Ionis Pharmaceuticals Annual Shareholder Meeting

June 3, 2016

TM

Forward Looking Language Statement

2

This presentation includes forward-looking statements regarding Ionis Pharmaceuticals’ financial position and outlook, Ionis’ business, and the therapeutic and commercial potential of Ionis’ technologies and products in development, including the commercial potential of IONIS-TTRRx, nusinersen, volanesorsen and KYNAMRO®. Any statement describing Ionis’ 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. Ionis’ 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 Ionis’ forward-looking statements reflect the good faith judgment of its management, these statements are based only on facts and factors currently known by Ionis. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Ionis’ programs are described in additional detail in Ionis’ annual report on Form 10-K for the year ended December 31, 2015, and its most recent quarterly report on Form 10-Q, which is 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, “Ionis,” “Company,” “we,” “our,” and “us” refers to Ionis Pharmaceuticals and its subsidiaries. Ionis Pharmaceuticals™ is a trademark of Ionis Pharmaceuticals, Inc. Akcea Therapeutics™ is a trademark of Ionis Pharmaceuticals, Inc. KYNAMRO® is a registered trademark of Kastle Therapeutics.

We have created and validated a drug discovery platform and developed a pipeline of first and

best-in-class medicines of high value for patients with significant unmet medical needs.

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We Are Revolutionizing Medicine. Saving Lives.

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Our Antisense Technology…

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Works Broadly Throughout the Body Liver, muscle, brain, spinal cord, eye, cancer cells, fat, kidney, heart, lung

Works Through Many Different Mechanisms Decrease or increase protein production, alter splicing, decrease toxic RNAs

Works on All Types of RNA mRNA, long non-coding RNA, toxic RNA, microRNA

Works by Many Routes of Administration SQ, IT, IV, IM, enema, inhaled, intra-ocular, oral

Ionis: Creating Value

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Three groundbreaking medicines close to commercialization

High-value pipeline of first-in-class and best-in-class drugs targeting inadequately treated diseases

Innovations in RNA-targeted drug technology creating better medicines and expanding opportunities

Near-term potential for profitability

Very few cases of serious platelet declines in Phase 3 studies

IONIS-TTRRx in NEURO-TTR study

Volanesorsen in APPROACH FCS study

Misperception that serious platelet declines may have broader implications

Issues Regarding Platelet Declines

7

Platelet reductions are a frequently observed sporadic side effect of many drugs

Most are “idiosyncratic” meaning mechanism unknown

Platelet reductions are easily monitored and managed

Many potential contributors to platelet reductions

Drug/disease-specific interaction

Concomitant medications

Infections

What We Know About Platelet Declines

8

Partial List of Drugs/Classes Known to Cause Thrombocytopenia

Antibiotic

Aminosalicylic acid

Amphotericin B

Ampicillin

Ceftriaxone

Co-trimoxazole

Ethambutol

Methicillin

Nalidixic acid

Novobiocin

Penicillin

Piperacillin

Rifampicin

Rifampin

Sulfisoxazole

Trimethoprim Sulfamethoxazole

Vancomycin

Over-the-Counter Acetaminophen

Aspirin Ibuprofen Naproxen

Blood thinner Abciximab

Eptifibatide

Heparin

Tirofiban

Beta-blocker Alprenolol

Oxprenolol

Cholesterol Simvastatin

Anti-inflammatory

Aminoglutethimide Diclofenac

Meclofenamate Sulfasalazine

Neuro/ Antidepressant

Carbamazepine Desipramine

Diazepam Haloperidol Mirtazapine Phenytoin

Valproic acid

Heartburn Cimetidine Ranitidine

Anti-parasitic Levamisole Quinidine Quinine

Stibophen Suramin

Chemotherapy Interferon-a lrinotecan Oxaliplatin

Arrhythmia Amiodarone

Digitoxin Digoxin

Quinidine

Others Danazol

(fibrotic breast disease)

Diatrizoate meglumine-diatrizoate sodium

(imaging agent)

