2020 Annual Meeting of Stockholders Brett P

2020 Annual Meeting of Stockholders Brett P. Monia, Ph.D. Chief Executive Officer 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, including those related to the impact COVID-19 could have on our business, including but not limited to the impact on our commercial products and the medicines in our pipeline, and 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, 2019, which is 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 A commitment to science, to medicine and to patients

3 The leader of innovation in biotech providing hope and transformational benefit to millions of patients living with Vision severe diseases

• Focus on innovation and scientific excellence • Expand the scope of antisense technology • Increase and diversify investments in new technologies • Prioritize growth of the Ionis-owned pipeline and optimize our commercialization strategies • Leverage our financial strength • Substantially and consistently increase delivery of our transformational medicines to patients in great need

4 Potential Next Wave of Commercial Products

AKCEA-APOCIII-LRx ION541 Anticipated NDA filings for both Severe hypertriglyceridemia Sporadic ALS broad and rare diseases through ION373 IONIS-TMPRSS6-LRx 2025 Alexander disease β-thalassemia

IONIS-GHR-LRx IONIS-HBVRx / IONIS-HBV-LRx Acromegaly Hepatitis B virus infection

AKCEA-APOCIII-L IONIS-C9Rx Vupanorsen Rx (BIIB078) FCS (AKCEA-ANGPTL3-LRx) C9-ALS CV/metabolic disease

Tominersen IONIS-PKK-L ION716 (IONIS-HTT / RG6042) Rx Rx Hereditary angioedema Prion diseases Huntington’s disease

Tofersen AKCEA-APO(a)-L AKCEA-TTR-L AKCEA-TTR-L Rx (IONIS-SOD1 / BIIB067) Rx Rx (TQJ230) Rx hATTR polyneuropathy ATTR cardiomyopathy SOD1-ALS Cardiovascular disease

2021 2025 and beyond

5 Ionis 2020: Stronger than Ever

▪ Executing on our strategic goals • Commercial products performing well • Phase 3 pipeline on track to achieve many potential approvals, short and mid-term • Excellent early/mid-stage pipeline performance with additional POC readouts this year • Advancing our Ionis-owned pipeline • Technology advancing at record pace ▪ Team of dedicated & resilient employees committed to serving patients in need ▪ Effectively managing the challenges of COVID-19 ▪ On track to deliver NDAs for 10 or more medicines through 2025

Well Positioned to Achieve Our 2020 Goals

6 Six or More Mid-Stage Clinical POC Achievements in 2020

AKCEA-APOCIII-LRx IONIS-ENaC-2.5Rx ✔️ (Hypertriglyceridemia) (Cystic fibrosis/Pulmonary delivery)

Vupanorsen IONIS-TMPRRS6-LRx ✔️ (Cardiometabolic diseases) (ꞵ-thalassemia)

IONIS-GHR-LRx IONIS-AGT-LRx (Acromegaly) (Hypertension)

IONIS-PKK-L Rx IONIS-AZ4-2.5LRx (Hereditary angioedema) (Cardiovascular diseases – SC/Oral)

7 Strong Financial Performance

Q1 2020 FY 2020 $133M Reaffirmed Revenue 2020 financial guidance $84M >$700M Commercial revenues Revenue Driven by SPINRAZA royalties of $66M ~$650M-$690M $2.4B Operating Expenses Cash Enabling investment across the business to drive value creation Meaningfully Profitable

8 Strong Growth from

Commercial • Commercial revenue continues to deliver Medicines with 24% YOY growth • Growth expected from all commercial medicines

9 Continued Blockbuster Performance with $565 Million in Q1 2020 Global Sales

1 $66M in Royalties to Ionis ▪ ~10,800 patients on SPINRAZA therapy worldwide2,3

• U.S. growth driven primarily by adult patients4

• Growth across all regions outside the U.S.

