease

Lessons Learned About Type 1 SMA

42

ISIS-SMNRx Phase 3 Study in SMA Infants 13-month Study, Planned Initiation Mid 2014

A Phase 3, randomized, double-blind, sham-procedure controlled study in

infants with SMA

Global study in ~110 SMA infants ≤ 7 months old with 2 copies of SMN2 gene

Planned mid-year initiation; study start up activities in progress

13 month study duration

All patients eligible to roll over to open label extension (OLE) study

Objectives

Evaluate the efficacy and safety of ISIS-SMNRx

Primary efficacy endpoint is survival or permanent ventilation

Additional efficacy endpoints include CHOP INTEND and motor milestones

Screening

Cohort

12 mg R

2:1

≤21 days

M13

Last

Visit

Study

Complete

OLE

4 Induction Doses

2 months 11 months

Maintenance Dose

Every 4 Months 43

ISIS-SMNRx Phase 3 Study in SMA Children 15-month Study, Planned Initiation 2H 2014

A Phase 3, randomized, double-blind, sham-procedure controlled study in children

with SMA

Global study in ~120 SMA children

Planned 2H 2014 initiation; more detail on study design will be provided later in year

15 month study duration

All patients eligible to roll over to open label extension (OLE) study

Objectives:

Evaluate the efficacy and safety of ISIS-SMNRx

Primary efficacy endpoint: change in Hammersmith Motor Function Scale–Expanded

Screening

Cohort

12 mg R

2:1

≤21 days

M15

Last

Visit

Study

Complete

OLE

3 Induction Doses Maintenance Dose

Every 6 Months

44

Magnitude of effect

ISIS-SMNRx has shown both dose and time-dependent

effects on motor function

Effects have been consistent

Effects on multiple measures of activity observed

SMN protein data supports mechanism

ISIS-SMNRx has been well tolerated to date

Phase 3 studies about to begin

Take Home Messages on ISIS-SMNRx

45

Dr. Adrian Krainer

Dr. Yimin Hua

Strong Partnerships in Support of ISIS-SMNRx

46

Partnered with

http://www.massachusetts.edu/

Richard Geary, Ph.D. Senior Vice President, Development

ISIS-TTRRx and ISIS-APOCIIIRx

ISIS-TTRRx

Toward a Better Treatment for Patients with

Transthyretin (TTR) Amyloidosis

Partnered with:

ISIS-TTRRx A Potential Treatment for TTR Amyloidosis

Mutant TTR forms amyloid deposits in

nerves, heart and other organs, resulting

poor quality of life and eventually death

Unmet Medical

Need

FAP: ~ 10,000

FAC: ~ 40,000

Patient Population

(World Wide)

Treatments limited

No treatments halt or reverse disease

Liver transplant for early stage FAP (not

FAC)

Current Treatment Options

49

ISIS-TTRRx

Potential to Treat All Forms & Stages of TTR Amyloidosis

Partnered with:

Drug Mechanisms

Prevents TTR protein production

Reduces all forms of TTR (normal & mutant)

Potential to be superior in halting disease progression vs. currently available strategies

50

ISIS-TTRRx Degrades RNA

ISIS-TTRRx Phase 3 Various & Abundant TTR Mutations Currently Enrolled*

Partnered with:

FAP PH3

*Data available as of April 14th, 2014

Reduces All Known TTR Mutations

51

Currently Being Planned

2011 2012 2013 2014 2015 2016 2017

ISIS-TTRRx Pursuing Development to Treatment All Forms of TTR Amyloidosis

HV PH1 FAP PH3

FAP OLE

ISIS-TTRRx

FAP

ISIS-TTRRx

FAC (Cardiomyopathy)

Healthy Volunteers

Partnered with:

52

Planned top-line data release

Robust, dose-dependent & significant sustained reductions in TTR levels

Undetectable levels of TTR in some subjects

~ 90% reduction in some subjects

> 75% reduction on average

Safety and Tolerability Profile; 5 doses evaluated

Very low incidence of flu-like symptoms

Infrequent, mild injection site reactions

Phase 1 data supported moving directly to Phase 3

ISIS-TTRRx Phase 1 Potent & Durable Reductions in TTR Levels

Partnered with:

HV PH1 Screen Period

(4-Week) Treatment Period

(4-Week) Post-Treatment Evaluation

(10-Week)

D1 D3 D5 D15 D8 D22 D92

53

ISIS-TTRRx Potentially First-In-Class & Best-In-Class

Partnered with:

Max TTR Reduction Range

~80 – 100 %

ISIS-TTRRx

Phase 3 Development

•15 months into study

•OLE Initiated

Subcutaneous Injection (SC)

1 injection / week

Self-Administered

at Home

ALN-TTRIV

Phase 3 Development

•Initiated <6 months •First Patient dosed Early’14

ALN-TTRSC

Phase 2 Development

•Open label

•15 patients

54


Partnered with:


~80 – 100 %

ISIS-TTRRx

Phase 3 Development


•OLE Initiated


1 injection / week

Self-Administered

at Home

ALN-TTRIV

Phase 3 Development


Intravenous Infusion (>1hr)

Pre-Medication Required to avoid infusion reaction

ALN-TTRSC

Phase 2 Development

•Open label

•15 patients

Subcutaneous Injections

(SC)

3-4 injections / week

55


Partnered with:


~80 – 100 %

ISIS-TTRRx

Phase 3 Development


•OLE Initiated


1 injection / week

Self-Administered

at Home

ALN-TTRIV

Phase 3 Development


Intravenous Infusion (>1hr)

Pre-Medication Required to avoid infusion reaction

In-Clinic

Professionally Administered

ALN-TTRSC

Phase 2 Development

•Open label

•15 patients

Subcutaneous Injections

(SC)

3-4 injections / week

Potentially

Self Administered (?)

56

ISIS-TTRRx Phase 3 FAP Study Well Underway

Randomized, double-blind, placebo controlled

International multicenter study

26 sites in 9 countries

~200 FAP patients randomized 2:1

Once-weekly SC injections

Self administered at home

Low volume single injection

Treatment period 15 months

Objective: Evaluate efficacy and safety of ISIS-TTRRx

Primary endpoints

Modified NIS+7 (mNIS+7)

Norfolk QOL-DN questionnaire

Partnered with:

FAP PH3

57

Previous Treatment withDiflunisal or Tafamidis

Tafam

idis

Difl

unisal

Both

Nei

ther

0

10

20

30

40

Baseline Stage of Previous Treatment

% P

ati

en

ts

Stage Disease(Stage 1 vs Stage 2)

Sta

ge 1

Sta

ge 2

0

20

40

60

80

Baseline Stage of Disease

% P

ati

en

ts

TTR Mutation Status(V30M vs Non-V30M)

V30

M

Non-V

30M

0

20

40

60

80

TTR Mutation Status

% P

ati

en

tsISIS-TTRRx Phase 3 Well Balanced Disease Status Amongst Patients Enrolled

Current Demographics*

*Data available as of April 14th, 2014

Partnered with:

FAP PH3

58

Previous Treatment Stage Disease TTR Mutation Status

Initiated this quarter (2Q14)

Open to Phase 3 FAP patients upon treatment completion to

allow continuing access to drug treatment

All patients receive 300 mg ISIS-TTRRx

Objectives:

Evaluate long-term safety, tolerability

Evaluate long-term efficacy

Self administered at home with once weekly SC injections

All clinical sites participating

ISIS-TTRRx Beyond Phase 3 FAP Open-Label Extension Study

Partnered with:

FAP OLE

59

ISIS-TTRRx Phase 3 Program Well Underway Potential Best-in-Class Treatment for TTR Amyloidosis

Partnered with:

Most Advanced TTR RNA Targeted Therapeutic Drug in Development

ISIS-TTRRx

60


Partnered with:


Convenient & Easy to Use

At-Home Weekly Low-Volume S.C. Injection

ISIS-TTRRx

61


Partnered with:




Well Tolerated to Date

ISIS-TTRRx

62


Partnered with:





On-Track to Complete Enrollment in 2015

ISIS-TTRRx

FAP

63

Orphan Drug Designation: U.S. & E.U.

Fast-track status in U.S.


Partnered with:






ISIS-TTRRx

FAP

64

Orphan Drug Designation: U.S. & E.U.

Fast-track status in U.S.