Hypertension Chlorothiazide

Methyldopa

Arnold, D.M. et al. (2013) Transfus Med Rev. 27:137-145 9

Partial List of Drugs/Classes Known to Cause Thrombocytopenia

Antibiotic

Aminosalicylic acid

Amphotericin B

Ampicillin

Ceftriaxone

Co-trimoxazole

Ethambutol

Methicillin

Nalidixic acid

Novobiocin

Penicillin

Piperacillin

Rifampicin

Rifampin

Sulfisoxazole

Trimethoprim Sulfamethoxazole

Vancomycin

Over-the-Counter Acetaminophen

Aspirin Ibuprofen Naproxen

Blood thinner Abciximab

Eptifibatide

Heparin

Tirofiban

Beta-blocker Alprenolol

Oxprenolol

Cholesterol Simvastatin

Anti-inflammatory

Aminoglutethimide Diclofenac

Meclofenamate Sulfasalazine

Neuro/ Antidepressant

Carbamazepine Desipramine

Diazepam Haloperidol Mirtazapine Phenytoin

Valproic acid

Heartburn Cimetidine Ranitidine

Anti-parasitic Levamisole Quinidine Quinine

Stibophen Suramin

Chemotherapy Interferon-a lrinotecan Oxaliplatin

Arrhythmia Amiodarone

Digitoxin Digoxin

Quinidine

Others Danazol

(fibrotic breast disease)

Diatrizoate meglumine-diatrizoate sodium

(imaging agent)

Hypertension Chlorothiazide

Methyldopa

Arnold, D.M. et al. (2013) Transfus Med Rev. 27:137-145 10

Not a class effect of 2’ methoxyethyl second generation antisense drugs

Serious platelet declines in only two of more than 15 second generation drugs studied in the clinic (over 3,000 people treated in our integrated safety database)

No evidence of cumulative dosing effect with second generation antisense drugs

Patients treated responsive to dose pause and steroid treatment

Platelet declines not due to these serious mechanisms:

Bone marrow suppression

Heparin-induced thrombocytopenia

Drug-dependent anti-platelet antibodies

Serious Declines in Platelets are Not a Class Effect Observed with Second Generation Antisense Drugs

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Serious Declines in Platelets are Not a Class Effect Observed with Second Generation Antisense Drugs

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Antisense Drug Dose, mg/week

Confirmed, n (%) Placebo (N=597)

ASO Total (N=1,516)

≤75 (N=152)

>75-175 (N=279)

>175-275 (N=776)

>275-375 (N=111)

>375-475 (N=168)

>475 (N=30)

N 566 1,416 144 260 720 107 156 29

≥75 to <100 K/mm3 0 (0.0%) 6 (0.4%) 0 (0.0%) 0 (0.0%) 3 (0.4%) 0 (0.0%) 3 (1.9%) 0 (0.0%)

≥50 to <75 K/mm3 2 (0.4%) 2 (0.1%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 2 (1.3%) 0 (0.0%)

≥25 to <50 K/mm3 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%)

<25 K/mm3 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%)

Post-Baseline Platelet Count in Completed Randomized, Controlled Clinical Studies

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Does not include patients in anticancer studies

Ongoing Investigations Regarding Serious Platelet Declines in Blinded Phase 3 Studies

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Status Completed and Ongoing Investigations

✓ Completed thorough review of safety database

✓ Confirmed not due to bone marrow suppression

✓ Confirmed not due to heparin-induced thrombocytopenia

✓ Confirmed not due to drug-dependent antiplatelet antibodies

In progress Potential drug and dose-specific interaction with disease or element of disease

In progress Potential contributing factors such as current or previous infections

In progress Potential contributing factors such as concomitant medications

Platelet Reductions and the Technology Actions

Introducing more frequent platelet monitoring in our studies

For earlier-stage programs, we benefit from technology advances that enable dramatically lower dosing

Most advanced Phase 2 programs, e.g. IONIS-FXIRX and IONIS-GCGRRX, are planned to be dosed <300 mg/wk

LICAs to be dosed at 20-30 mg/wk

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Three Groundbreaking Medicines Close to Commercialization

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Volanesorsen IONIS-TTRRx Nusinersen

Severe, Progressive and Fatal Disease

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TTR Amyloidosis (ATTR) One Disease Caused by the Formation of TTR Amyloid Deposits Leading to Organ Failure

~10k patients worldwide Age of onset: 30 – 50 TTR amyloid primarily

infiltrates peripheral nerves Loss of nerve function Multi-organ failure Fatal in 5 – 15 years

FAC ~40k patients worldwide Age of onset: 60 – 70 years

Wild-type ~200k patients worldwide Age of onset: >70 years

– Fabio – Dawn – Eric

FAP TTR Cardiomyopathy

TTR amyloid primarily infiltrates the heart

Congestive heart failure Fatal in 3 – 5 years

Mean Max TTR Reduction = 76% Max TTR Reduction = 92%

Robust TTR Reductions Observed in NEURO-TTR Open Label Extension Study As of October 2015

