Ionis Pharmaceuticals, Inc. Akcea Therapeutics® Is a Registered Trademark of Akcea Therapeutics, Inc

Jefferies 2019 London Healthcare Conference

November 21, 2019 Forward Looking Language Statement

This presentation includes forward-looking statements regarding our business, financial guidance and the therapeutic and commercial potential of SPINRAZA® (nusinersen), TEGSEDI® (inotersen), WAYLIVRA® (volanesorsen) and Ionis' technologies and products in development, including the business of Akcea Therapeutics, Inc., Ionis' majority owned affiliate. 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 medicines that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such medicines. 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, 2018 and our most recent Form 10-Q quarterly filing, which are on file with the SEC. Copies of these and other documents are available at www.ionispharma.com. 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 registered trademark of Akcea Therapeutics, Inc. TEGSEDI® is a trademark of Akcea Therapeutics, Inc. WAYLIVRA® is a registered trademark of Akcea Therapeutics, Inc. SPINRAZA® is a registered trademark of Biogen.

2 Creating Patient and Shareholder Value by Delivering Transformative Medicines

3 commercial medicines 30 years advancing 40+ medicines in technology development Leader in RNA Ever-better targeted therapeutics Medicines targeting rare performance and common diseases Strong financial Greater commercial foundation 4 Phase 3 programs opportunities underway by YE 2019

3 Substantially Improved 2019 Financial Guidance Driven by Strong YTD Financial Results

Total Operating Net Cash revenue income income balance

~$1 >$375 >$300 ~$2.2 billion million* million* billion

Previous: Previous: >$725 million Previous: >$100 million achieve net income Previous: ~$2 billion

Returning Value to Shareholders in the Near-Term: Board Authorized up to $125M Share Repurchase

4 *Non-GAAP – please see reconciliation to GAAP in Q319 press release; R&D expense and SG&A expense guidance unchanged Delivering Value Today and in the Future

3 Commercial Medicines 4 Phase 3 Programs Underway 10+ Phase 2 Studies Underway

Neurological Diseases: RG6042 (IONIS-HTT ) Rx Alzheimer's, ALS, Parkinson’s ✔️ Huntington’s disease ✔️

Tofersen (IONIS-SOD1 ) Rare Diseases: Rx Cystic fibrosis, acromegaly, ✔️ SOD1 ALS ✔️ ꞵ-Thalassemia

AKCEA-APO(a)-LRx ✔️ Lp(a)-driven Cardiovascular Cardiometabolic Diseases: Disease ✔️ NASH, CVD, diabetes, hypertension, thrombosis AKCEA-TTR-LRx ✔️ ATTR Cancer & Other Diseases: ✔️Cancer, chronic HBV, AMD, IgA nephropathy

5 Delivering Value Today and in the Future

3 Commercial Medicines 4 Phase 3 Programs Underway 10+ Phase 2 Studies Underway

Neurological Diseases: RG6042 (IONIS-HTT ) Rx Alzheimer's, ALS, Parkinson’s ✔️ Huntington’s disease ✔️

Tofersen (IONIS-SOD1 ) Rare Diseases: Rx Cystic fibrosis, acromegaly, ✔️ SOD1 ALS ✔️ ꞵ-Thalassemia

6 The Foundation-of-Care for SMA Patients of All Ages

> 9,300 patients now on therapy worldwide, some for ~ 7 years*

Earlier and/or longer treatment = greater benefit

>$3.1>$ 4billion** billion** in sales in sales since launchsince andlaunch growing and growing

Blockbuster medicine, commercialized by Biogen Logan, living with SMA

*Includes commercial, EAP and clinical trial patients **As of September 30, 2019 7 For important prescribing and safety information, please refer to: www.spinraza.com Continued Blockbuster Performance with over $1.5 Billion in Global Sales Q3 2019

$212M in Royalties to Ionis ▪ ~9,300 patients now on SPINRAZA therapy worldwide*

• ~11% increase in patients on therapy worldwide • ~8% increase in adult patients in the U.S.**

• Strong performance outside the U.S. in established markets and key markets in Latin America and Asia Pacific