Partnered with:






ISIS-TTRRx

FAP

65

FAC Study Currently Being Planned

ISIS-APOCIIIRx

Toward a Better Treatment For Patients with

Familial Chylomicronemia Syndrome (FCS)

& Severely High Triglycerides

ISIS-APOCIIIRx Targeting Apolipoprotein C-III (ApoC-III)

ApoC-III is a pivotal target for lowering triglycerides (TG)

Principally expressed in the liver

Functions as a key regulator of serum TG levels

Plays a key role in determining serum TG levels

Inhibits lipoprotein lipase

Inhibits hepatic lipase

Inhibits hepatic uptake of TG-rich particles

Independent risk factor for cardiovascular disease

Genetically validated target

67

A Wholly Owned Program

67

ISIS-APOCIIIRx The Significant Need for New TG-lowering Drugs

High TG levels are a health risk,

severely high triglyceride levels

are associated with severe disease

and death

68


For patients with severely high

TGs, existing TG-lowering

drugs are:

Inadequate for achieving

target TG levels

Insufficient for reducing risk

of pancreatitis

Not used by most patients

68

Classic risk factors Emerging risk factors Metabolic risk factors

* Factors that can increase your risk of heart disease and diabetes

CVD

Elevated triglycerides

Elevated

blood pressure

Inflammatory markers

Smoking Elevated

blood

glucose

Elevated

LDL

Type 2

Diabetes Insulin

resistance

Abdominal adiposity

Low HDL

Pancreatitis

FCS is associated with extremely high levels of TG, often

>2,000 mg/dL)

FCS patients are at extreme risk for acute pancreatitis

events and other serious conditions

Unmet Medical Need

ISIS-APOCIIIRx FCS: A Rare Genetic Disease Due to Mutations in LPL

Approximately 3,000 – 5,000 patients Patient

Population

(World Wide)

No currently available therapies



European Orphan Drug Designation

Patient Serum Sample

69

TG levels >880 mg/dL are associated with severe

disease >30% have diabetes and many more have metabolic

syndrome

Increased risk of recurring pancreatitis, often requiring

hospitalizations

High risk for cardiovascular disease

ISIS-APOCIIIRx TG Levels >880mg/dL: Another Rare Disease Commercial Opportunity

Unmet Medical Need

Approximately 50K patients

Potential for broader utility in patients with metabolic syndrome, including type 2 diabetes

Patient Population

(U.S. & E.U.)

Standard therapies, including niacin, fibrates and fish

oil are inadequate to achieve normal TGs



70

ISIS-APOCIIIRx Phase 2 Program Establishing the Profile of Lowering ApoC-III in Hypertriglyceridemia


Patients not on TG-

lowering

therapy with TG

levels

≥440 & ≤2000 mg/dL

100, 200, 300 mg

3:1 (active: placebo)

MONOTHERAPY FCS

FCS patients with TG levels ≥440mg/dL

300 mg

Open label

ADD-ON TO FIBRATE

Patients on stable

dose

fibrate TG levels

≥225

& ≤2000 mg/dL

200, 300 mg

2:1 (active: placebo)

Patients with TG levels ≥ 200 & ≤500 mg/dL and T2D on stable metformin ≥1g

300 mg

2:1 (active:placebo) Insulin sensitivity and

glucose control assessed

HIGH TG WITH T2D*

D1* D8 D15

Screen Period/Diet Run In (8-Weeks)

Treatment Period (13-Weeks)

Post-Treatment Evaluation (13-Weeks)

D22 D29 D36 D43 D50 D57 D64 D71 D78 D85

*Patients in the T2D study were dosed on Day 1, Day 3 and Day 5

Phase 2 Studies in High to Very High TG Patients

Study Design

71

ISIS-APOCIIIRx Phase 2 Program Robust TG Lowering in All Patients Treated

-71%

TG

MONOTHERAPY

-69%

TG

HIGH TG WITH T2D

-64%

TG

ADD-ON TO FIBRATE

-69%

TG

FCS

Triglyceride Reductions Mean % Decrease from Baseline

72


73


Space of

Disse

Endothelial cell

Hepatocyte

Sinusoid Triglyceride-Rich

Remnant Lipoproteins

LRP

LDLR

TRL C-III

E

E E

C-III

TRL C-III

E

E E

C-III

TRL C-III

E

E E

C-III

TRL C-III

E

E E

C-III

TRL C-III

E

E E

C-III TRL C-III

E

E E

C-III

TRL C-III

E

E E

C-III

TRL C-III

E

E E

C-III

TRL C-III

E

E E

C-III

TRL C-III

E

E E

C-III

LPL

HSPG

Metabolism of Triglyceride-Rich Particles in

the Liver

E

TRL

HSPG

LDLR

LRP

C-III

TG-rich lipoprotein

ApoC-III

ApoE

ApoB

Heparan sulfate proteoglycan

LDL receptor

LDL receptor-related protein

LPL Lipoprotein lipase

74



the Liver Clearance Dysregulated in FCS Patients (No Lipoprotein Lipase Activity)

Hepatocyte

LRP

LDLR

Space of

Disse

Endothelial cell



TRL C-III

E

E E

C-III

TRL C-III

E

E E

C-III TRL C-III

E

E E

C-III

TRL C-III

E

E E

C-III

HSPG TRL C-III

E

E E

C-III

TRL C-III

E

E E

C-III

TRL C-III

E

E E

C-III

TRL C-III

E

E E

C-III

TRL C-III

E

E E

C-III

TRL C-III

E

E E

C-III

TRL C-III

E

E E

C-III

E

TRL

HSPG

LDLR

LRP

C-III

TG-rich lipoprotein

ApoC-III

ApoE

ApoB


LDL receptor


75



the Liver Clearance Enhanced Post ISIS-APOCIIIRx Treatment by LRP and LDLR

Hepatocyte

LRP

LDLR

Space of

Disse

Endothelial cell



TRL E

E E

TRL E

E E

TRL E

E E TRL

E

E E

TRL E

E E

TRL E

E E HSPG

TRL E

E E

TRL E

E E

TRL E

E E TRL E

E E TRL E

E E

E

TRL

HSPG

LDLR

LRP

C-III

TG-rich lipoprotein

ApoC-III

ApoE

ApoB


LDL receptor


ISIS-APOCIIIRx Phase 2 Program Significantly Improved Lipid Profile Across All Patient Groups

76

-71% to

-88%

-11% to

-58%

-64% to

-71%

+42% to

+78%

Mean % Lipid Changes in Phase 2 Studies*

* Data from 13 weeks 300mg ISIS-APOCIIIRx treatment

ApoC-III TG Non-

HDL-C

HDL-C Good

Cholesterol

Consistent as a Single Agent or in Combination


76

ISIS-APOCIIIRx Additional Profile Benefits Improved Glucose Control By Multiple Measures

HbA1c Analysis in Diabetic Patients


Euglycemic Clamp A Measure of Tissue Insulin Sensitivity

Reduced ApoC-III Improved

Glucose Control

Decreased HbA1c

1.22 percentage-point decrease

(Pbo-adjusted)

Improved Insulin Sensitivity

Decreased:

Glycated Albumin

Fasting Fructosamine

77

Important Added Benefit

ISIS-APOCIIIRx Phase 2 Program Substantial and Consistent TG Reductions Across Four Patient Populations

Dose-dependent, significant, rapid, robust and durable reductions in

TG and ApoC-III

Significantly improved lipid profile

Significantly decreased atherogenic particles

Equally effective as a single agent or in combination with fibrates

Equally effective irrespective of the TG levels at entry

Reduced TG levels by more than 1,500 mg/dL in FCS patients

Significantly reduced HbA1c and improved measures of glucose

control and insulin sensitivity


78

ISIS-APOCIIIRx Phase 2 Safety and Tolerability Summary Well Tolerated in Multiple Clinical Studies

Placebo Drug Treated

Adverse Events

ALTs >3x ULN 3% 3%

Renal Function No Change No Change

Biochemical labs No Change No Change

Flu-like Symptoms None None

Injection site reactions None Infrequent/mild

79


Well tolerated in ~100 subjects

ISIS-APOCIIIRx

Potential to Provide Multiple Benefits for Patients with FCS and Patients

with Severely High TG

80


What Patients Need…

Current TG-

lowering Drugs(1)

ISIS-

APOCIIIRx(2)

Substantial TG lowering - +++

Equal lowering at all incoming TG levels - +++

Substantial ApoC-III lowering - +++

Improved glucose control, insulin sensitivity - +++

Improved lipid profile + +++

Increased HDL-cholesterol ++ +++

Safety and tolerability +++ +++

(1)Based on approved labels

(2)Based on clinical trial results to date

Rapid Path to Market for ISIS-APOCIIIRx

80

81

ISIS-APOCIIIRx

Rapid Path Toward Commercialization

FCS and Patients with > 880 mg/dL Severely High Triglycerides

Two Phase 3 programs planned to run in parallel

■ End of Phase 2 meetings with US and EU regulators ■ Finalize Phase 3 plan – 1H 2014

■ Initiate Phase 3 studies – Mid 2014

81


82

82

Targeting ApoC-III Moving Beyond the Initial Indications

Follow-on to ISIS-APOCIIIRx identified

7-10 times more potent

Potential for monthly dosing

Potential to enhance patient convenience

Potential for broader utility in patients with

cardiovascular disease and metabolic syndrome,

including patients with diabetes

Extend ApoC-III product life cycle


Sanjay Bhanot, M.D., Ph.D. Vice President, Clinical Development and Translational Medicine

Diabetes Franchise

Isis’ Type 2 Diabetes Pipeline Three Phase 2 Study Readouts in 2014/2015

Isis has created a franchise of multiple, novel late-stage drugs designed to

treat type 2 diabetes and other metabolic disorders

Isis’ metabolic drugs specifically reduce molecular targets, many of which

are undruggable or difficult to target with small molecules

Each drug in the franchise focuses on unique opportunities and is

complementary

* Late-breaker presentation at ADA (June 13-17, 2014); Investor event on June 15, 2014 at