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Attacking the disease at its source

TTR

(mg/

dl)

Mea

n (+

SEM

)

76% reduction

Phase 3 NEURO-TTR Baseline

Phase 3 NEURO-TTR OLE > 3 months (nadir) N=38

Lower limit of quantitation

Preliminary Evidence of Disease Stabilization in FAC and wt-TTR Patients Compared to Natural History Study Presented at EC-ATTR Meeting Nov. 2, 2015

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IONIS-TTRRx vs. Natural History Data from investigator-initiated study (IIS) (Dr. Benson)

No SAEs

Well tolerated

Safety and Tolerability Profile in IIS

-1.9%

14%

Left

Vent

ricul

ar M

ass

% C

hang

e at

12

mon

ths

IONIS-TTRRx (N=3) Natural History Study* (N=5)

Left

Vent

ricul

ar M

ass

% C

hang

e at

12

mon

ths

1.9%

14%

Am. J. Cardiol. 108:285-289, 2011 (*Based on subset of patients with IVS ≥ 1.3cm)

IONIS-TTRRx Development Program Status

Phase 3 NEURO-TTR study and OLE progressing as scheduled with data planned in H1:17

Dr. Benson’s investigator-initiated study in TTR cardiomyopathy patients continuing on schedule

FDA hold relieved

Encouraged by the strong patient retention in NEURO-TTR and the robust participation in the OLE

Pre-specified subgroup analysis for patients with cardiac involvement in NEURO-TTR

Should support optimization of cardiac outcome study

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Potential Mechanisms for Platelet Declines in NEURO-TTR Study

Current hypotheses:

Interaction between IONIS-TTRRx and disease, resulting in anti-platelet antibodies

300 mg dose may be a contributing factor due to high peak plasma concentrations

Multiple potential contributing factors:

Severe, fatal disease with patients who have multiple organ involvement

Contributions from TTR amyloid protein

Concomitant medications

Infections

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We Believe that IONIS-TTRRx has the Potential to be a New Treatment Standard

TTR amyloidosis is a progressive, debilitating, fatal disease for which people have limited or no treatment options

We believe IONIS-TTRRx has the potential to fulfill a high unmet medical need

Robust and sustained TTR reductions One subcutaneous injection, once a week

A committed support program should ensure that both patients and physicians receive:

Appropriate disease education and support Support through reimbursement Training and support for self-administration Appropriate safety monitoring

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IONIS-TTRRx and Patisiran Profiles

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IONIS-TTRRx Patisiran TTR Knockdown 75% - 90% Comparable

Frequency of Administration Once a week Every 3 weeks

Route of Administration SubQ injection, <5 minutes IV Infusion, hours

Administration Setting Home or clinic Clinic only

Pre-treatment Required None

IV steroids, IV and oral antihistamines and acetaminophen

**Chronic administration of steroids • Immunosuppression • Metabolic disorders • Osteoporosis • Affective disorders

Key Reported Safety Concern

*Very few cases of serious platelet declines, which are easily monitored

and managed

†Infusion related reactions despite steroid pre-treatment: 18.5%

Top Reported Tolerability Issues

*Injection site reactions in approximately 1% of all injections

• †Flushing: 25.9% • †Diarrhea: 22.2% • †Nasopharyngitis: 22.2% • †Nausea: 18.5% • †Vomiting: 18.5%

* Blinded Phase 3 study **Berger, M.J. et al. (2012) Support Care Cancer. 20: 1991-1997; † Phase 2 data from Alnylam Investor Presentation April 2016.

IONIS-TTRRx: Continued Progress Toward Commercialization

Next Steps

Upcoming Data Catalysts

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•

• Updated data from Dr. Benson’s investigator-initiated study in patients with TTR cardiomyopathy at ISA in July

• Updated data from the NEURO-TTR OLE at R&D Day in July

• Actively preparing for potential filing and commercial launch

• Once GSK has evaluated data from ongoing studies, they will decide on appropriate next steps for TTR cardiomyopathy

Complete in H1:17

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~3-5k patients worldwide LPL deficiency, resulting in triglycerides

in the 1,000s Metabolic abnormalities, risk of diabetes Multiple hospital admissions Potentially fatal pancreatitis