• Patients initiated treatment in China

▪ Approved in over 50 countries ▪ Formal reimbursement in 40 countries

Source: Biogen Q3 2019 Financial Results and Business Update; *Includes commercial patients and patients from the clinical and EAP settings; **Adult SMA patients are the largest SMA patient segment 8 Creating New Futures for SMA Patients and their Families

• Ionis and Biogen are committed to expanding SMA franchise by bringing new, innovative therapies for SMA patients • We are working on a follow-on medicine that increases efficacy and decreases dosing frequency • Candidate expected to enter development in 2020

9 hATTR Polyneuropathy: A Devastating, Fatal Genetic Disease

Characterized by formation of TTR amyloid deposits leading to multi-organ failure

Patients experience progressive neuropathy, nephropathy and severe gastrointestinal symptoms

Rapid decline in quality of life with 3 – 15 year life expectancy from disease onset Chuck, living with hATTR

For safety information about serious side effects, including thrombocytopenia and 10 glomerulonephritis, please see full prescribing information at www.TEGSEDI.com U.S. launch progressing

Commercializing throughout TEGSEDI Multi-Country Europe Launch Underway* Approved in Brazil and launching**

Launched in Canada *Commercialized by Akcea, **PTC launching in Latin America

For safety information about serious side effects, including thrombocytopenia and 11 glomerulonephritis, please see full prescribing information at www.TEGSEDI.com Familial Chylomicronemia Syndrome (FCS), a Severe, Devastating Disease

FCS caused by extremely high triglyceride (TG) levels Potentially fatal, acute pancreatitis and chronic abdominal pain TG and symptoms not meaningfully improved with TG-lowering therapies ~ 3,000 – 5,000 FCS patients worldwide, ~1,000 patients in the EU

*Commercialized by Akcea To view full EU summary of product characteristics for WAYLIVRA, please visit www.WAYLIVRA.eu Alvin, living with FCS 12 Launched in Europe

Only Approved Medicine Discussions with U.S. & for People with FCS* Canadian regulators to determine path forward Plan to expand into Latin America**

*Commercialized by Akcea **Partnered with PTC in Latin America

To view full EU summary of product characteristics for WAYLIVRA, please visit www.WAYLIVRA.eu 13 Medicines Indication Partner Phase 1 Phase 2 Phase 3

IONIS-HTTRx (RG6042) Huntington’s Disease Roche

Tofersen (IONIS-SOD1Rx) ALS Biogen

IONIS-MAPTRx Alzheimer’s Disease Biogen

IONIS-C9Rx ALS Biogen

IONIS-DNM2-2.5 Centronuclear Myopathy Dynacure

Neurological Rx

ION859 (LRRK2) Parkinson’s Disease Biogen

WAYLIVRA® (volanesorsen) FPL Akcea

AKCEA-ANGPTL3-LRx Rare Hyperlipidemias Akcea / Pfizer

Clinical IONIS-GHR-LRx Acromegaly Ionis

IONIS-PKK-LRx Hereditary Angiodema Ionis

IONIS-TMPRSS6-LRx ꞵ-Thalassemia Ionis Pipeline: Rare & Severe

IONIS-ENAC-2.5Rx Cystic Fibrosis Ionis

AKCEA-APO(a)-L CVD Akcea / Novartis Ionis-Owned Rx

AKCEA–TTR-LRx ATTR Akcea

AKCEA–ANGPTL3-L NAFLD/Met. Comp. Akcea / Pfizer & Partnered Rx

AKCEA-APOCIII-LRx CVD Akcea / Novartis

IONIS-GCGR Diabetes Suzhou-Ribo* Medicines Rx

IONIS-FXIRx Clotting Disorders Bayer

IONIS-AGT-LRx Hypertension Ionis

IONIS-AZ4-2.5-LRx CVD AstraZeneca

Cardiometabolic & Renal & Cardiometabolic IONIS-FXI-LRx Clotting Disorders Bayer

ION839 NASH AstraZeneca

IONIS-AR-2.5Rx Prostate Cancer Suzhou-Ribo*

Danvatirsen Cancer AstraZeneca Cancer

IONIS-HBVRx /HBV-LRx Hepatitis B Virus Infection GSK

IONIS-FB-LRx Geographic Atrophy/AMD Roche

Other IONIS-FB-LRx IgA Nephropathy Roche 14 *China rights only ION357 Retinitis Pigmentosa ProQR Delivering Value Today and in the Future