▪ Continued opportunity for growth

• Significant number of untreated patients in established and emerging markets

▪ Potential to achieve greater efficacy with a higher dose in the DEVOTE Phase 2/3 study

Source: Biogen Q1 2020 Financial Results and Business Update; 1. SPINRAZA royalty tier resets at the beginning of each year; 2. Includes patients from commercial, clinical and EAP settings; 3. As of March 31, 2020; 4. Adult SMA patients are the largest SMA patient segment

10 For important prescribing and safety information, please refer to: www.spinraza.com TEGSEDI: A Transformative Medicine for the Treatment of Patients with hATTR Amyloidosis with Polyneuropathy

• Consistent quarter over quarter growth • Strong growth in the U.S. • Launching in additional EU countries • Expanding in Latin America with PTC

Commercially available in 13 countries

11 Only Approved Treatment for FCS Patients

Approximately 1,000 patients eligible for treatment

Increased risk of diabetes, chronic • Approved in Europe pancreatitis and acute, potentially fatal pancreatitis • Commercially available in Germany & Austria • Continued ATU enrollment in France Major emotional and psychosocial effects • Partnership with PTC in Latin America; 2H20 Brazil filing planned Difficulty maintaining employment due to repeated hospitalizations and chronic WAYLIVRA was discovered by Ionis and co-developed by Ionis and Akcea physical & cognitive symptoms

On track to refile with the FDA this year

12 2020 Pipeline Performance

13 IONIS CLINICAL PIPELINE MEDICINES INDICATION PARTNER P HAS E 1 P HAS E 2 P HAS E 3

Tominersen (IONIS-HTTRx) Huntington’s disease Roche

Tofersen (IONIS-SOD1Rx) ALS Biogen SPINRAZA (nusinersen) SMA Biogen

IONIS-MAPTRx Alzheimer’s disease Biogen

IONIS-C9Rx ALS Biogen

NEUROLOGICAL ION859 Parkinson’s disease Biogen

IONIS-DNM2-2.5Rx Centronuclear myopathy Dynacure

AKCEA–TTR-LRx ATTR cardiomyopathy Akcea

AKCEA–APO(a)-LRx CVD Akcea

Vupanorsen (AKCEA–ANGPTL3-LRx) NAFLD/Metabolic disease/CVD Akcea / Pfizer

AKCEA-APOCIII-LRx CVD Akcea

IONIS-GCGRRx Diabetes Ionis / Suzhou-Ribo*

IONIS-AGT-LRx Treatment-resistant hypertension Ionis

IONIS-FXI-LRx Clotting disorders Bayer

IONIS-AZ4-2.5-LRx CVD AstraZeneca ION839 NASH AstraZeneca

CARDIOMETABOLIC & RENAL & CARDIOMETABOLIC ION532 Kidney disease AstraZeneca ION224 NASH Ionis

AKCEA-TTR-LRx hATTR polyneuropathy Akcea

AKCEA-APOCIII-LRx FCS Akcea

IONIS-GHR-LRx Acromegaly Ionis

IONIS-PKK-LRx Hereditary angioedema Ionis RARE IONIS-TMPRSS6-LRx b-thalassemia Ionis

IONIS-ENAC-2.5Rx Cystic fibrosis Ionis ION357 Retinitis pigmentosa ProQR

IONIS-AR-2.5Rx Prostate cancer Ionis / Suzhou-Ribo*

CANCER Danvatirsen Cancer AstraZeneca IONIS-HBV /HBV-L Hepatitis B virus infection GSK Rx Rx 14

OTHER IONIS-FB-LRx Complement mediated diseases Roche *China rights only Ionis Delivering Medicines for Most Major Severe Diseases

NEUROLOGICAL NEUROMUSCULAR CARDIOVASCULAR METABOLIC UltraPULMONARY-rare to Common Diseases CANCER HEMATOLOGICAL KIDNEY OPHTHALMOLOGY INFECTIOUS DISEASE

15 Ionis Leads the Way in Neurological and Cardiometabolic Drug Development

AKCEA-TTR-LRx AKCEA-APO(a)-L Tominersen (IONIS-HTTRx) Rx IONIS- Vupanorsen (AKCEA-ANGPTL3-L ) Tofersen (IONIS-SOD1Rx) Rx OWNED AKCEA-APOCIII-L SPINRAZA ION283 Rx IONIS-GCGR IONIS-MAPTRx ION373 Rx ION716 IONIS-AGT-L IONIS-C9Rx Rx AKCEA-TTR-L NEUROLOGICAL Rx CARDIOMETABOLIC AKCEA-APOCIII-LRx IONIS-GCGR ION859 Rx IONIS-AZ4-2.5-LRx IONIS-AGT-L Rx IONIS-FXI-LRx IONIS-DNM2-2.5Rx ION224 ION283 ION547 ION839 ION373 ION904 ION532 ION716 ION224 ION547 ION904