7:00 a.m. PT

84

Patients with severe diabetes

failing OAD or injectable therapies

Patients with Cushing’s Disease or with

diabetes driven by glucocorticoid

dysregulation failing OAD or injectable

therapies

ISIS-PTP1BRx

ISIS-GCCRRx

Isis’ Drugs for Type 2 Diabetes Focus on Distinct High-Value Opportunities

ISIS-GCGRRx

Patients with diabetes and insulin resistance

that could benefit from an insulin sensitizer

85






therapies

ISIS-PTP1BRx

ISIS-GCCRRx


ISIS-GCGRRx



86






therapies

ISIS-PTP1BRx

ISIS-GCCRRx


ISIS-GCGRRx



87

Toward a Better Therapy for Patients with Severe

Diabetes

ISIS-GCGRRx

Glucagon Receptor (GCGR) A Validated Target for the Treatment of Diabetes

Glucagon is a hormone that opposes the action of

insulin

Increased glucagon action leads to increased glucose

production by the liver

Glucagon receptor reduction in animal models

produces dramatic reductions in glucose even in the

most severe models

Several small molecule inhibitors have reduced

glucose but have been associated with off-target side

effects

89

Reasons to Develop ISIS-GCGRRx:

The Potential to Be Best in Class

Likely to have greater glucose reduction than small molecules by directly

reducing production of the receptor

Likely not to have side effects associated with some small molecules

Increases in LDL-cholesterol

Increases in triglycerides

Increases in blood pressure

Increases in body weight

Likely to have a broader separation of doses that produce glucose

reduction from those that produce target-related ALT increases

Optimal balance between glucose reduction and ALT increases achievable

Robust and long lasting effect on glucose lowering provides opportunity

to balance glucose control with liver safety

Likely to be dual acting and potential to preserve pancreatic function

To be developed for treatment of advanced diabetes 90

91

Dual sites of action

Reduces hepatic glucagon action, which attenuates hyperglycemia

Increases GLP-1, which improves insulin secretion and leads to pancreatic

regeneration (potential for disease modification)

Robust effects in very insulin resistant animals

No fatty liver or increase in hepatic glycogen; no change in plasma lactate

levels, liver ALTs or LDL cholesterol levels

No hypoglycemia up to 24h fast in rodents and 16h in monkeys

No effect on recovery from insulin-induced hypoglycemia in rodents

No alpha cell hyperplasia or pancreatic tumors up to 6–month treatment in

monkeys

Glucagon Receptor Antisense Drug Key Attributes

92

Glucagon Receptor Antisense Treatment Significantly

Reduces Glucose, Increases GLP1 Levels and Improves

Insulin Production in Diabetic Rats

0

50

100

150

200

GCGR ASO

Control ASO

Acti

ve G

LP-1

(pM

)

Plasma Active GLP-1 – Fed Male ZDF rats treated for 30 days

Sloop et al, JCI 113(11):1571-81 (2004)

93

Efficacy of Glucagon Receptor Antisense in Extremely

Diabetic Animals in Which Rosiglitazone is Ineffective

Saline

GCGR ASO

Rosiglitazone

(3 mg/kg)

0 7 14 21 28

0 100 300

400

500

600

700

Day

Pla

sm

a G

lucose (

mg/d

L)

Plasma Glucose - Fed

Male ZDF Rats 14 Weeks Old at Study Initiation

ISIS-GCGRRx

13-week Phase 2 Study (Completed)

Randomized, double-blind placebo-controlled study in patients with

type 2 diabetes on stable metformin

Objectives

Evaluate effects of ISIS-GCGRRx on HbA1c and other measures of glucose control

Evaluate the safety & tolerability of ISIS-GCGRRx in combination with metformin

Reporting full analysis as Phase 2 late-breaker presentation at the

American Diabetes Association Meeting (June 13-17)

Cohorts n

100mg 36

200mg

39 200mg,

no load Pre-Treatment

Post-Treatment

f/u Period

13 weeks R

Treatment Period Once Weekly Dosing

3 weeks

2:1 13 weeks

Wk1 Loading

Doses

94

ISIS-GCGRRx Treatment Produced Robust Improvements in Glycemic Parameters and Was Well Tolerated Phase 2 Study Interim Top-line Data - Activity

Robust, highly statistically significant improvements

(vs. baseline) in glycemic parameters after only 13

weeks of treatment

200mg: >2 percentage-point reduction in HbA1c (p = 0.001)

100mg: >1 percentage-point reduction in HbA1c (p = 0.001)

Placebo response was modest (~0.25 percentage-point reduction)

Normal glucose levels (HbA1c ≤ 7%) achieved by a

large fraction of patients in both dose groups

Plasma GLP-1 increases observed; potential to

preserve pancreatic function and enhance insulin

secretion

95

ISIS-GCGRRx Treatment Produced Robust Improvements in Glycemic Parameters and Was Well Tolerated Phase 2 Study Interim Top-line Data – Safety and Tolerability

Antisense specificity of ISIS-GCGRRx avoided many off target effects seen with

small molecules

No changes in LDL-cholesterol

No changes in triglycerides

No changes in blood pressure

No gain in body weight

Safety Summary

Well tolerated

No flu-like symptoms

Infrequent, predominantly mild injection site reactions, resolved rapidly

No cases of symptomatic hypoglycemia

Easily managed target-related ALT elevations consistent with the pharmacology of glucagon

receptor inhibition and similar to those observed with small molecule glucagon inhibitors

No severely elevated ALTs

Very few ALT elevations in the 100 mg dose cohort

ALTs declined during and after dosing discontinued

No increases in bilirubin; no Hy’s Law cases

96

ISIS-GCGRRx

Next Steps Towards Significant Value Inflection Opportunity

Present Phase 2 Data – Late-Breaker Presentation at the

American Diabetes Association Meeting (June 13-17)

Investor event June 15, 2014 at 7:00 a.m. PT

Optimize dose and dosing schedule: Robust glucose lowering

provides broad opportunity to optimize efficacy and safety

Continue discussions with partners

Strong partner interest to date

Complete long-term toxicology studies to support long-term

clinical studies

97

A Unique Approach to Treat Diabetes Patients with

Glucocorticoid Dysregulation

ISIS-GCCRRx

Tissue-specific Inhibition of the Glucocorticoid Receptor A Unique Therapeutic Target for the Treatment of Diabetes

Excessive glucocorticoids (GC) action in liver and fat is

involved in obesity, insulin resistance and glucose

intolerance

Glucocorticoid receptor (GCCR) is an intracellular

receptor that mediates the action of GCs

Attenuation of GC action through its receptor is

a very attractive therapeutic approach for type 2

diabetes and disorders related to excessive

and chronic steroid action (e.g., Cushing’s disease)

Efficacy exceeds that observed with small molecule

inhibitors of 11bHSD1

99

Tissue-specific Inhibition of the Glucocorticoid Receptor A Unique Therapeutic Strategy for the Treatment of Diabetes

Small molecule inhibitors of GCCR have failed or have limited

utility

GCCR inhibition in the brain can cause increases in ACTH, adrenal

insufficiency, hypokalemia and blood pressure

ISIS-GCCRRx has the potential to be best in class by taking

advantage of distribution of antisense drugs

Inhibits GCCR in liver and fat without crossing the blood-brain barrier

Provides therapeutic benefits of inhibiting GC action systemically without

central nervous system side effects

100

ISIS-GCCRRx Phase 1 Study Design

Screening

Post-Treatment

f/u Period

10 weeks R

2:1

Randomized double-blind placebo-controlled study in healthy

volunteers

Objectives:

Evaluate the effect on glucocorticoid action in the brain

Evaluate effect on blood pressure

Evaluate effects on lipid profile

Evaluate safety & tolerability

2 Weeks

Wk1 Loading

Doses

PD

Endpoints

Wk7

DEXA Challenge

(420 mg dose group)

Once Weekly

Dosing

6 Weeks

Cohorts n

60mg 9

120mg 9

210mg 9

420mg 12

101

ISIS-GCCRRx – Encouraging Activity and Safety Profile Results from Phase 1 Studies

Parameter Result

Triglycerides Decreased

Total cholesterol Decreased

LDL-cholesterol Decreased

VLDL-cholesterol Decreased

ACTH No change

Aldosterone No change

Renin No change

Angiotensin II No change

Blood pressure No change

Hypoglycemia No

Positive effects on lipid profile, consistent

with preclinical data

No evidence of GCCR antagonism in brain

or other tissues outside of liver and

adipose

No change in blood pressure

Observed safety profile suggests ISIS-

GCCRRx does not have the limitations

observed with small molecule inhibitors of

GCCR

Best-in-class; no other liver and fat specific GCCR antagonist on market

102

Randomized double-blind placebo controlled study in patients with type 2

diabetes on metformin

Objectives:

Evaluate short-term measures of glycemic control

Evaluate the safety and tolerability of ISIS-GCCRRx

Changes in markers of GCCR antagonism in the brain

Hypoglycemia

Evaluate effects on lipid profile

Provide supportive data to move into longer-term studies

Data planned for late 2014/early 2015

ISIS-GCCRRx Phase 2 (ongoing) Six-Week Study, Data Planned for Late 2014/Early 2015