3 Commercial Medicines 4 Phase 3 Programs Underway 10+ Phase 2 Studies Underway

Neurological Disease: RG6042 (IONIS-HTT ) Rx Alzheimer's, ALS, Parkinson’s ✔️ Huntington’s disease ✔️

Tofersen (IONIS-SOD1 ) Severe & Rare Disease: Rx Cystic fibrosis, acromegaly, ✔️ SOD1 ALS ✔️ ꞵ-Thalassemia

AKCEA-APO(a)-LRx ✔️ Lp(a)-driven Cardiovascular Cardiometabolic Disease: Disease ✔️ NASH, CVD, diabetes, hypertension, thrombosis AKCEA-TTR-LRx ✔️ ATTR Cancer & Non-core Diseases: ✔️Cancer, chronic HBV, AMD, IgA nephropathy

15 Four Phase 3 Programs in Progress: Each Employing Ground-Breaking Technology Advances

• Optimization of antisense medicines for CNS diseases ▪ A premier platform for neurodegenerative diseases (rare and common) ▪ Attractive safety and tolerability profile with IT dosing ▪ Experience with IT dosing continues to expand ▪ Addressing targets previously undruggable ▪ Continuing to improve drug profile (e.g., dosing frequency) through medicinal chemistry

• LICA technology represents another recent advancement in Antisense technology ▪ Increased potency ▪ Less frequent dosing ▪ Addressing new tissues ▪ Improved safety and tolerability profile (>1,000 subjects treated to date)

16 Four Medicines in Phase 3 Studies by YE 2019

• Late-stage pipeline targets rare to broad patient populations • Upcoming Phase 3 data readouts AKCEA- AKCEA- APO(a)-L AKCEA- Rx TTR-LRx (Cardiomyopathy) > 8M patients IONIS- TTR-LRx Tofersen (Polyneuropathy) HTTRx > 200K patients (IONIS-SOD1Rx) ~50K patients ~200K patients ~3K patients

2021 Projected Data Readout Timing 2024 and beyond

17 IONIS-HTTRx (RG6042)

Potential Breakthrough Medicine for Huntington’s Disease (HD)

Charles, living with Huntington’s Disease 18 IONIS-HTTRx (RG6042) Potential Breakthrough Medicine for Huntington’s Disease (HD) • Potentially the first disease-modifying medicine for HD

• ~30,000 symptomatic patients in the U.S., similar number in EU

• Robust reductions in mutant huntingtin protein (mHTT)*

• mHTT reduction correlated with improvement in clinical measures of HD**

• Favorable safety and tolerability profile*

*Based on results from open-label extension (OLE) study; **Based on a post-hoc analysis of data from the Phase 1/2 study 19 Pivotal GENERATION HD1 Study Phase 3 Study in Patients with Huntington’s Disease (HD) • Randomized, multicenter, double-blind, placebo-controlled, Phase 3 study of intrathecally administered RG6042 (IONIS-HTTRX) in approximately 800 patients with Huntington’s disease • Enrollment expanded to enable more thorough evaluation of Q16W dosing and to broaden global representation, including sites in China

Intrathecal procedures every 2 months

RG6042 120 mg Q8W GEN-EXTEND OLE

1:1:1 RG6042 120 mg Q16W RG6042 120mg

Randomized Randomized Q8W or Q16W Placebo Q8W

25 months of dosing ~5 years 20 Q8W, every 2 months; Q16W, every 4 months; OLE, open-label extension. Tofersen

(IONIS-SOD1Rx)