FCS ~3-5k patients worldwide Inability to store fat, resulting in

triglycerides in the 1,000s NASH, severe insulin resistance Premature death from pancreatitis, liver

cirrhosis and cardiovascular disease

FPL

Familial Chylomicronemia Syndrome (FCS) and Familial Partial Lipodystrophy (FPL) Two Life-threatening Genetic Rare Diseases Marked by Extreme Triglyceride Levels

Constant Risk of Incapacitating Abdominal Pain and Potentially Fatal Pancreatitis

– Lindsey – Andra & Briana

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Volanesorsen: Phase 2 Study Achieved Triglyceride Reductions >1,000 mg/dL in FCS Patients

APOC-III levels reduced up to 90%

TG levels reduced up to 86%

All FCS patients achieved TG levels <500 mg/dL with treatment; below the level recognized for risk of pancreatitis

Volanesorsen: Ideal Profile as a Potential Treatment for Patients with Both FCS and FPL Results From a Broad Phase 2 Program Showed Significantly Improved Lipid Profile

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In FCS patients reduced triglyceride levels up to 86%

Only drug to specifically lower ApoC-III

Improved glucose control, insulin sensitivity

Improved lipid profile including increased HDL-cholesterol

-71% to -88% ApoC-III

-64% to -71% TG

-11% to -58% Non-

HDL-C

+42% to +78% HDL-C

Good Cholesterol

Mean Changes

Volanesorsen Phase 2 Safety and Tolerability Summary Gen 2+ Well Tolerated in Multiple Clinical Studies

Well tolerated in ~100 subjects and patients No flu-like symptoms

Infrequent injection site reactions

No renal function changes

Liver enzymes same as placebo

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Volanesorsen Development Program Status

Phase 3 APPROACH FCS study and OLE progressing as scheduled with data planned in H1:17

Phase 3 COMPASS study continuing on schedule

Platelet levels recovering

DSMB unanimously approved continuing the trial with the modifications we proposed

Reports to regulatory agencies have been filed

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Potential Mechanisms for Platelet Declines in Phase 3 APPROACH Study

Current hypotheses:

Disease could be the cause or a contributing factor

Concomitant medications could be the cause or a contributing factor

Multiple potential contributing factors:

Severe, debilitating disease with patients who have extremely elevated triglycerides

300 mg dose may be a contributing factor due to high peak plasma concentrations

Infections

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Daniel Gaudet, MD, PhD

Associate Professor of Medicine, Université de Montréal Scientific Director and Strategic Development Officer of BioBank, Genome Quebec’s Technological Centers

European Atherosclerosis Society (EAS) June 1, 2016 Plenary session 4: Future Therapeutic Challenges

Specific talk title: Lessons Learned from Emerging Therapies for Severe HTG

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FCS Natural History Program (The SMASH Initiative at ECOGENE)

Systematic review of medical files and hospitalizations of 59 FCS patients

Database of 410 patients with TG > 10 mmol/L

Extensive questionnaires

Genotyping, exome sequencing, gene expression analyses, epigenetics, gut microbiome

Post prandial lipoprotein kinetic studies

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Ref: EAS June 1, 2016 Plenary session 4: Future therapeutic challenges Specific talk title: Lessons Learned from Emerging Therapies for Severe HTG, Daniel Gaudet

Untreated Patients with FCS Experience Low Platelets

Total Sample n = 42

Men n = 22

Women n = 20

Platelets x 103 175.5 (157.6 – 195.4)

171.6 (147.3 – 200.0)

180.4 (154.8 – 210.3)

Platelets < 100 x 103 (%) 9.1 12.5 5

Bleeding n (%) 0 0 0

Ref: EAS June 1, 2016 Plenary session 4: Future therapeutic challenges Specific talk title: Lessons Learned from Emerging Therapies for Severe HTG, Daniel Gaudet

Natural history shows platelet levels below 100K in people with FCS

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Data are geometric mean ± 95% CI

Historical Platelet Count Distribution in FCS Patients (N=42)

Historical platelet count (103)* (at least one value)

Total n=42 (%)

Men n=22 (%)

women n=20 (%)

≤50 2 (4.8) 2 (9.1) 0 (0.0)

≤100 14 (33.3) 8 (36.4) 6 (30.0)

≤130 24 (57.1) 13 (59.1) 11 (55.0)

<200 36 (85.7) 17 (77.3) 19 (95.0)

≥200 37 (88.1) 20 (90.9) 17 (85.0)

≥400 7 (16.7) 3 (13.6) 4 (20.0)

≥500 6 (14.3) 3 (13.6) 3 (15.0)

Group 1 4/42 (9.5)

exclusively <200 (103)