16 2020 Neurological Pipeline Performance Neurological

▪ Enrollment complete in the tominersen Phase 3 GENERATION HD1 study for Huntington’s disease, with data expected in 20221 Enrollment complete in the tominersen Phase 3 GENERATION HD1 study for Huntington’s disease with data expected in 20221 ▪ First patient treated in Phase 2/3 DEVOTE study of higher dose SPINRAZA2

▪ Tofersen Phase 3 VALOR study for SOD1-ALS on track with data expected in 20212; granted Orphan Drug Designation by the FDA

2 2 ▪ IONIS-C9TofersenRx granted Phase Fast Track 3 VALOR Designation study for in SOD1 the U.S.;-ALSPhase on track 2 study with datain C9 expected-ALS progressing in 2021 on track ; ION541 on track to initiate first-in-human study in patients with sporadic ALS this year2

2 ▪ IONIS-MAPTRx Phase 2 study for Alzheimer’s disease progressing on track

3 ▪ Advanced IONIS-DNM2-2.5Rx into Phase 1/2 study for the treatment of centronuclear myopathies

1. Roche study; 2. Biogen study; 3. Dynacure study 17 Tominersen • Phase 3 program for Huntington’s disease (IONIS-HTTRx) • The first and only late-stage medicine that targets the cause of Huntington’s disease

• Fully enrolled, data expected in 2022

Huntington’s disease • Granted PRIME designation by the EMA

18 Huntington’s disease (HD): A devasting, fatal genetic neurological disease

• Fatal disease characterized by progressive physical and Normal brain cognitive degeneration

• ~40,000 symptomatic patients in the U.S.1

• Described as suffering from ALS, Parkinson’s and Alzheimer’s – simultaneously2

• Genetic disease passed-down from parents to their children – devastation continues across multiple generations Huntington’s brain

• Symptom onset typically occurs between ages 30-50, progressing to death 15-20 years from symptom onset • No effective treatments or cure

1. Roche data on file; 2. The Huntington’s Disease Society of America 19 Charles Sabine Delivers a Message of Hope

20 Tominersen (IONIS-HTTRx) Potential breakthrough medicine for Huntington’s disease

• Potential to be the first and only disease-modifying medicine because it targets the cause of HD • Robust and sustained reductions in mutant huntingtin protein (mHTT)* in patients • Favorable safety and tolerability profile* • Long durability of action (bi-monthly and tri-annual dosing) • Granted PRIME designation by the EMA

*Based on results from open-label extension (OLE) study 21 Pivotal GENERATION HD1 Study Phase 3 study in patients with Huntington’s disease

• Randomized, multicenter, double-blind, placebo-controlled, Phase 3 study of intrathecally administered tominersen (IONIS-HTTRx) in approximately 800 patients with Huntington’s disease

Intrathecal procedures every 2 months

tominersen 120 mg Q8W GEN-EXTEND OLE

tominersen 120 mg Q16W tominersen 1:1:1 120mg Q8W or Randomized Q16W placebo Q8W

25 months of dosing ~5 years

Fully enrolled Results expected in 2022 22 Q8W, every 2 months; Q16W, every 4 months; OLE, open-label extension. Amyotrophic Lateral Sclerosis (ALS) • ALS is a rapidly progressing fatal neurodegenerative disease

• There are two forms of ALS: Genetic (familial) and Sporadic

• We are committed to treating all forms of ALS “Lou Gehrig’s Disease”

23 Amyotrophic Lateral Sclerosis A fatal disease with a tremendous unmet medical need

Genetic forms (familial) and non-genetic forms (sporadic) of ALS exist*

▪ ~ 51,000 of ALS cases have sporadic causes • More than 1,000 SOD1-ALS patients • More than 3,000 C9ORF-ALS patients ▪ Devastating and rapidly progressing disease ▪ Patients become paralyzed, yet still have normal cognitive abilities ▪ Patients usually die of their disease within 3 to 5 years from symptom onset

*ALS prevalence for G7 countries include the U.S., Germany, the U.K., France, Italy, Spain and Japan 24 We Are Committed to Treating All Forms of ALS • Tofersen: Phase 3 VALOR study in SOD1-ALS underway ▪ Data expected 2021

• IONIS-C9Rx: Phase 2 study ongoing in C9-familial ALS ▪ Data expected 2021

• ION541: Targeting ATXN2 in sporadic ALS advancing ▪ On track to start clinical testing in 2020