Potential Breakthrough Medicine for SOD1 Familial ALS

Sonny, living with ALS

21 Tofersen (IONIS-SOD1Rx/BIIB067): Potential First-in-Class and Best-in-Class Medicine to Treat SOD1-ALS

• More than 1,000 ALS patients diagnosed with SOD1 mutations worldwide

• Mutant SOD1 causes ALS through toxic gain of function in neurons and glia

• Tofersen directly targets a genetic cause of ALS

• Intrathecal delivery to the CSF provides widespread distribution throughout the brain and spinal cord

Phase 3 VALOR study ongoing

* Based on preclinical data 22 Treatment With Tofersen 100 mg Demonstrated Disease Stabilization in Measures of Clinical, Functional and Respiratory Function

Clinical Outcome Lung Function ALSFRS-R % Predicted SVC

0 5 1 5 2 9 5 7 8 5 0 - 4

e - 5

e n

n - 1 0

a i

l - 8

e C

s - 1 5

)

E B

- 1 2 - 2 0

(

m n

o - 2 5

a F e - 1 6

M - 3 0 1 5 2 9 5 7 8 5 - 3 5 - 2 0 Study Day Study Day

O v e r a ll p la c e b o ( n = 1 2 ) O v e r a ll p la c e b o ( n = 1 2 )

a F a s t - p r o g r e s s i n g p l a c e b o ( n = 4 ) F a s t - p r o g r e s s i n g p l a c e b o ( n = 4 )

O v e r a ll t o f e r s e n 1 0 0 m g ( n = 1 0 ) O v e r a ll t o f e r s e n 1 0 0 m g ( n = 1 0 )

F a s t - p r o g r e s s i n g t o f e r s e n 1 0 0 m g ( n = 4 ) F a s t - p r o g r e s s i n g t o f e r s e n 1 0 0 m g ( n = 4 )

a Missing values due to deaths were imputed using last observation carried forward. ALSFRS-R = ALS Functional Rating Scale–Revised; FP = fast-progressing mutation; SVC = slow vital capacity 23 Ionis and Biogen Committed to Treating Patients with All Forms of ALS • Tofersen: The first to demonstrate Breakdown of ALS Other significant reductions in SOD1 and trends Familial in slowing of disease progression 3% (Phase 3 VALOR study underway) C9ORF • IONIS-C9 : Phase 2 study ongoing in 10% Rx SOD1 C9-familial ALS (data expected 2021) 2% Sporadic 85% • Programs advancing focused on treating all forms of ALS (e.g., sporadic)

Taylor, J., et. al., (2016) Nature; 539: 197-206 24 Michael, living with Lp(a) driven Cardiovascular Disease

AKCEA-APO(a)-LRx

Addressing a Remaining Major Lipid Risk Factor in Cardiovascular Disease (CVD)

25 AKCEA-APO(a)-LRx (TQJ230)* First and Only Medicine to Selectively and Robustly Reduce Lp(a) Levels

• Lp(a) is a genetically determined risk factor for cardiovascular disease

• > 8 million people worldwide that have Lp(a) driven CVD

• No approved pharmacological therapies, statins ineffective

• Completed Phase 2 study was the largest, longest study conducted in patients with Lp(a)-driven CVD ▪ Robust, dose-dependent and durable reductions in Lp(a) levels in patients treated for 6 months, with some patients treated for up to 1 year in Phase 2 ▪ Favorable safety and tolerability profile and excellent compliance • Convenient, once monthly, low volume, subcutaneous dosing

*Co-developing with Akcea and Novartis 26 AKCEA-APO(a)-LRx Phase 2 Study: ~98% of Patients in the High Dose Group Achieved Lp(a) Levels Below 50 mg/dL

Percent of patients achieving Lp(a) ≤ 50 mg/dL (≤ 125 nmol/L)

-15

-40 ≤ 50 mg/dL is considered below the threshold for

-65 risk of CVD events Percent

Monthly Total 20 mg 40 mg 40 mg 60 mg 80 mg 27 QW, once a week; Q2W, every 2 weeks; Q4W, every 4 weeks AKCEA-APO(a)-LRx (TQJ230) Pivotal Phase 3 HORIZON Study Novartis Planning to Begin Enrolling Patients Early 2020