Group 2 6/42 (14.3) exclusively ≥200 (103)

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Ref: EAS June 1, 2016 Plenary session 4: Future therapeutic challenges Specific talk title: Lessons Learned from Emerging Therapies for Severe HTG, Daniel Gaudet

Natural History Shows Substantial Platelet Variability in Patients with FCS

Substantial fluctuations independent of changes in the severity of disease or other factors

Two groups of FCS patients identified:

Group 1: Maximum levels at low end of normal (<200K), minimum levels can be in severely low range (<50K)

Group 2: Maximum platelet counts at high end (~400K), minimum levels still in normal range (>=200K)

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Conclusions and Actions from New FCS Natural History Data

Low platelet counts in people with FCS is transient and fluctuate over months and years without any intervention or health consequences

What we have observed in the Phase 3 APPROACH FCS study is consistent with the natural history

Submitting this new information to regulatory agencies and investigators

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Volanesorsen Platelet Reductions Take Home Messages

Today, we cannot exclude volanesorsen as a contributor

However, natural history study suggests the incidence of severe platelet declines is approximately 5% of monitored patients with FCS

Cyclical variations of platelets in patients with FCS complicate evaluation

Concomitant medications may also contribute

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We Believe that Volanesorsen has the Potential to be a New Treatment Standard

FCS is a severe, debilitating disease for which people have no treatment options to sufficiently lower their triglycerides

We believe volanesorsen has the potential to fulfill a high unmet medical need

Phase 2 data suggest potential TG reductions of 1,500 mg/dL or greater

A best-in-class support program planned to ensure that both patients and physicians receive:

Appropriate disease education and support

Support through reimbursement

Nutritional and lifestyle support

Training and support for self-administration

Appropriate safety monitoring

37

•

Volanesorsen: Continued Progress Toward Commercialization

Next Steps

Upcoming Data Catalysts

Complete in H1:17

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• Ionis and Akcea are actively preparing for potential filing and commercial launch

• Akcea building US and EU sales leadership

•

Complete enrollment

Spinal Muscular Atrophy (SMA) Progressive Muscle Atrophy Caused by Genetic Defects in the SMN1 Gene

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Number one genetic cause of infant death

Most infants will never see their 2nd birthday

Infantile Onset Shortened life expectancy

Difficulty sitting, raising arms, lifting, standing and walking

Childhood Onset

No Currently Approved Therapies

– Miller, Survived 87 days – Peter

~30-35k Patients Worldwide For All Forms of SMA

Increased Muscle Function Scores in Nusinersen-treated Infants with SMA Compared to Natural History (PNCR) As of January 26, 2016

Mean Value*

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Individual CHOP INTEND Change Scores: 12 mg Cohort (N=15)

• Infants continue to demonstrate increases in motor function scores with a mean increase of 22.2 points at 26 months

PNCR Natural History

Individuals

Cha

nge

from

Bas

elin

e in

CH

OP-

INTE

ND

Tot

al S

core

Months on Study

*Mean value calculated based on patient values at each time point.

Baseline Milestones

As of January 26th, 2016

Achieving new sitting motor milestones

Achievement of New Motor Milestones Observed in Nusinersen-treated Infants: Sitting Blue—6 mg, Red—12 mg

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Baseline Milestones

As of January 26th, 2016

Achieving new standing motor milestones

Achievement of New Motor Milestones Observed in Nusinersen-treated Infants: Standing Blue—6 mg, Red—12 mg

42

Baseline Milestones

As of January 26th, 2016

Achieving new walking motor milestones

Achievement of New Motor Milestones Observed in Nusinersen-treated Infants: Walking Blue—6 mg, Red—12 mg

43

44

Increased Permanent Ventilation-free Survival

Surv

ival

Pro

babi

lity

Nusinersen-treated SMN2 2 Copy Patients (N=17) PNCR Control Group (N=23) Survival Time (Months)

Increased Event-Free Survival in Nusinersen-treated Infants with SMA Compared to Natural History (PNCR) As of January 26, 2016

Increased Muscle Function Scores Observed in Nusinersen-treated Children with SMA As of May 2015

Increase in Mean 6MWT Distance Increase in Mean HFMSE Score

Increase in multiple measures of muscle function

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4.4

Phase 2 Study OLE Study Phase 2 Study OLE Study

Mea

n C

hang

e (S

EM) i

n 6M

WT

in M

eter

s

Mea

n C

hang

e (S

EM) i

n H

FMSE

Poi

nts

In the latest analysis, some infants have been dosed for nearly two years, some for nearly three years