• Advancing additional programs addressing all forms of ALS

25 Tofersen • Phase 3 for SOD1-ALS (IONIS-SOD1Rx) • The first medicine to demonstrate halting of ALS disease progression • Enrollment in the VALOR Phase 3 study to complete 2020, data expected 2021 • Granted Orphan Drug Designation by the FDA SOD1-ALS

26 Tofersen (IONIS-SOD1Rx) First investigational medicine to demonstrate clinical benefit in SOD1-ALS patients • Treatment with tofersen in Phase 1/2 study demonstrated robust SOD1 reductions in the CSF

• Tofersen (100 mg) in Phase 1/2 study demonstrated benefit in functional and respiratory measures after only 3 months of treatment

• Well tolerated

• VALOR Phase 3 study in adult ALS patients with SOD1 mutations underway, data expected in 2021

27 Treatment with Tofersen Demonstrated Disease Stabilization in Measures of Clinical and Respiratory Function (Phase 1/2 Study)

Clinical Outcome Lung Function ALSFRS-R % Predicted SVC

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

e - 5

Fast

g e

n Disease

n - 1 0 a i Progressors

l - 8 Fast h

e (- - -) Disease

C s

- 1 5 Progressors )

a (- - -)

E B

- 1 2 Placebo - 2 0

S Placebo

(

m n o Tofersen - 2 5

r Tofersen

a F e - 1 6

M - 3 0 1 5 2 9 5 7 8 5 - 2 0 - 3 5 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 28 Phase 3 VALOR Study of Tofersen Innovative study design with potential to support registration

• A global, randomized, double-blind, placebo-controlled study in up to 99 patients with ALS and a confirmed SOD1 mutation, randomized 2:1 to tofersen 100 mg by intrathecal injection or placebo • Outcome measures: ▪ Primary: Change from baseline in ALSFRS-R total score ▪ Secondary: Clinical measures, change in SOD1 CSF levels, safety and tolerability

Loading period Maintenance period Three doses Q2W 5 doses Q4W

Tofersen 100 mg Open-label

Screening 2:1

8 weeks) weeks) 8 extension

- Follow up Follow

Placebo (4 Randomized Randomized

≥4 weeks 24 weeks ~4 years

Orphan Drug Designation Phase 3 enrollment complete 2020 Data expected in 2021

ALS = amyotrophic lateral sclerosis; ALSFRS-R = ALS Functional Rating Scale–Revised; CSF = cerebrospinal fluid; Clinicaltrials.gov, NCT02623699 29 Chris Snow is Living and Thriving One Year After Being Diagnosed with SOD1-ALS

• Chris knew what he was facing when he was diagnosed as Chris, his wife and two kids a fast progressor with SOD1-ALS in June 2019

• Before his diagnosis, Chris witnessed the devastation of this disease – losing his father, two uncles and a cousin, all within 1 year of diagnosis

• Shortly after diagnosis, Chris entered the Phase 3 VALOR study of tofersen, completed the study in January 2020 and continues on tofersen today

• Chris has reported feeling stronger and is performing physical activities with his family – like playing baseball and skating with his kids

• Chris continues his fight against ALS

Chris is a beacon of hope living and thriving 1 year later 30 Chris Snow: A Beacon of Hope to Many March 2020, 9 months after diagnosis

Video posted by Kelsie Snow, Chris’s wife, at kelsiesnowwrites.com 31 We Are Committed to Treating All Forms of ALS

• Tofersen: Phase 3 VALOR study underway (data expected 2021) Multiple ALS Medicines in Development • IONIS-C9Rx: Phase 2 study ongoing in C9-familial ALS (data expected 2021) MEDICINE INDICATION PRECLINICAL P H A S E 1 P H A S E 2 P H A S E 3

Tofersen • ION541 targeting ATXN2 in sporadic ALS SOD1-ALS (IONIS-SOD1Rx) advancing IONIS-C9Rx C9-ALS

ION541 Sporadic ALS (ATXN2)

• Additional programs advancing focused on Numerous medicines advancing treating all forms of ALS into development

Taylor, J., et. al., (2016) Nature; 539: 197-206 32 LICA: Enhancing

Delivery of Our • LICA, or Ligand Conjugated Antisense, is a technology we developed to enhance the Medicines delivery of our medicines • LICA continues to deliver tremendous value today and sets a foundation for even better performance of our medicines in the future