Pre-Treatment

Post-Treatment

f/u Period

12 weeks R

2:1

3 weeks

Once Weekly Dosing

6 weeks

Wk1 Loading

Doses

Cohorts n

210mg 40

103

ISIS-GCCRRx Potential Opportunities and Next Steps Toward Market

Near Term, High Value Patient Populations

Cushing’s Disease – orphan indication

Subset of dyslipidemic type 2 diabetes patients most likely to benefit

from reduced glucocorticoid drive

Next Steps

Initiate Phase 2 study in patients with Cushing's Disease - 2H 2014

Complete Phase 2 study and report data in patients with type 2

diabetes – late 2014/early 2015

104

Toward a Safer, More Effective Insulin Sensitizer for

Patients with Type 2 Diabetes

ISIS-PTP1BRx

ISIS-PTP1BRx Toward A Safer, More Effective Insulin

Sensitizer

Other insulin sensitizers, such as glitazones, are transcriptional

activators with limitations due to their significant side effects

ISIS-PTP1BRx is the only insulin sensitizer with a novel

mechanism of action currently in development

ISIS-PTP1BRx selectively targets protein tyrosine phosphatase 1B

(PTP1B), a negative regulator of insulin action, to enhance

cellular insulin response

PTP1B inhibition has been shown to improve glycemic control in

human studies

There remains a significant unmet need for safer insulin

sensitizers

106

ISIS-PTP1BRx: Potential to Have an Ideal

Profile as a Novel and Safe Insulin Sensitizer

Drug Glucose

reduction

Hypo-

glycemia

Lipids

reduction

Body

Weight

reduction

GI

Side

Effects

Insulin Sensitivity

&

Adipocytokines

Target

Toxicity

PTP-1B

Antisense1 Yes No Yes Yes No

Yes, adiponectin

increase No

PPAR-2 Yes Yes

(Minimal)

No or

Minimal

No,

wt gain No Yes

Yes

(Cardiac, BW

gain & bone

loss)

1. Based on preclinical data and preliminary clinical data 2. Based on published data including label claims

107

Randomized double-blind placebo-controlled study in obese

patients with type 2 diabetes taking metformin or metformin +

sulfonylurea

Objectives:

Evaluate efficacy and potency versus previous PTP-1B drug

Evaluate the safety and tolerability of ISIS-PTP1BRx

Enrollment complete, data planned for YE 2014

ISIS-PTP1BRx Phase 2 (Ongoing) Six-Month Study, Data Planned YE 2014

Pre-Treatment

Post-Treatment

f/u Period

12 weeks R

2:1

3 weeks

Cohorts n

200mg 75

26 weeks

Once Weekly Dosing

108

PTP1B Inhibition – Encouraging Activity and Safety Profile Results from Preclinical and Clinical Studies

Parameter Result

Insulin ↓

Glycemic control Improved

Hypoglycemia No

HOMA-insulin

resistance ↓

Body weight ↓

Adiponectin ↑

Lipids ↓

Potency ↑

Phase 1 Results:

ISIS-PTP1BRx lowered insulin levels and

reduced insulin resistance (as measured by

HOMA-IR)

ISIS-PTP1BRx increased plasma adiponectin, a

biomarker associated with weight loss

Effects observed at doses as low as 100 mg in

Phase 1 study, demonstrating increased

potency vs. previous PTP-1B inhibitor (ISIS-

113715)

Favorable safety and tolerability profile with no

hypoglycemia

Preclinical and Clinical Profile

109

Isis’ Type 2 Diabetes Pipeline Three Phase 2 Study Readouts in 2014/2015

Isis has created a franchise of multiple, novel late-stage drugs designed to

treat type 2 diabetes and other metabolic disorders

Isis’ metabolic drugs reduce novel molecular targets many of which are

undruggable or difficult to target with small molecules

Each drug in the franchise focuses on unique opportunities and is

complementary

* Late-breaker presentation at ADA (June 13-17, 2014); Investor event on June 15, 2014 at

7:00 a.m. PT

110

Sanjay Bhanot, M.D., Ph.D. VP, Clinical Development and Translational Medicine

ISIS-FXIRx

Toward a More Effective, Safer Antithrombotic for

Patients at High Risk for Thrombosis

ISIS-FXIRx for Thrombotic Disorders Significant need for anticoagulants with superior benefit to risk

profile

Thrombosis (heart attacks, strokes, pulmonary embolism) is

the leading cause of morbidity and mortality worldwide

Although effective, warfarin, new Factor Xa and thrombin

inhibitors do not prevent all thromboembolic events

Safety concerns of warfarin, Factor Xa and thrombin inhibitors

limit their use in some therapeutic settings

Because of its novel mechanism of action, ISIS-FXIRx has the

potential to have a benefit-to-risk profile superior to existing

anticoagulants

Potential to be of high value in a broader array of indications

Potential to perform better than existing drugs in many indications

112

112

Factor XI is a Genetically Validated Target for

Antithrombotic Therapy

Factor XI contributes to thrombosis in humans

Patients with Factor XI levels in the upper 10% have an increased risk of

venous and arterial thrombosis

Patients with elevated Factor XI levels have a higher incidence of stroke

Patients with lower levels of Factor XI have a decreased incidence of

venous thrombosis

Congenital deficiency of Factor XI in humans is not associated

with spontaneous bleeding

In animal models, Factor XI deficiency or inhibition is

associated with attenuated thrombosis without increased

bleeding

113

114

Platelet Activated

Platelet

Vascular Injury

(TF/Collagen Exposure

VII

VIIa

X Xa

Prothrombin Thrombin

Fibrinogen Fibrin

Fibrin

Polymer

Extrinsic

Pathway

XII XIIa

XI XIa

IX IXa

VIII VIIIa X

Intrinsic

Pathway

Collagen / Tissue Factor

Endothelium

ISIS-FXIRx

ISIS-FXIRx Reduces Clot Propagation, but NOT Clot Initiation

Therefore, Risk of Bleeding is Low

Common

Pathway

FXI

ISIS-FXIRx Reduces Clot Propagation, but NOT Clot Initiation

Therefore, Risk of Bleeding is Low

In contrast to Factor Xa or Factor VIIa, Factor XI is involved in clot

stabilization and expansion, not clot initiation, resulting in a low risk of

bleeding

115

115

Selective Antisense Inhibition of Factor XI

116

Antisense Inhibition of Factor XI Reduces Thrombosis

Without Increased Bleeding in Mice

Factor Xl Antisense Drug

0

40

80

120

160

1.25 2.5 5 10 20 40

FXI Antisense (mg/kg)

Th

rom

bo

sis

(n

orm

alized

)

-0.2

0

0.2

0.4

0.6

0.8

Tail B

leed

ing

(Blo

od

/gra

ms)

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

0.8 Thrombosis Bleeding

Thrombosis Bleeding

Warfarin

0

40

80

120

160

0.5 1 2 3 4 5

Warfarin (mg/kg)

Th

rom

bo

sis

(no

rma

lize

d)

0

0.2

0.4

0.6

0.8

Ta

il B

lee

din

g

(Blo

od

/gra

ms

)

Th

rom

bo

sis

(no

rma

lize

d)

Ta

il B

lee

din

g

(Blo

od

/gra

ms

)

117

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

2

0 20 40 60 80

Pla

tele

t d

ep

osi

tio

n x

10

9

Time (min)

Control

Day 37

ISIS-FXIRx Reduces Thrombosis Without

Increased Bleeding in Baboon Consistency of Effect Between Species

Crosby et al. 2013. ATVB

118


ISIS-FXIRx Preclinical Data Summary Significant Antithrombotic Activity Without Bleeding

Specifically reduces Factor XI levels in several animal species

Even with Factor XI levels reduced by over 90%

No spontaneous bleeding

No change in other coagulation factors

Antithrombotic activity comparable to that of currently available

anticoagulants, but less bleeding demonstrated in multiple

animal models

Potential for safer therapy as single agent or as combination

therapy with antiplatelet drugs

119


ISIS-FXIRx Phase I Study Design

Randomized, double-blind, placebo-controlled, dose-ascending

study in healthy volunteers

Objectives

Evaluate effects on Factor XI levels

Evaluate the safety and tolerability of ISIS-FXIRx

120

120

Cohorts n

50 mg 12

100 mg 12

200 mg 12

300 mg 12 Screening

Post-Treatment

f/u Period

12 weeks R

3:1

2 Weeks

Wk1 Loading

Doses

Once Weekly

Dosing

6 Weeks

Wk7

PD End

Point


ISIS-FXIRx Produced Dose-dependent and Sustained

Reductions in Factor XI Levels 121

121


ISIS-FXIRx Phase 1 Study Summary

ISIS-FXIRx reduced Factor XI levels in a dose-dependent

fashion; maximum reduction with 200 and 300 mg doses

No major bleeding or clinically relevant non-major bleeding

No change in bleeding time (measured 24h after last dose)

Well tolerated


No changes in liver function

No changes in kidney function

No clinically meaningful changes in laboratory values

122 122


Jeffrey Weitz, M.D. Professor, Division of Hematology & Thromboembolism,

Dept. of Medicine, McMaster University

ISIS-FXIRx – Phase 2 Study Update

ISIS-FXIRx Phase 2 Six-week Study (Completed)