• A multicenter, randomized, double-blind, placebo-controlled study in approximately 7,500 patients with elevated Lp(a) levels and established cardiovascular disease (CVD) • Primary objectives: ▪ Time to occurrence of first major adverse cardiovascular event in patients with Lp(a) levels of ≥ 70 mg/dL ▪ Time to occurrence of first major adverse cardiovascular event in a population of patients with Lp(a) levels of ≥ 90 mg/dL • Secondary objectives: ▪ Evaluate the time to fatal and non-fatal major adverse cardiovascular events in patients with elevated levels of Lp(a)

Monthly 80mg SubQ Injections or Placebo

Up to 4 years R

Screening & Follow-up Period Diet Stabilization

Projected Study Completion 2024 28 AKCEA-TTR-LRx

For Patients with Hereditary and Wildtype ATTR

Clay, living with ATTR

29 AKCEA-TTR-LRx: Expanding the ATTR Franchise LICA follow-on medicine in development for all forms of ATTR (hereditary and wild type) • >250K people worldwide have TTR amyloidosis (hereditary and non-hereditary) • Phase 3 program includes patients with hATTR & wtATTR cardiomyopathy and hATTR polyneuropathy; enrollment expected to begin soon Robust target reduction and positive safety profile demonstrated in healthy volunteers • Robust TTR reductions of greater than 90% demonstrated • Favorable safety and tolerability observed Utilizes our most advanced LICA chemistry, providing high potency with greatly improved convenience and tolerability

30 AKCEA-TTR-LRx Phase 1 Study (Healthy Volunteers)

• Robust, dose- dependent reductions in TTR levels • Favorable safety profile – no SAEs, no treatment- Nadir related safety -86% signals -86% -94%

31 AKCEA-TTR-LRx Phase 3 Study: TTR Cardiomyopathy Enrollment Expected to Begin Shortly

• A Phase 3 global, double-blind, randomized, placebo-controlled study to evaluate the efficacy and

safety of AKCEA-TTR-LRx in approximately 750 patients with TTR cardiomyopathy • Objectives ▪ Primary composite endpoint: CV death and CV clinical events ▪ Secondary endpoints: 6MWT, KCCQ, CV clinical events ▪ Exploratory endpoints: Echo, biomarkers, PROs, (potential CMRI sub-study)

1:1 AKCEA-TTR-LRx Patients with hATTR-CM or

wtATTR-CM on treatment -

available SoC Screening Post

Placebo Evaluation Period Randomization Randomization

D1 W4 W8 W12 W24 W36 W48 W60 W72 W84 W96 W108 W120

32 AKCEA-TTR-LRx Phase 3 Study: hATTR Polyneuropathy Enrollment Expected to Begin Shortly

• Adults with hATTR polyneuropathy meeting all 3 of the following criteria: ▪ Stage 1 or Stage 2 ▪ Documented TTR genetic mutation ▪ Symptoms and signs consistent with polyneuropathy (NIS ≥ 10 and ≤ 130)

NEURO-TTR Historical Placebo (60 patients)

AKCEA-TTR-LRx ~120 patients AKCEA-TTR-LRx Patients with Post Tx / hATTR-PN OLE

Screening Inotersen AKCEA-TTR-L

~20 patients Rx Randomization 6:1 Randomization

Baseline Week 35 Week 66 Week 85

33 Delivering Value Today and in the Future

3 Commercial Medicines 4 Phase 3 Programs Underway 10+ Phase 2 Studies Underway

Neurological Disease: RG6042 (IONIS-HTT ) Rx Alzheimer's, ALS, Parkinson’s ✔️ Huntington’s disease ✔️

Tofersen (IONIS-SOD1 ) Severe & Rare Disease: Rx Cystic fibrosis, acromegaly, ✔️ SOD1 ALS ✔️ ꞵ-Thalassemia