33 LICA: Enhancing Delivery of our Antisense Medicines

LICA technology precisely delivers our medicines to the intended target organs and cell types

Liver LICA is enabling more therapeutic benefit and delivering tremendous value to patients today ▪ 20-30x increase in potency ▪ Allows monthly or less frequent dosing ▪ Excellent safety and tolerability across 16 LICA medicines in development today

Enhancing the delivery of our medicines through LICA sets a foundation to further increase the scope of our medicines ▪ Expanding our LICA platform to include more organ systems and cell types ▪ Optimizing intracellular distribution

34 Technology Advances Enhancing the Value of Our Pipeline 16 LIVER-TARGETED LICA MEDICINES IN PIPELINE

MEDICINE INDICATION PHASE 1 PHASE 2 PHASE 3

AKCEA-TTR-LRx Transthyretin amyloidosis

AKCEA-APO(a)-LRx Cardiovascular disease

Vupanorsen (AKCEA-ANGPTL3-LRx) NAFLD/Metabolic disease/CVD

AKCEA-APOCIII-LRx Cardiovascular disease

IONIS-GHR-LRx Acromegaly

IONIS-HBV-LRx Hepatitis B virus infection

IONIS-FB-LRx Complement-mediated diseases

IONIS-PKK-LRx Hereditary angioedema

IONIS-TMPRSS6-LRx b-thalassemia

IONIS-AGT-LRx Treatment-resistant hypertension

IONIS-FXI-LRx Clotting disorders

IONIS-AZ4-2.5-LRx Cardiovascular disease CARDIOMETABOLIC ION839 Nonalcoholic steatohepatitis AND RENAL

ION224 Nonalcoholic steatohepatitis RARE ION547 Cardiometabolic disease OTHER ION904 Cardiometabolic disease 35 2020 Cardiometabolic Pipeline Performance

Cardiometabolic AKCEA-APO(a)-L granted fast track designation in the U.S., HORIZON Phase 3 study ▪ AKCEA-APO(a)-L grantedRx Fast Track Designation in U.S.; Phase 3 study progressing on track1 Rx progressing on track1 in patients with Lp(a)-driven CVD

▪ Reported positive topline Phase 2 results for vupanorsen (AKCEA-ANGPTL3-LRx)

2 ▪ Initiated PhaseReported 1 study positive of ION532, topline targeting Phase APOL12 results for for the vupanorsen treatment (AKCEAof kidney-ANGPTL3 disease -LRx) in patients with NAFLD with metabolic complications ▪ Cardiometabolic program on track to validate commercially viable oral delivery2

1. Novartis study; 2. AstraZeneca study 36 • Phase 3 study of Lp(a)-driven cardiovascular AKCEA-APO(a)-LRx disease (TQJ230) • First and most advanced medicine in development to selectively and robustly reduce Lp(a) levels • Elevated Lp(a) recognized as a major untreated cardiovascular risk factor • Granted Fast Track Designation by the FDA Lp(a)-driven Cardiovascular Disease

37 Lipoprotein(a) A major untreated risk factor for cardiovascular disease (CVD) • Lp(a) level genetically determined at birth

• Elevated levels recognized as a major untreated cardiovascular risk factor

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

• No approved pharmacological therapies

AKCEA-APO(a)-LRx Selective and robust reductions of Lp(a) demonstrated in patients with CVD

38 AKCEA-APO(a)-LRx (TQJ230) Phase 2 Study* First and only medicine to selectively and robustly reduce Lp(a) levels • 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

• Reduced Lp(a) levels below threshold associated with CVD in 98% of patients on 80 mg monthly dose – same dose in Phase 3 study

• Favorable safety and tolerability profile and excellent compliance ▪ Approximately 90% of patients completed treatment ▪ Comparable discontinuation between the active and placebo groups

• Convenient, once monthly, low volume, subcutaneous dose

*Co-developing with Akcea and Novartis 39 AKCEA-APO(a)-LRx (TQJ230) Phase 3 HORIZON Study Pivotal cardiovascular outcomes study with Novartis

• Multicenter, randomized, double-blind, placebo-controlled study in ~7,500 patients with elevated Lp(a) levels, established CVD • Primary objectives: time to first major adverse cardiovascular event in patients with Lp(a) levels of ≥ 70 mg/dL and patients with Lp(a) levels of ≥ 90 mg/dL • Secondary objectives: time to fatal or non-fatal major adverse cardiovascular events in patients with elevated Lp(a)