Open-label, randomized, active comparator-controlled* study in patients

undergoing knee replacement surgery

VTEs determined by blinded independent adjudication committee

Bleeding events determined by blinded independent adjudication committee

Objectives

Compare the effects of ISIS-FXIRx on incidence of venous thromboembolism (VTE) and bleeding

to enoxaparin

Evaluate the safety and tolerability of ISIS-FXIRx

Planned presentation of complete analysis at upcoming medical meeting

124

*Patients treated with enoxaparin (40 mg, s.c.) the evening before surgery, 6-8hrs post surgery and daily injections for at least 8

additional days; **Data as of May 7, 2014

Screening W1 W3 W6

(6hr post

surgery)

12 wks

3:1

R

Surgery

Treatment

8-12 d

Bilateral

Venography

4-6 wks

6 wks

Post-Treatment

f/u Period

W2 W4 W5 3d post

surgery

124

Cohorts n**

40 mg

Enoxaparin* 72

200 mg

ISIS-FXIRX

144

300 mg

ISIS-FXIRx 75


ISIS-FXIRx: Dose-dependent Reduction of VTEs

with a Low Incidence of Bleeding Data Cutoff May 7, 2014

With 200 mg ISIS-FXIRx, rate of venous

thromboembolism (VTE) is similar to enoxaparin

200 mg cohort expanded to further enhance comparison to

enoxaparin

With 300 mg ISIS-FXIRx, rate of VTE is 7-fold lower

than enoxaparin (p<0.0001)

Patients treated with enoxaparin and ISIS-FXIRx

experienced a very low rate of bleeding

ISIS-FXIRx-treated patients experienced numerically fewer

bleeding events than with enoxaparin

125


ISIS-FXIRx: Safety and Tolerability Equivalent

to Enoxaparin

Well tolerated

No flu-like symptoms


No drug-related SAEs

No observed differences in safety compared

to enoxaparin group

126 126

ISIS-FXIRx: Conclusions from Phase 2 Study

127

■ Enoxaparin efficacy and bleeding rates were within expected

ranges in this patient population

■ Findings provide proof-of-principle that ISIS-FXIRx is an effective

and safe anticoagulant

■ ISIS-FXIRX decreases VTE in a dose-dependent fashion

■ Rate of VTE in 300 mg cohort is substantially lower than published

reports of Factor Xa or thrombin inhibitors in this therapeutic

setting

Bleeding rates were very low in the enoxaparin group and

numerically lower in the ISIS-FXIRx-treated patients

■ Only Factor XI inhibitor in clinical studies

Pathway validated by Isis

127


128 128

ISIS-FXIRx: Potential Best-in-Class Profile for an Novel Anticoagulant

Drug Arterial

Thombosis

Venous

Thombosis

Low

Bleeding

Risk

No

Drug-drug

Interactions

No Routine

Monitoring

Antidote

Available

ISIS-FXIRx Yes Yes Yes Yes Yes Yes

Warfarin Yes Yes No No No Yes

Heparins Yes Yes No Yes No Partial

Factor Xa

Inhibitors No Yes No No Yes No

Thrombin

Inhibitors No Yes No No Yes No

Efficacy Parameters Safety Parameters


Potential Indications for ISIS-FXIRx

129

Initial

Patient populations with an unmet need in which relatively small

studies can be conducted

■ Unprovoked VTE

■ Atrial fibrillation in patients with end-stage kidney disease

Long-term

Prevention of secondary events in patients with cardiac diseases

■ Acute coronary syndrome

■ High-risk patients with atrial fibrillation

■ Mechanical heart valves

129


ISIS-FXIRx: Next Steps

130

Present full analysis Phase 2 results at an

upcoming medical meeting

Publish results in medical journal

130


Richard Geary, Ph.D. Senior Vice President, Development

Pipeline Overview

132






ISIS-HBVRx HBV

RG-101 HCV




Commercialized

Phase 2


Phase 1


ISIS-APOCIIIRx FCS


ATL1103 Acromegaly


ISIS-CRPRx CAD




ISIS-EIF4ERx Cancer

Apatorsen

(OGX-427) Cancer

ISIS-STAT3Rx Cancer


EXC 001






Custirsen

(OGX-011)

Prostate / Lung

Cancer





ISIS-DGAT2Rx NASH

ISIS-ARRx Cancer


Preclinical

* Named Patient Supply 132

Isis’ Robust, Mature Pipeline

133

Isis’ Cardiovascular Pipeline

133

134

Isis’ Lipid Franchise

134

Treatment For HoFH

KYNAMRO®

Marketed in the U.S. and approved in

additional countries

Winner of 2014 NORD Corporate Award

In 2014, Genzyme will continue to invest

significantly in KYNAMRO

Increased sales growth in 2014

Minimal investment by Isis to reach

profitability

KYNAMRO® (mipomersen sodium) Injection 200 mg/ml 1st Systemic Antisense Drug Approved for Chronic Use

Continuing investment in market with

FOCUS FH

Enrollment completed 2013

FOCUS FH data planned early 2015

136

Toward a Better Treatment For Patients with

Severely High Lp(a)

ISIS-APO(a)Rx

ISIS-APO(a)Rx

Targeting Apolipoprotein(a) to Reduce Lipoprotein(a)

Apo(a) is liver-derived and

linked to the apoB-component

of LDL via disulfide

Lp(a) is an independent risk

factor for cardiovascular

disease

No other drugs directly affect

Lp(a) levels

138

138

Apo(a) + LDL = Lp(a)

138

139

Very High Lp(a) is a Risk Factor for Cardiovascular Disease Lp(a) Distribution - Copenhagen General Population

Modified from Nordestgaard et al., Eur Heart J. 2010 Dec;31(23):2844-53

Fra

ctio

n o

f P

opu

latio

n

Very High CHD Risk Very High CHD Risk

MEN WOMEN

139

140

ISIS-APO(a)Rx Target Patient Populations

Severely elevated Lp(a) with existing cardiovascular disease

and controlled LDL-C

Orphan patient population

Lp(a) reduction planned as study endpoint

Very high Lp(a) (>50 mg/dL) with early stage aortic valve

stenosis

Medium size and growing patient population

Benefits can be measured by echocardiogram in modest number of

patients in a reasonable timeframe

ISIS-APO(a)Rx Produces Robust and Prolonged Dose-Dependent

Reduction in Plasma Lp(a) in Healthy Volunteers

141

Mean % Change in Lp(a)

141

Me

an

Perc

en

t C

han

ge L

p(a

) (±

SE

M) 30

0

-50

-100

Study Day

Placebo

100mg (n=8)

200mg (n=8)

300mg (n=7)

1 5 8 15 22 29 36 50 64

ISIS-APO(a)Rx Phase 1 Safety Summary

Well tolerated

Low incidence of flu-like symptoms

Infrequent, predominantly mild injection site reactions

No SAEs

No meaningful changes in laboratory values

No liver enzyme elevations

142

142

143

Screening

Post-Treatment

f/u Period

12 weeks

R

Treatment Period

12 Weeks

28 days

100 mg 200 mg

300 mg

12 weekly s.c. injections

ISIS-APO(a)Rx Phase 2 Planned 12-week Study in Patients with High Lp(a)

Cohorts n

A 25

B 8

Randomized, double-blind, placebo-controlled, dose-titration study

2 Cohorts

Cohort A: High Lp(a); 1:1 (active : placebo)

Cohort B: Very high Lp(a); 4:1 (active : placebo)

Intra-patient dose titration

Objectives

Evaluate activity of ISIS-APO(a)Rx in lowering Lp(a)

Evaluate the safety & tolerability of ISIS-APO(a)Rx

Phase 2 initiation 1H 2014

143

Toward a Better Treatment For Patients with Severe

Hyperlipidemia, including

■ Homozygous FH

■ Severe heterozygous FH

■ Severe mixed dyslipidemia

ISIS-ANGPTL3Rx

ANGPTL3 Target Overview

ANGPTL3 is synthesized in liver and secreted

ANGPTL3 targeting should provide unique LDL-C and TG lowering

profile

ANGPTL3 is a genetically validated target for patients with

hyperlipidemia

Individuals with no/low ANGPTL have good CV health

Individual with high ANGPTL have poor CV health

145

ISIS-ANGPTL3Rx Phase 1 (Ongoing) Study Design

Double-blind, placebo-controlled, dose-ascending study in healthy

volunteers

Objectives

Evaluate the activity of ISIS-ANGPTL3Rx on plasma levels of ANGPTL3 and

lipoprotein profile

Evaluate the safety and tolerability of ISIS-ANGPTL3Rx

Phase 1 initiated in March 2014; data planned YE 2014

Post-Treatment

f/u Period

D1 D3 D5 D15

13 weeks R

3:1

D22 Screening

4 weeks

6 weeks

Treatment Period

D8 D36 D29

Cohorts n

100 mg 8

200 mg 8

300 mg 8

400 mg 8

146

Isis’ Cancer Drugs

147

Custirsen (OGX-011)

& Apatorsen (OGX-427)

Toward a Better Treatment For Patients with Cancer

Custirsen & Apatorsen

Custirsen

SYNERGY - Failed to achieve better survival outcome in Phase 3 study in patients with

castration-resistant prostate cancer (CRPC) (first-line combo with docetaxel &

prednisone)

Two other ongoing Phase 3 studies: AFFINITY (second-line in patients with CRPC) and