The LP injection procedure in infants and children with SMA has been well tolerated

Nusinersen has been well tolerated with no safety concerns to date

No drug-related SAEs

No drug-related adverse changes on neurological exams

No clinically significant changes in CSF safety labs

AEs mostly mild in severity

In the children Phase 2 OLE study, the most frequently observed were related to the injection procedure: post LP syndrome, back pain, puncture site pain and headache (attributed to LP procedure)

Nusinersen Safety and Tolerability Profile in Infants and Children with SMA Safety Profile Supports Continued Development

46

Robust Development Plan to Support Commercialization of Nusinersen

Infant Onset

Pre-symptomatic

Newborns

Childhood Onset

Biogen Study

Phase 3

Biogen Study

OLE Study for Phase 3 Studies

Phase 3

Phase 2 Open Label (Infants)

Phase 2 Open Label (Children)

47

Global Commercial Opportunity

Infant or Childhood

Onset

Nusinersen Phase 3 Study in SMA Infants

Randomized, double-blind, sham-procedure controlled study Global study in 122 SMA infants ≤ 7 months old with two SMN2 genes 13 month study duration, enrollment complete

Recent changes made to primary endpoint based on positive regulatory discussions

Primary efficacy endpoints now include: Proportion of motor milestone responders Time to death or permanent ventilation

Screening ≤ 21 days

R

Study Complete

OLE Induction Doses

2 months 11 months

Maintenance Dose Once Every 4 Months

M13 Last Visit 1 15 29 64 183 302

Cohort Sham Control (n)

nusinersen (n)

12 mg ~40 ~80

48

Randomized, double-blind, sham-procedure controlled study Global study in 126 SMA children 15 month study duration, enrollment complete

Primary efficacy endpoints: Change in Hammersmith motor function score

Cohort Sham Control (n)

nusinersen (n)

12 mg ~42 ~84

49

Nusinersen Phase 3 Study in SMA Children

R

OLE 3 Induction Doses

Maintenance Dose at 6 months

3 months

Screening ≤ 28 days

12 months

Study Complete

M15 Last Visit 274 1 29 85

Nusinersen: Continued Progress Toward Commercialization

Next Steps

• Ionis and Biogen are committed to achieving the most rapid approval possible

• Ongoing, productive conversations with regulatory agencies focused on the fastest path to approval

• Actively preparing for potential filing and commercial launch

Upcoming Data Catalysts

Complete in H1:17

Complete in H1:17

50

Akcea Therapeutics Transforming the Treatment of Serious Cardiometabolic Lipid Disorders

Broad Lipid and Cardiovascular Pipeline with Near-term Commercial Opportunity

Phase 1 Phase 2 Phase 3

IONIS- APO(a)-LRx

Volanesorsen

IONIS-APOCIII-LRx

IONIS-ANGPTL3-LRx

Familial Chylomicronemia Syndrome (FCS)

Familial Partial Lipodystrophy (FPL)

Hyperlipoproteinemia(a) with premature CVD with recurrent MACE

Hyperlipoproteinemia(a) with Calcific Aortic Valve Stenosis

Hyperlipoproteinemia(a) with CV Risk

Mixed Dyslipidemias

Data H1:17

Data 2018

Initiate Ph. 2/3 H2:16

Initiate Ph. 2/3 H1:17

Data H2:16/ H1:17

Initiate Ph. 1/2 H2:16

Initiate Ph. 1/2 H2:16

Planned Next Milestone Preclinical

Drug

Triglycerides above 500 mg/dL

High Triglycerides with Type 2

Diabetes

52

53 53

In Our Pipeline Today, We Have 38 Drugs with the Potential to Transform

the Lives of Patients

Three Groundbreaking Phase 3 Drugs Close to Commercialization

Phase 3 Phase 2 Phase 1 Entering Clinic

54

Entering Pipeline

Nusinersen Infantile Onset SMA Biogen

Nusinersen Childhood Onset SMA Biogen

IONIS-TTRRx Familial Amyloid Polyneuropathy GSK

Volanesorsen Familial Chylomicronemia Syndrome Ionis/Akcea

Volanesorsen Familial Partial Lipodystrophy Ionis/Akcea

Seve

re a

nd R

are

Drugs Indication Partner Phase I Phase II Phase III

High-value Pipeline of First-in-class and Best-in-class Phase 2 Drugs

Phase 3 Phase 2 Phase 1 Entering Clinic

55

Entering Pipeline

IONIS-DMPK-2.5Rx Myotonic Dystrophy 1 Biogen

IONIS-HTTRx Huntington’s Disease Roche

IONIS-SOD1Rx Amyotrophic Lateral Sclerosis Biogen

IONIS-APO(a)-LRx Hyperlipoproteinemia(a)