Monthly 80mg SC Injections or Placebo

Up to 4 years R

Screening & Follow-up Period Diet Stabilization Enrollment underway Granted Fast Track Designation Data expected in 2024 40 Vupanorsen • Positive topline Phase 2 Data reported in early (AKCEA-ANGPTL3-LRx) 2020 • Full Phase 2 data presentation expected in 2020 • Pfizer to conduct Phase 2b in patients with cardiovascular disease

41 Elevated Levels of ANGPTL3 are Associated with an Increased Risk of CVD and Metabolic Disorders

• Angiopoietin-like 3 (ANGPTL3), a genetically validated target, is a key regulator of triglycerides, cholesterol, glucose and energy metabolism • Elevated levels of ANGPTL3 are associated with an increased risk of: ▪ Premature heart attacks ▪ Increased arterial wall thickness ▪ Multiple metabolic disorders, such as insulin resistance

• Vupanorsen, formerly known as AKCEA-ANGPTL3-LRx, is a LICA medicine we designed to reduce ANGPTL3 • Positive topline vupanorsen Phase 2 data reported in 2020

42 Vupanorsen (AKCEA-ANGPTL3-LRx) Phase 2 study in patients with metabolic diseases

• Randomized, double-blind, placebo-controlled, dose-finding study in 105 patients • Primary objective: Assess the effects of vupanorsen 20mg to 80mg dosed weekly and monthly on reduction in fasting triglycerides (TG) • Secondary objectives: safety, tolerability and effects on multiple measures of cardiovascular and metabolic disease

Weekly and Monthly SC Injections 3:1 26 weeks R 13 weeks Screening & Diet Stabilization Follow-up Period

Positive topline data reported in 2020

43 Positive Topline Vupanorsen Phase 2 Data Robust reductions in TGs and multiple additional measures of CV Risk

• Statistically significant dose-dependent reductions in fasting triglycerides compared to placebo at all dose levels • Dose-dependent reductions in ANGPTL3, apoC-III, very low-density lipoprotein, non-HDL cholesterol and total cholesterol compared to placebo • Favorable safety and tolerability profile demonstrated in the study • Report full Phase 2 results at an appropriate medical meeting this year

• Pfizer to conduct a Phase 2b study of AKCEA-ANGPTL3-LRx in patients with cardiovascular disease to determine the optimal dose for a Phase 3 cardiovascular outcomes study

44 2020 Ionis-owned Pipeline Performance

Ionis-owned

▪ CARDIO-TTRansform and NEURO-TTRansform Phase 3 studies of AKCEA-TTR-L progressing Initiated and enrolling CARDIO-TTransform and NEURO-TTransformRx Phase 3 studies of AKCEA-TTR-L in patients with all forms of ATTR ▪ Reported positive topline Phase 2 results for AKCEARx -APOCIII-LRx

▪ Initiated Phase 2 studies of IONIS-PKK-LRx in HAE and IONIS-TMPRSS6-LRx in ꞵ-thalassemia

▪ Initiated PhaseReported 2 study positive of ENaC topline in patientsPhase 2with results CF for AKCEA-APOCIII-LRx in patients with hypertriglyceridemia who are at risk for or have established CVD ▪ Initiated Phase 1 study of ION224 for the treatment of NASH

▪ Advanced medicines for the treatment of Alexanders, Prion and Lafora diseases towards the clinic

45 AKCEA-TTR-LRx • Phase 3 studies of LICA medicine in patients with all forms of ATTR underway • Robust target reduction demonstrated in Phase 1 study • Data expected in 2023

TTR Amyloidosis (ATTR)

46 TTR Amyloidosis (ATTR) A devastating and fatal disease

Ocular Manifestations • Fatal disease affecting over 250,000 patients worldwide1,2 Cardiovascular • Characterized by the formation of TTR Manifestations amyloid deposits leading to multi-organ Nephropathy failure1,2