ESPIRIT (second-line in patients with NSCLC)

Apatorsen

6 ongoing Phase 2 studies

■ Metastatic Bladder – 2 studies; data from Borealis-1 (overall survival in combo with

gemcitabine and cisplatin) expected 2H:2014

■ Prostate – first-line

■ CRPC in combo with Zytiga

■ NSCLC in patients with Stage IV non-squamous

■ Metastatic pancreatic in combo with Abraxane and gemcitabine

Phase 2 study in lung cancer planned to start in 2014

Partnered with:

149

ISIS-EIF4ERx

Toward a Better Treatment For Patients with Cancer

ISIS-EIF4ERx: Two Phase 2 Studies Non-small Cell Lung Cancer & Castration-resistant Prostate Cancer

Randomized controlled trials in combination with chemotherapy

Both studies confirmed good target engagement by ISIS-EIF4ERx

Insufficient increases in progression-free survival to support

additional investment

Ongoing study

Investigator-initiated study: Tim Greten, MD at NCI

■ A Phase 1/2 study of ISIS-EIF4ERx in combination with irinotecan

in irinotecan-refractory colorectal cancer

151

Isis’ Gen 2.5 Antisense Cancer Drugs

152

ISIS-STAT3Rx and ISIS-ARRx are Gen 2.5 antisense drugs

Gen 2.5 chemistry antisense drugs exhibit greater

potency to broaden applicability to different cell types,

including tumor cells

Gen 2.5 antisense compounds demonstrated markedly

superior responses over Gen 2.0 antisense compounds

in preclinical cancer models

Gen 2.5 superior activity profile has translated into

increased activity in human cancer studies

Cancer Strategy – Why Gen 2.5 Antisense?

153

Gen 2.5 ISIS-STAT3Rx Has Superior Activity in Tumor

Cells Over Gen 2.0 STAT3 Antisense Compound

Human STAT3 Protein Level

154

A Gen 2.5 Antisense Drug for The Treatment of

Patients with Cancer

ISIS-STAT3Rx

Receptor-mediated activation of

tyrosine kinases leads to activation of

STAT3

Mutations in STAT3 and other

regulatory genes result in constitutively

active STAT3, which promote tumor

growth

Ideal target for antisense drug

(undruggable by small molecules or

antibodies)

STAT3 as a Tumor Target STAT3 Pathway

From Yu et al. 2007

156

Partnered with:

ISIS-STAT3Rx Phase 1/2 (Ongoing) Study in Patients with Advanced Cancers

Screening

D1 D3 D5 D8 D15 D22

Treatment Period

(until progression)

Pre-dose

biopsy for

biomarker

D29 D36 D43 D50

Post-dose biopsy

for biomarker

PET/CT

for response

Phase 1 ascending study in patients with advanced cancer completed;

data presented at ASCO 2014

Phase 2 expansion (3 mg/kg dose) in lymphoma, including diffuse

large B-cell lymphoma

Objectives:

Determine response rate in diffuse large B cell lymphoma

Determine level of target engagement via tumor biopsy

Identify biomarkers that can predict response

Evaluate the safety and tolerability of ISIS-STAT3Rx

Decision on next stage of development planned for Q4 2014

157

Partnered with:

ISIS-STAT3Rx Phase 1/2 (Ongoing) Study in Patients with Advanced Hepatocellular Carcinoma

Open-label, multicenter study in 24 patients with advanced HCC

Study divided into dose-ascending phase and dose-expansion phase

Objectives:

Assess preliminary anti-tumor activity of ISIS-STAT3Rx

Evaluate the safety, tolerability and pharmacokinetics of ISIS-STAT3Rx

Dose-ascending phase completed

Planned Phase 2 expansion study to begin shortly

Screening

D1 D4 D8 D11 D15 D22

Treatment Period

(until progression or unacceptable tox)

158

D1 D8 D15 D22

Cycle 1 Subsequent Cycles

Partnered with:

ISIS-STAT3Rx Clinical Program Advancing in Patients with DLBCL and HCC

Encouraging durable partial responses observed in patients with

DLBCL

Expansion cohort in DLBCL and Phase 1/2 in HCC ongoing

Acceptable, manageable safety profile

AstraZeneca is planning for a potential Phase 3 study initiation

in DLBCL in 2015

Partnered with:

159

A Gen 2.5 Antisense Drug for the Treatment for

Patients with Castration Resistant Prostate

Cancer

ISIS-ARRX

Partnered with:

Multiple AR-mediated resistance mechanisms in

CRPC

Amplified AR

Mutated AR

Ligand-Independent AR

Spliced AR

Tumour Androgen Synthesis

ISIS-ARRx targets mRNA which is not susceptible to

traditional AR-mediated resistance mechanisms

ISIS-ARRx Has Potential to Provide Benefit in All

Androgen Receptor (AR) Resistance Settings

161

Days Post Tumor Implantation

Tu

mo

r V

olu

me

(m

m3)

30 35 40 45 50 55 60

0

200

400

600

800

1000

PBS

560131 50mpk/QDx5

* *p=0.027

by Two-way RMANOVA followed

by Bonferroni's post-hoc

Treatment

Tu

mo

r W

eig

ht

(g)

PBS 560131 50mpk/QDx50.0

0.2

0.4

0.6

0.8

1.0

*

*p=0.018

by t-test

• In animal prostate cancer model

• Tumor weight reduction: ~50%

• 15 doses for 3 weeks

ISIS-ARRx demonstrated significant antitumor activity in prostate

cancer model with mutated AR

ISIS-ARRX Second Gen 2.5 Antisense Drug to Enter Clinic

Partnered with:

162

ISIS-ARRx Phase 1/2 Study in Patients With Advanced Solid Tumors (AZ Study)

Partnered with:

An open-label, dose-ascending study in patients with advanced solid

tumors where the androgen receptor pathway is a potential factor

2 cohorts

Cohort 1: dose ascending in patients with advanced cancer

Cohort 2: expansion in patients who have received a 2nd generation anti-hormonal

therapy but have not responded or have relapsed

Objectives:

Provide early signal of clinical activity

Optimize dosing schedule

Evaluate safety and tolerability in patients with cancer

Planned 1st patient dose May 2014

163

Screening

D1 D4 D8 D11 D15 D22

Treatment Period

(until progression or unacceptable tox)

D1 D8 D15 D22

Cycle 1 Subsequent Cycles

164

Isis Leads the Industry in Severe & Rare Disease Pipeline

164

165

Two New Antisense Drugs Entering the Clinic

165

Toward a Better Treatment for Patients with

Hereditary Angioedema

ISIS-PKKRx

ISIS-PKKRx for Hereditary Angioedema Approximately 15-20K Patients in US and EU

Hereditary Angioedema (HAE) is a potentially life threatening immune

disease

Characterized by low levels or dysfunction of the C1 inhibitor protein

HAE patients have attacks that are often disabling and sometimes fatal, and

characterized by rapid and painful swelling in the hands, feet, limbs, face,

abdomen, larynx and trachea

ISIS-PKKRx reduces Prekallikrein (PKK), a clinically validated target

PKK disrupts the kinin contact cascade that triggers HAE attacks

The role of kinins in HAE has been established by acute treatments used after an

attack has already occurred

Current prophylactic treatments (e.g., androgens, C-1 inhibitor

replacement) are either inadequate or very difficult to use

Unmet need: Up to 80% of patients are not using IV prophylaxis and would use a

s.c. prophylactic if effective and available

167


ISIS-PKKRx for HAE Prophylaxis for patients with frequent HAE attacks

ISIS-PKKRx: potential best-in-class treatment for HAE

Targeted, mechanism-based therapy that could prevent attacks by altering the cause

of the disease

Antisense reduction in PKK prevented or ameliorated tissue swelling in animal

models of HAE

Convenient, at-home self-administered subcutaneous injections

Infrequent, low-volume injections

Improved tolerability and safety compared to existing prophylactic treatments

Rapid path to proof-of-concept study

Phase 1 study in healthy volunteers has already begun

Planned clinical study in HAE patients in 2H 2014

168


ISIS-DMPKRx

A Gen 2.5 Antisense Drug for Patients with

Myotonic Dystrophy 1 (DM1)

170

DM1 Disease Overview RNA-caused Disease Uniquely Suited to Antisense Therapy

Autosomal dominant genetic disease that causes

Severe muscle problems that include weakness (myopathy), trouble relaxing muscles

(myotonia) and muscle wasting

Affects other body functions, including the heart and gastrointestinal system

DM1 is caused by production of toxic RNA in the cell nucleus

Caused by expanded CUG repeat in 3’-UTR of Dystrophia Myotonica-Protein Kinase

(DMPK)

Repeat length ranges from 50 to 3000 repeats & correlates to disease severity

DM1 often affects an entire family: ‘anticipation’ can occur with each

generation getting a more severe form of the disease due to expansion of

repeat

Affects 40,000 patients in US: 150,000 patients in US, EU and Japan

170

171

ISIS-DMPKRx

Reducing Toxic RNA to Positively Affect Disease

ISIS-DMPKRx targets the DMPK

transcript to decrease the level of

this toxic RNA, restoring normal

cellular function

Phase 1 study in healthy

volunteers

Planned for mid year 2014

initiation

Phase 2 study in DM1 patients

planned to initiate in 2H 2014

Growing Pipeline Multiple Phase 1 Assets Advancing in the Clinic

2014 2015

ISIS-ANGPTL3Rx

Hyperlipidemia


ISIS-DMPKRx

Myotonic Dystrophy 1 (DM1)