with premature CVD with recurrent MACE Ionis/Akcea

IONIS-ANGPTL3-LRx Mixed Dyslipidemias Ionis/Akcea

IONIS-FXIRx Clotting Disorders Bayer

IONIS-APO(a)-LRx Hyperlipoproteinemia(a) with CAVS Ionis/Akcea

IONIS-APO(a)-LRx Hyperlipoproteinemia(a) with CV Risk Ionis/Akcea

IONIS-ANGPTL3-LRx Mixed Dyslipidemias Ionis/Akcea

IONIS-AR-2.5Rx Cancer Ionis

IONIS-STAT3-2.5Rx Cancer AstraZeneca

CV

Seve

re a

nd

Rar

e O

nco

Drugs Indication Partner Phase I Phase II Phase III

IONIS-GCGRRx Diabetes Ionis

IONIS-GCCRRx Diabetes Ionis

IONIS-PTP1BRx Diabetes Ionis

IONIS-FGFR4Rx Obesity Ionis Met

abol

ic

High-value Pipeline of First-in-class and Best-in-class Phase 1 Drugs

56

Phase 3 Phase 1 Phase 2 Entering Clinic

Entering Pipeline

IONIS-PKKRx Hereditary Angioedema Ionis

IONIS-GSK4-LRx Ocular Disease GSK

IONIS-HBVRx HBV GSK

IONIS-HBV-LRx HBV GSK

Seve

re

& R

are

Oth

er

Drugs Indication Partner Phase I Phase II Phase III

IONIS-DGAT2Rx NASH Ionis M

Expanding our Pipeline to Broader Disease Opportunities

57

Phase 3 Entering Clinic Phase 1 Phase 2 Entering

Pipeline

Drugs Indication Partner

IONIS-BIIB4Rx Neurodegenerative

Disease Biogen

IONIS-BIIB5Rx Neurodegenerative

Disease Biogen

IONIS-BIIB6Rx Neurodegenerative

Disease Biogen

IONIS-GHR-LRx Acromegaly Ionis

IONIS-RHO-2.5Rx Autosomal Dominant Retinitis Pigmentosa GSK

IONIS-TMPRSS6-LRx β-Thalassemia Ionis

Severe and Rare Cardiovascular

Drugs Indication Partner

IONIS-AGT-LRx Treatment-Resistant

Hypertension Ionis

IONIS-APOCIII-LRx Severely High TGs Ionis/Akcea

Innovations in Technology Creating Better Medicines and Expanding Opportunities

New Chemistries

New Mechanisms

New Targets

58

New Tissues

59

LICA is a Game Changing Advance in the Potency of Ionis’ Antisense Drugs

1

2

3

4

3

4

Ultra-low dose volume (ED50 = 4.5 mg/wk), easy to administer

Flexible dosing: weekly, monthly, quarterly or less frequently

Good tolerability observed in clinical studies

>30-fold more potent in humans as demonstrated by Ionis’ first LICA drug

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Technology Advancements are Translating into Real Value in the Pipeline Today

Drugs Indication Phase

IONIS-APO(a)-LRx Hyperlipoproteinemia(a)

with premature CVD with recurrent MACE Ph. 2 Ph. 2

IONIS-ANGPTL3-LRx Rare Mixed Dyslipidemias

Mixed Dyslipidemias Ph. 2 Ph. 2

IONIS-GSK4-LRx Ocular Disease Ph. 1

IONIS-HBV-LRx HBV Ph. 1

IONIS-GHR-LRx Acromegaly PC

IONIS-TMPRSS6-LRx β-Thalassemia PC

IONIS-AGT-LRx Treatment-Resistant Hypertension PC

IONIS-APOCIII-LRx Severely High TGs PC

Cardiovascular

8 LICA Drugs in Clinical Development

Other Severe & Rare

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Generation 2.5 Broadens Utility and Value of Antisense Technology

1

2

3

4

3

4

Enhanced affinity for target sequence

Up to 10-fold increase in potency

Enhanced target engagement in new tissues, i.e. stromal cells, muscle cells

Good tolerability observed in clinical studies

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Technology Advancements are Translating into Real Value in the Pipeline Today