34 A Broad and Advancing Mid-Stage Pipeline

MORE MEDICINES ADDRESSING THE LARGEST PATIENT POPULATIONS WORLDWIDE

MEDICINE INDICATION MARKET OPPORTUNITY PHASE PARTNER

IONIS-MAPTRx Alzheimer’s disease Broad

ION859 (LRRK2) Parkinson’s disease 2 Biogen Neuro IONIS-C9Rx Familial ALS Rare

IONIS-GHR-LRx Acromegaly

IONIS-PKK-LRx Hereditary Angioedema Rare 2 Ionis-owned

Rare IONIS-TMPRSS6-LRx b-Thalassemia Severe & & Severe IONIS-ENaC-2.5Rx Cystic fibrosis

AKCEA-ANGPTL3-LRx Cardiometabolic disorders Akcea/Pfizer AKCEA-APOCIII-L - Rx Cardiovascular disease Akcea/Novartis 2 Ionis-owned IONIS-GCGR Diabetes Broad Rx (Suzhou-Ribo China)

Cardio IONIS-AGT-L metabolic Rx Hypertension Ionis-owned

IONIS-FXI-LRx Thrombosis 1 Bayer Ionis-owned IONIS-AR-2.5 Prostate Cancer Rx (Suzhou-Ribo China) Danvatirsen Cancer AstraZeneca Broad 2

Other IONIS-HBV-LRx Hepatitis B virus infection GSK Cancer & & Cancer IONIS-FB-LRx Complement-mediated diseases Roche 35 Key Pipeline Programs and Recent Achievements Robust Pipeline Positioned to Deliver Growth

• Robust, sustained reductions in HBsAg and viral load observed in Phase 2 studies HBVRx/HBV-LRx • $25M from GSK to license HBV program Chronic Hepatitis B • More than 200 million people with chronic hepatitis B virus infection worldwide

• Data from Phase 2 study planned for early 2020; Pfizer to conduct & fund future studies ANGPTL3-LRx Cardiometabolic • Pfizer licensed for $250M upfront & milestones up to $1.3B + royalties in low 20% range Diseases • Millions of patients with cardiovascular and metabolic diseases worldwide

• Demonstrated reduction in thrombosis without increased risk of bleeding with parent IONIS-FXI-LRx • $10M milestone from Bayer to advance IONIS-FXI-LRx Thrombosis • Millions of people with thromboembolic disorders worldwide

• Phase 1/2 study in patients with sporadic and LRRK2 Parkinson’s disease underway ION859 (LRRK2) • $8M from Biogen for initiation of Phase 1/2 study Parkinson’s Disease • ~3 million people with Parkinson’s disease worldwide

36 Advances in Antisense Technology

37 Methods of Administration and Technology Advances Create Breadth in Our Pipeline Today

ADMINISTERED THROUGH BROAD CLINICAL ACTIVITY MULTIPLE ROUTES OF DELIVERY IN MULTIPLE TISSUES

Intraocular Oral Eye Brain

Inhalation Lung Intradermal Intrathecal Skin Spinal Cord I.V. Subcutaneous Liver Tumor Enema Pancreas Kidney Bowel Fat Muscle

Multiple routes of delivery, multiple target tissues 38 Methods of Administration and Technology Advances Create Breadth in Our Pipeline Today

ADMINISTERED THROUGH BROAD CLINICAL ACTIVITY MULTIPLE ROUTES OF DELIVERY IN MULTIPLE TISSUES

Intraocular Oral Eye Brain

Inhalation Lung Intradermal Intrathecal Skin Spinal Cord I.V. Subcutaneous Liver Tumor Enema Pancreas Kidney Bowel Fat Muscle

Multiple routes of delivery, multiple target tissues 39 Ionis Created, Validated, and Continues to Advance an Efficient RNA-Targeting Platform

DELIVERING GREAT VALUE TODAY AND BEYOND

Most Direct Route Uniquely specific and broadly applicable from Gene to Medicine

Efficient Discovery & Dramatically reduced cost and increased Early Development success through clinical proof of concept

Consistent Performance Within Higher success rate in discovery and Chemical Classes development

Advances Rapidly Incorporated Chemistry, manufacturing, formulation, Across the Entire Pipeline analytical methods

Consistent Pipeline Robust, mature, diversified pipeline, Growth adding 3-5 new medicines per year

40 IONIS: A FORCE FOR LIFE