ISIS-HBVRx

HBV

ISIS-ARRx

Cancer

Phase 1

Healthy Volunteers

Phase 1

Healthy Volunteers

Phase 2

Chronic HBV Patients

Phase 1

Healthy Volunteers Phase 1/2

HAE Patients

Phase 1

Healthy Volunteers

Phase 1/2

DM1 Patients

Phase 1/2

Cancer Patients

Phase 1 Data

YE2014

172

Cardiovascular Severe & Rare Cancer Other

Completed study On-going study Planned study

173

Advancing the Pipeline Multiple Phase 2 and 3 Data Read Outs & Planned Study Initiations in 2014

Phase 2 data

Phase 3 data

Phase 3 initiation

Phase 2 initiation

Phase 2 or 3 Data Release

Phase 2 or 3 Study Initiation

ISIS-SMNRx

• Infant SMA study

ISIS-APOCIIIRx

• FCS study

ISIS-SMNRx

• Childhood SMA study

ISIS-APOCIIIRx

• TG >880 mg/dL

Plazomicin

• MDR study

ISIS-GCCRRx

• Cushings study

ISIS-APO(a)Rx

• High Lp(a) study

Phase 2

or

3

Stu

dy I

nitia

tion

iCo-007

• Diabetic macular edema

ISIS-SMNRx

• Spinal Muscular Atrophy

ISIS-EIF4ERx

• Prostate/Lung Cancer

ISIS-STAT3Rx

• Lymphoma

• HCC

ISIS-FXIRx

• Thrombosis in Knee replacement

ISIS-CRPRx

• Atrial Fibrillation

OGX-427

• Bladder cancer

OGX-011

• Prostate cancer

ISIS-GCGRRx

• Type 2 Diabetes

ISIS-PTP1BRx

• Type 2 Diabetes

173

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

Isis’ Future: Focused on Value

Created the third platform for drug discovery

Only direct route from gene to patients

Used efficiency of antisense to build a broad and mature

pipeline of 32 first-in-class or best-in-class drugs

Controlled the technology through innovation and IP

strategy

Employed a novel partnering strategy to fully exploit the

breadth and potential of antisense technology

Enhanced long-term innovation through maintaining a

small innovation-centered organization

What Has Isis Accomplished Over the Last 25 Years?

175

176 176

Basic Antisense Research at Isis: The Impact

1000-fold improvement

in therapeutic index

● More than 100-fold improvement in potency

● More than 100-fold improvement in safety

● Substantial advances in tolerability

● Activity in multiple organs in animals and humans

● Nearly all routes of delivery

● Multiple mechanisms of action

● Broad applicability to many diseases

● Precision dosing

● Extraordinary improvements in drug discovery

and development efficiency

● Dominant evergreen patent estate

177


Very broad utility












178


Broad, mature and

enlarging pipeline












179


Continue control












The Future: Focus on Value

Broad, Robust and Mature Pipeline

180

180






ISIS-HBVRx HBV

RG-101 HCV




Commercialized

Phase 2


Phase 1


ISIS-APOCIIIRx FCS


ATL1103 Acromegaly


ISIS-CRPRx CAD




ISIS-EIF4ERx Cancer

Apatorsen

(OGX-427) Cancer

ISIS-STAT3Rx Cancer


EXC 001






Custirsen

(OGX-011)

Prostate / Lung

Cancer





ISIS-DGAT2Rx NASH

ISIS-ARRx Cancer


Preclinical

* Named Patient Supply



181

181






ISIS-HBVRx HBV

RG-101 HCV




Commercialized

Phase 2


Phase 1


ISIS-APOCIIIRx FCS


ATL1103 Acromegaly


ISIS-CRPRx CAD




ISIS-EIF4ERx Cancer

Apatorsen

(OGX-427) Cancer

ISIS-STAT3Rx Cancer


EXC 001






Custirsen

(OGX-011)

Prostate / Lung

Cancer





ISIS-DGAT2Rx NASH

ISIS-ARRx Cancer


Preclinical


Need

Opportunity

Antisense: A Solution

182

The Need

Research and development efficiency: The number of new drugs approved by the US Food and Drug Administrator per billion

dollars (inflation adjusted) spent on research and development (R&D) from 1950 to 2010.

Declining Productivity of

Drug Discovery

Scannell et al. 2012. Nature Rev Drug Discov. 183

The Redefinition of Disease into

Actionable Molecular Terms Antisense: Direct from Gene to Treatment

Utilize molecular pathological methods to genetically

validate targets

Focus on factors in or causes of cellular dysfunction or

dysregulation

Develop treatment based on molecular targets and

identifying the patients most likely to respond to

altering that molecular target

The Opportunity:

184

185

Examples of Current Diagnostic

Classifications

Congestive

heart failure

Increased abdominal girth

associated with weak pulse

Psoriasis

Asthma

Cancer

First Use Definition

1550 B.C.

1684 A dry, itching scab

1819 Paroxysmal dyspnea

Ancient Greece Crab-like

invasive tissue

1867 Histological

description of

carcinomas

The Opportunity:

186

Evolution in the Definitions of

Diseases Example: Psoriasis

Qu, Xiaoyan, et al. Drug Discovery Today. 2014. Integrative clinical transcriptomics analyses for

new therapeutic intervention strategies: a psoriasis case study.

The Opportunity:

187

Today’s Molecular Target Identification Analyses for new therapeutic intervention strategies:

a psoriasis case study

Qu, Xiaoyan, et al. Drug Discovery Today. 2014. Integrative clinical transcriptomics analyses for new therapeutic

intervention strategies: a psoriasis case study.

Molecular pathologic methods enable

us to:

Genetically identify and validate

targets in humans

Genetically identify patient

subpopulations

Focus on key molecular pathways

The Opportunity:

22% Undruggable

188

Meeting the productivity needs of the industry

Exploiting the opportunities presented by molecular

medicine

Creating drugs to novel, genetically identified targets

Developing drugs to treat patients most sensitive to treatment and

most likely to achieve greatest benefit

Pursuing the most direct development paths

The Future of Antisense: Creating

the Highest Value Medicines for

Patients with the Greatest Need

The Opportunity:

Isis’ Strategy

Strategy (1 of 2)

190

Broadly exploit antisense technology

Undruggable targets

Multiple targets

Multiple tissues

Multiple routes of administration

Multiple mechanisms

Focus on creating the highest value medicines

Genetically, epigenetically or functionally defined rare diseases

Genetically or functionally defined subpopulations of traditionally defined

diseases

First-in-class or best-in-class

Staged development

190

Strategy (2 of 2)

191

Continue to advance antisense technology

Utilize advanced screening to enhance drug performance

Expand into new routes of delivery (e.g., oral)

Design more potent chemical classes

Create chemical solutions to enhance delivery to specific tissues

Exploit new molecular mechanisms

Apply molecular insights to make more potent and specific antisense drugs

Control technology

Focus on innovation and evergreening IP strategy

Add 3 to 5 new development candidates per year to pipeline

191

Targets

Diseases and subdividing diseases

Making better antisense drugs

Advanced screening

Advanced chemistry

RNA-caused diseases

Maturing pipeline


192 192

193 193

Multi-gene families

PTP-1B, STAT-3

Proteins difficult or impossible to address with small molecules

or antibodies

ApoB-100, clusterin, Factor XI, CRP

Diseases associated with toxic or mis-spliced RNA

ISIS-SMNRx, ISIS-DMPKRx,

Targets that take advantage of antisense tissue specificity

ISIS-GCCRRx


Undruggable Targets

194 194

Subdivide lipid opportunities

Severely elevated LDL-C: KYNAMRO® (HoFH, severe HeFH)

Severely high TGs: ISIS-APOCIIIRx (FCS, >880 mg/dL)

Very high Lp(a) MACE and aortic stenosis: ISIS-APO(a)Rx

HoFH and severe HeFH: ISIS-ANGPTL3Rx

Subdivide diabetes

Severe diabetes: ISIS-GCGRRx

Glucocorticoid related problems: ISIS-GCCRRx (Cushing’s,

obesity associated diabetes, iatrogenic diabetes)


Genetically or Functionally Defined Subpopulations of

Traditionally Defined Diseases

Continue to Advance Antisense Technology

Newer Gen 2.0 Antisense Drugs are More Potent and

Better Tolerated

Newer Gen 2.0 antisense drugs are more potent than

KYNAMRO

Newer Gen 2.0 antisense drugs have fewer and more

mild injection site reactions

Potency derived from target protein reduction after 4 Weeks of Treatment with

200 mg. Compared to KYNAMRO Phase 1 Studies.