• Patients suffer from progressive Bilateral Carpal Tunnel neuropathy, cardiac disease, Syndrome nephropathy and gastrointestinal symptoms GI Manifestations • Progressive disease resulting in a rapid decline in quality of life and a 3-15 year Autonomic Neuropathy life expectancy3 and 2-5 years with cardiac involvement4 Peripheral Sensorimotor Neuropathy GI, gastrointestinal. 1. Conceição I et al. J Peripher Nerv Syst. 2016;21:5-9. 2. Ando Y et al. Orphanet J Rare Dis. 2013;8:31. 3. Gertz MA. Am J Manag Care. 2017;23:S107-S112. 4. Maurer MS 47 et al. Circulation. 2017;135:1357-1377. AKCEA-TTR-LRx: A Follow-On Medicine to TEGSEDI that Expands Our ATTR Franchise

Phase 1 Studies • AKCEA-TTR-LRx utilizes our highly advanced LICA chemistry, providing high potency with greatly120 improved convenience and tolerability

• Robust target reduction100 and positive safety profile demonstrated in healthy volunteers 80

▪ Robust TTR reductions60 of greater than 90% demonstrated

TTR-LRx Tegsedi ▪ Favorable safety40and tolerability observed

• Enrolling Phase 3(%Baseline)Reduction Target TTR studies in patients with all forms of ATTR

0 0.1 1 10 100 1000 Dose (mg/week)

TTR-LRx Tegsedi TTR-LRx observed Tegsedi observed

48 AKCEA-TTR-LRx NEURO-TTRansform Phase 3 study in patients with hereditary ATTR polyneuropathy underway

• A multicenter, open-label study in up to 140 patients with hereditary TTR amyloid polyneuropathy (hATTR-PN) • Co-primary efficacy endpoints at week 66: ▪ Change from baseline in measures of neurological impairment (mNIS+7) ▪ Change from baseline in the Norfolk Quality of Life Diabetic Neuropathy (QoL-DN) Questionnaire ▪ Percent change from baseline in serum TTR concentration ▪ Interim analysis at week 35: change in baseline in mNIS+7 and percent change from baseline in serum TTR concentration

NEURO-TTR Historical Inotersen (Tegsedi) Placebo (60 patients)

AKCEA-TTR-LRx ~120 patients AKCEA-TTR-LRx Patients with Open-Label hATTR-PN Extension

Screening Inotersen AKCEA-TTR-L

~20 patients Rx Randomization 6:1

Baseline Week 35 Week 66 Week 85 Interim Analysis Primary Endpoint 49 AKCEA-TTR-LRx CARDIO-TTRansform Phase 3 study in patients with ATTR cardiomyopathy underway • A global, randomized, double-blind, placebo-controlled study in up to 750 patients with hereditary or wild- type TTR amyloid cardiomyopathy (hATTR-CM or wtATTR-CM) receiving monthly subcutaneous AKCEA-

TTR-LRx or placebo • Primary endpoint: Cardiovascular death and frequency of cardiovascular clinical events at week 120 • Secondary endpoints: ▪ Change from baseline at 120 weeks: 6MWT, patient-reported outcomes (KCCQ), rate of CV death and clinical events ▪ Exploratory endpoints: Echo, biomarkers

Patients with AKCEA-TTR-LRx hereditary or

wild type

1:1 treatment

TTR-CM on - Screening

available SoC Placebo Post

Randomization Randomization Evaluation Evaluation Period

Day Week W8 W12 W24 W36 W48 W61 W72 W84 W96 W108 W120 W140 1 4

Interim analysis: Subgroup Final analysis Functional Endpoint 50 Advancing AKCEA-TTR-LRx Program For the treatment of people with all forms of TTR amyloidosis

• Initiated and enrolling Phase 3 CARDIO-TTRansform study • Initiated and enrolling Phase 3 NEURO-TTRansform study • Data expected in 2023 from both studies

51 AKCEA-APOCIII-LRx • Positive topline Phase 2 data reported in early 2020 • Full phase 2 data presentation expected in 2020 • Phase 3 start in FCS expected in 2020 • Planning underway for additional disease indications

52 Apolipoprotein C-III: A Key Regulator of Triglycerides

• Apolipoprotein C-III (apoC-III) is a protein that plays an integral role in triglyceride metabolism in the blood

• Elevated levels of apoC-III correlate with high triglyceride levels & are associated with multiple metabolic abnormalities, including insulin resistance & elevated risk of CVD

• People with severely elevated triglycerides, such as people with FCS, are at high risk for potentially fatal acute pancreatitis, chronic abdominal pain & other serious conditions

• Genetically reduced levels of apoC-III are correlated with lower levels of triglycerides and lower risk of cardiovascular disease