Drugs Indication Phase

IONIS-DMPK-2.5Rx Myotonic Dystrophy 1 Ph. 2

IONIS-STAT3-2.5Rx Cancer Ph. 2

IONIS-AR-2.5Rx Cancer Ph. 2

IONIS-RHO-2.5Rx Autosomal Dominant Retinitis Pigmentosa PC

Oncology

4 Gen 2.5 Drugs in Clinical Development

Severe & Rare

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Successes Across Our Business: Sustained Financial Strength

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Partners' Extensive R&D Activities Support Robust Pipeline

Researching novel delivery methods

Researching antisense medicines to treat metabolic cardiovascular and renal diseases

Performing clinical and pre-clinical studies

Initiated 2 Phase 2 studies for nusinersen

Contributing significantly to core antisense research

Researching and developing antisense medicines to treat neuro diseases

Initiating Phase 2 for IONIS-HBV-LRx and Phase 2 for IONIS-HBVRx

Researching oral formulation of antisense medicines to treat autoimmune disorders of the GI tract

PoC work in animal models

Conducting biomarker work to support IONIS-HTTRx development plan

Developing IONIS-FXIRx broadly for the prevention of thrombosis

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Kastle Therapeutics is Committed to Growing the Commercial Value of KYNAMRO®

Provides the expertise, financial resources and initiative to maximize the commercial value of KYNAMRO

Ensures that patients with HoFH who need treatment most will be able to receive KYNAMRO

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Turns a profit share agreement into one that immediately adds to our income

Upfront $15M, $10M on the 3 year anniversary of the deal Share in success, mid teens royalties Share in success, $70M in sales milestones Share in success, 10% common equity position

Ionis’ Early-stage Research Collaboration with MDACC Leading to Oncology Franchise Growth

MDACC’s access to genetically defined patient populations, preclinical models and clinical expertise will enable us to increase the number of cancer programs in our pipeline

Access to MDACC’s novel, undruggable cancer targets could potentially offer breakthrough approaches to treating cancer

Our Gen 2.5 chemistry provides enhanced potency for effectively engaging targets in solid and liquid tumors

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We and MDACC can focus on our respective areas of expertise facilitating rapid progress in moving each drug through clinical POC

Revenue 2012 – 2015

Ionis Has Built a Strong Financial Foundation

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Pro Forma Operating Loss 2012 – 2015

Profitable in 6 Quarters Since the Beginning of 2012

($100)

($80)

($60)

($40)

($20)

$0

2012

2013

2014 2015

2015

Sustainable Revenue and Cash Base from Partnerships

Cash 2012 – 2015

$102M

$147M

$214M

$284M

$0

$50

$100

$150

$200

$250

$300

2012 2013 2014 2015E

$374M

$657M $729M

$779M

$0

$100

$200

$300

$400

$500

$600

$700

$800

$900

2012 2013 2014 20152015

Key Clinical Data Events Planned in 2016 and Early 2017

Q3:16 Q4:16 Ph. 3 Events H1:17

IONIS-TTRRx: Ph. 2 Data in ATTR-CM (Benson)

IONIS-TTRRx: Ph. 3 Data Update in FAP OLE

IONIS-FGFR4Rx: Ph. 2 Data

IONIS-DMPK-2.5Rx: Ph. 1/2 (MAD) Data

IONIS-DGAT2Rx: Ph. 1 Data

IONIS-ANGPTL3-LRx: Ph. 1 Data

Nusinersen: Ph. 3 Data for CHERISH

Volanesorsen: Ph. 3 Data for FCS

Nusinersen: Ph. 3 Data for ENDEAR

IONIS-TTRRx: Ph. 3 Data for NEURO-TTR

IONIS-FXIRx: Ph. 2 Data

IONIS-STAT3-2.5Rx: Ph. 2 Data

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IONIS-AR-2.5Rx Ph. 2 Data

IONIS-GSK4-LRx Ph. 1 (SAD) Data

IONIS-GCGRRx Ph. 2 Data (interim)

IONIS-APO(a)-LRx Ph. 1 Data

Join Us for Ionis’ R&D Day

• Highlights from three Phase 3 drugs

• New data from earlier stage pipeline

• Insights on technology advances

• Experts on SMA, FCS, and TTR Amyloidosis

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Ionis’ R&D Day Presentation London Hotel, New York

8:30 am EST, July 13, 2016

Presentation Highlights

Revolutionizing Medicine. Saving Lives.