195


Medicinal Chemistry Objectives

Improve potency

Improve tolerability

Enhance therapeutic index

Broaden accessible tissues

Lower cost of therapy

Enhance patient convenience

196

197

Gen 2.5 chemistry

Activity in less accessible tissues (e.g., tumors, muscle)

Lower dosing for targets in more accessible tissues (e.g., liver)

LIgand-Conjugated ASOs (LICA) for targeting specific

tissues (e.g., liver)


More Potent Chemical Classes


Isis’ Proprietary Advanced Chemistries

Adds stability Improves

distribution to tissues

Increases potency Increases stability Reduces non-specific

toxicities

Improves potency and therapeutic index

Expands range of targets and tissues

1200 to 3500 mg/week ~100 to 400 mg/week Expect 20 to 80 mg/week

198


Isis’ Novel and Proprietary LICA Technology

Improves distribution to liver Decreases amount of drug needed to

achieve target knockdown in hepatacytes

Up to 10x more potent than corresponding Gen 2.0 or Gen 2.5 compound

LICA

199


LICA Improves Potency of Gen 2.0 and Gen 2.5

Antisense Compounds

Log Dose (mpk)

SR

B m

RN

A (

% U

TC

)

-1 0 1 20

20

40

60

80

100 440762

651900

353382

655861

mR

NA

(%

UT

C)

Gen 2.5-LICA

Gen 2.5

Log Dose (mpk)

SR

B m

RN

A (

% U

TC

)

-1 0 1 20

20

40

60

80

100 440762

651900

353382

655861

mR

NA

(%

UT

C)

Gen 2.0-LICA

Gen 2.0

Antisense

compound

Projected Dose in

Humans (mg/wk)

Gen 2.0 200

Gen 2.0-LICA 20

Gen 2.5 20

Gen 2.5-LICA 2

200

(Mouse)


Multiple Tissues, Multiple Routes of Delivery

Antisense drugs are proven

to work in multiple tissues

Antisense drugs can be effectively

delivered through multiple routes

Demonstrated that oral delivery of antisense drugs is

feasible with KYNAMRO

Gen 2.5 antisense drugs are more potent and may

enable commercial feasibility of oral delivery

201

202


Example of the Application of Isis’ Strategy: Rare Disease Program

Major programs within Isis R&D spanning a

broad range of therapeutic areas

10 rare disease programs currently in

development

5-10 new programs to enter development

in the next two years

Genetically defined targets and diseases

Monogenic diseases

Gain-of-toxic protein functions

Gain-of-toxic RNA functions

Loss of function due to altered RNA processing

Polygenic diseases

202

203

Isis Rare Disease Program Relies on a Consortium of Broad

Collaborations for Continued Infusion of New Targets

Disease causal information obtained directly from the source

Close working relationships established

Collaborative working relationships that have led to multiple rare disease

clinical programs today

Isis

NIH/NCI NINDS

The Cancer Genome Atlas

Academic

Investigators Sequencing

Centers

Cold Spring Harbor

MIT

U. of Michigan

Garvan Institute

U. Of Washington

Stanford U.

U. Of Queensland

Beijing U.

UCSD

Beijing Genomic

Institute (BGI)

Illumina

Rare Disease

Organization

Patient

Advocacy

Groups

Genomic

Consortium

National Organization for

Rare Disorders (NORD)

Rare Diseases Europe

(EURORDIS)

Canadian Organization for

Rare Disorders (CORD)

100K Genome Project

Rare Diseases Clinical

Research Network (RDCRN)

Canadian Pediatric Genetic

Disorders Sequencing

Consortium

The BRIDGE consortium

(NIHR)

MDA

AFM

Families of SMA

Amyloid Foundation

Isis’ Rare Disease Strategy

Complete development of

current antisense drug

candidates

Continue to mine for

antisense opportunities for

monogenic disease

Near-term

204




candidates



monogenic disease

Continue to mine GWAS

and transcriptome data sets

for genetically caused rare

disease opportunities

Identify additional

opportunities for polygenic

rare diseases and to

subset larger polygenic

diseases into smaller rare

disease opportunities (e.g.

familial hypercholesteremia)

Near-term Mid-term

205




candidates



monogenic disease

Expand to intermediary

metabolic pathways and

other pathways which are

associated with rare


Leverage new RNA biology

and genomic

methodologies to identify

new opportunities for

treating rare diseases

Continue to mine GWAS

and transcriptome data sets

for genetically caused rare


Identify additional

opportunities for polygenic

rare diseases and to

subset larger polygenic

diseases into smaller rare

disease opportunities (e.g.

familial hypercholesteremia)

Near-term Mid-term Long-term

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207

207






ISIS-HBVRx HBV

RG-101 HCV




Commercialized

Phase 2


Phase 1


ISIS-APOCIIIRx FCS


ATL1103 Acromegaly


ISIS-CRPRx CAD




ISIS-EIF4ERx Cancer

Apatorsen

(OGX-427) Cancer

ISIS-STAT3Rx Cancer


EXC 001






Custirsen

(OGX-011)

Prostate / Lung

Cancer





ISIS-DGAT2Rx NASH

ISIS-ARRx Cancer


Preclinical


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208






ISIS-HBVRx HBV

RG-101 HCV




Commercialized

Phase 2


Phase 1


ISIS-APOCIIIRx FCS


ATL1103 Acromegaly


ISIS-CRPRx CAD




ISIS-EIF4ERx Cancer

Apatorsen

(OGX-427) Cancer

ISIS-STAT3Rx Cancer


EXC 001






Custirsen

(OGX-011)

Prostate / Lung

Cancer





ISIS-DGAT2Rx NASH

ISIS-ARRx Cancer


Preclinical



First-in-class

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209






ISIS-HBVRx HBV

RG-101 HCV




Commercialized

Phase 2


Phase 1


ISIS-APOCIIIRx FCS


ATL1103 Acromegaly


ISIS-CRPRx CAD




ISIS-EIF4ERx Cancer

Apatorsen

(OGX-427) Cancer

ISIS-STAT3Rx Cancer


EXC 001






Custirsen

(OGX-011)

Prostate / Lung

Cancer





ISIS-DGAT2Rx NASH

ISIS-ARRx Cancer


Preclinical



Potential Best-in-class

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210






ISIS-HBVRx HBV

RG-101 HCV




Commercialized

Phase 2


Phase 1


ISIS-APOCIIIRx FCS


ATL1103 Acromegaly


ISIS-CRPRx CAD




ISIS-EIF4ERx Cancer

Apatorsen

(OGX-427) Cancer

ISIS-STAT3Rx Cancer


EXC 001






Custirsen

(OGX-011)

Prostate / Lung

Cancer





ISIS-DGAT2Rx NASH

ISIS-ARRx Cancer


Preclinical



Add 3 to 5 New Drugs to Development

Evolution of Isis’ Pipeline Mature Pipeline: Continuing to Grow and Mature

Preclinical

26% (10)

Phase I

18% (7)

Phase II

37% (14)

Phase III

11% (4) Commercial

15%

Preclinical

20%

Phase I

20%

Phase II

24%

Phase III

20%

2014 (projected)

38 Drugs in Development

3 Drugs Commercialized

2020 (projected)

54 Drugs in Development

8 Drugs Commercialized

11 Drugs in Phase 3

Commercial

8% (3)

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Evolution of Pipeline Growing Focus on Genetically and Functionally Defined Targets

Genetically Defined

23% (8)

Functionally

Defined

34% (12)

2014 (projected)

38 drugs in development

Equal distribution between broadly

useful drugs and genetically and

functionally defined drugs

2020 (projected)


Genetically and functionally

defined drugs dominate

Functionally

Defined

32%

Broadly Useful

51% (18)

Broadly Useful

40%

Genetically Defined

28%

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Evolution of Pipeline Growing Focus on Undruggable Targets

Diff. to Target Proteins

57% (22)

2014 (projected)


Targets from multigene families,

tissue selective targets and

targets not druggable by small

molecule or antibodies dominate

2020 (projected)


Expansion of splicing or non-

coding RNA targets

Tissue Selective

11% (4) Splicing & non-

coding RNA

11% (4)

Diff. to Target Proteins

51%

Druggable

17%

Tissue Selective

13%

Splicing or non-

coding RNA

19%

Druggable

21% (8)

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2014 Objectives – On Track

Together with Genzyme, Isis will continue to support KYNAMRO®

development, marketing and commercialization activities

Mature the pipeline

Report Phase 2 data on ISIS-SMNRx at AAN

Report data from up to seven drugs in late-stage development, including Phase

2 data on ISIS-FXIRx and ISIS-GCGRRx

Initiate up to five Phase 3 studies, including Phase 3 studies on ISIS-APOCIIIRx

and ISIS-SMNRx, Plazomicin

Initiate Phase 2 studies on up to three drugs

Broaden pipeline by adding up to five new drugs in both partnered

and unpartnered programs

ISIS-HTTRx and RG-012 have been added to the pipeline to date

Continue to successfully execute business strategy to generate

revenue and cash

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Antisense technology

Proven

Broadly applicable

Genetic-like specificity

Dramatically more efficient than other drug discovery platforms

Broad, mature pipeline of 32 potential first-in-class and best-in-class drugs

that will continue to grow

Opportunities to apply antisense technology continue to expand

Genomics

Epigenomics

RNA functions and targets

Unique business strategy coupled to efficiencies of antisense technology

Isis’ Future: Focused on Value 2014 – A Unique Moment

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The product of years of basic research at Isis ANTISENSE...ANTISENSE years of basic research at Isis...

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