• AKCEA-APOCIII-LRx is a LICA medicine we designed to reduce the production of apoC-III

53 AKCEA-APOCIII-LRx Phase 2 study in patients with hypertriglyceridemia and established CVD

• Double-blind, placebo-controlled, dose-ranging study in 114 patients • Primary objectives: ▪ Safety, tolerability and reduction of serum triglyceride (TG) levels across different doses and dose regimens

of AKCEA-APOCIII-LRx ▪ Four cohorts with doses up to 50 mg of total monthly dose

Weekly, bi-weekly or monthly SC Injections

4:1 26 weeks min last patient in R & up to 52 weeks Screening & 13 weeks diet stabilization Follow-up

Positive topline data reported in 2020

54 Positive Topline AKCEA-APOCIII-LRx Phase 2 Data Significant reductions in TGs and multiple measures of CV risk

• Statistically significant reductions in fasting triglycerides compared to placebo at all dose levels ▪ >90% of patients achieved serum TGs below the recognized threshold for CV risk (≤ 150 mg/dL) at the highest monthly dose • Significant reductions in additional risk CV factors: apoC-III, VLDL-C, remnant cholesterol • Significant increases in HDL-C at all dose levels • Favorable safety and tolerability profile demonstrated in the study • Report full Phase 2 results at a medical conference and initiate Phase 3 development in patients with FCS this year • Planning to pursue additional disease indications

55 Technology

Advancing and broadening the reach of our technology

56 Investing in All Aspects of our Technology to Further Increase our Impact on the Treatment of Human Diseases

INVESTMENTS IMPACT

Improved Drug Candidate • Improved drug discovery efficiency Selection Processes • Improved overall drug performance

• Novel target identification • Improved drug discovery efficiency (e.g. patient selection, biomarkers, Human Genomics Investments disease natural history) • Increased probability for clinical success

• Even more patient convenience (e.g. oral) New Routes of Delivery • Opens up new target organs/cell types (e.g. pulmonary, ocular)

Medicinal Chemistry • Even more patient convenience (e.g. monthly, quarterly dosing) (e.g. LICA) • Opens up new target organs/cell types (e.g. cardiac, muscle, immune) • Enhanced overall safety and efficacy performance

57 Strong Start to 2020 is Just the Beginning

58 Key Catalysts for the Remainder of 2020

Initiate AKCEA-APOCIII-LRx Phase 3 study in FCS

Re-file U.S. NDA for WAYLIVRA

Report vupanorsen and AKCEA-APOCIII-LRx Phase 2 results

Report clinical POC results for ≥ 4 programs*

Add ≥ 5 new medicines to development pipeline

*Vupanorsen (AKCEA-ANGPTL3-LRx) and AKCEA-APOCIII-LRx Phase 2 studies reported data in Jan. 2020. Four or more remaining data readouts expected in 2020 59 Potential Next Wave of Commercial Products

AKCEA-APOCIII-LRx ION541 Anticipated NDA filings for both Severe hypertriglyceridemia Sporadic ALS broad and rare diseases through ION373 IONIS-TMPRSS6-LRx 2025 Alexander diseases β-thalassemia

IONIS-GHR-LRx IONIS-HBVRx / IONIS-HBV-LRx Acromegaly Hepatitis B virus infection

AKCEA-APOCIII-L IONIS-C9Rx Vupanorsen Rx (BIIB078) FCS (AKCEA-ANGPTL3-LRx) C9-ALS CV/metabolic disease

Tominersen IONIS-PKK-L ION716 (IONIS-HTT / RG6042) Rx Rx Hereditary angioedema Prion diseases Huntington’s disease

Tofersen AKCEA-APO(a)-L AKCEA-TTR-L AKCEA-TTR-L Rx (IONIS-SOD1 / BIIB067) Rx Rx (TQJ230) Rx hATTR polyneuropathy ATTR cardiomyopathy SOD1-ALS Cardiovascular disease

2021 2025 and beyond

60 Ionis Continues to Lead the Way in RNA-targeted Therapeutics

Growing leadership position Strong financial position Rapidly advancing pipeline

Rapidly advancing Commitment to expand the Ionis- Accelerating momentum technology owned pipeline & our commercial supporting even greater capabilities success in the future

61 2020 Annual Meeting of Stockholders Brett P. Monia, Ph.D. Chief Executive Officer Q&A