Slides
Page 1
ZANVASTROTM FDA Approval ZANVASTRO (zilganersen) First and only disease modifying treatment for Alexander disease in pediatric and adult patients September 2026 Nasdaq: IONS
Page 2
This presentation includes forward-looking statements regarding our business, financial guidance and the therapeutic and commercial potential of ZANVASTRO and our commercial medicines, additional medicines in development and technologies and our expectations regarding development and regulatory milestones. Any statement describing Ionis’ goals, expectations, financial or other projections or guidance, 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 but not limited to those related to 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. Except as required by law, we undertake no obligation to update any forward-looking statements for any reason. 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 our Form 10-K for the year ended December 31, 2025, 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.ionis.com. In this presentation, unless the context requires otherwise, “Ionis,” “Company,” “we,” “our,” and “us” refers to Ionis Pharmaceuticals and its subsidiaries. Ionis Pharmaceuticals®, TRYNGOLZA® and DAWNZERA® are registered trademarks of Ionis Pharmaceuticals, Inc. ZANVASTROTM and Ionis Every StepTM are trademarks of Ionis Pharmaceuticals, Inc. QALSODY® and SPINRAZA® are registered trademarks of Biogen. WAINUA® is a registered trademark of the AstraZeneca group of companies. Forward-Looking Statements 2
Page 3
On Today’s Call 3 Brett Monia, Ph.D. Chief Executive Officer Holly Kordasiewicz, Ph.D. Chief Development Officer Kyle Jenne Chief Global Product Strategy Officer
Page 4
Agenda 4 Topic Speaker ZANVASTRO: The First and Only Disease Modifying Treatment Approved for Alexander Disease Brett Monia, Ph.D., Chief Executive Officer Alexander Disease: An Ultra-Rare, Progressive and Often Fatal Neurological Disorder Holly Kordasiewicz, Ph.D., Chief Development Officer Accelerating Value through Commercial Execution Kyle Jenne, Chief Global Product Strategy Officer Delivering a Steady Cadence of Transformational Medicines for Serious Diseases Brett Monia, Ph.D., Chief Executive Officer Agenda
Page 5
Brett Monia, Ph.D. Chief Executive Officer The First and Only Disease Modifying Treatment Approved for Alexander Disease
Page 6
The first and only disease modifying therapy approved by the FDA for the treatment of pediatric and adult patients with Alexander disease NOW APPROVED 1. ZANVASTRO is now approved in the U.S.; see Full Prescribing Information.
Page 7
ZANVASTRO: Ionis’ First Independent Neurology Medicine Launch 1 7 approved ZANVASTRO with a broad label, enabling treatment for children and adults with Alexander ZANVASTRO for the treatment of Alexander disease First and only disease modifying treatment approved for Alexander disease Positive pivotal study data: statistically significant stabilization of motor function, favorable trends across key symptoms and favorable safety 1. ZANVASTRO is now approved in the U.S.; see Full Prescribing Information. 2. Assuming approval. Grayson living with Alexander disease Commercializing outside the U.S. with Recordati2 Broad label, enabling treatment for children and adults with Alexander disease Awarded a Rare Pediatric Disease Priority Review Voucher in connection with the ZANVASTRO approval
Page 8
Holly Kordasiewicz, Ph.D. Chief Development Officer Alexander Disease: An Ultra-Rare, Progressive and Often Fatal Neurological Disorder
Page 9
9 Alexander Disease: An Ultra-Rare, Progressive and Often Fatal Neurological Disorder 1. Yoshida T, Sasaki M, Yoshida M, et al. Nationwide survey of Alexander disease in Japan and proposed new guidelines for diagnosis. J Neurol. 2011;258(11):1998-2008; 2. L. Bonkowsky, X. Ma, K. Householder, M. Vera-Llonch, M.R. McClain, A. Thomas, F. Pathan, X. Wu, S.M. Kymes. HealthCare Cost and Service Utilization by People Living with Alexander Disease. Neurology Clinical Practice (Manuscript in submission). 3. Heim et al., Am J Med Genet 1997; 71:475-478 and Cohen et al., Ann Hum Genet 2020; 84:11–28. Messing, Albee. Alexander Disease: A Guide for Patients and Families. Colloquium Series on Neuroglia in Biology and Medicine: From Physiology to Disease. Vol. 3. No. 1. Morgan & Claypool Life Sciences, 2017; 4. Prust M, et al. GFAP mutations, age at onset, and clinical subtypes in Alexander disease. Neurology. 2011;77(13):1287-1294. 5. Srivastava et al., 1993. Max with his mother living with Alexander disease Alexander Disease (AxD)1-5 Characterized by progressive gross/fine motor and cognitive decline, speech difficulties, ataxia and bulbar dysfunction Caused by mutations in GFAP gene ~65% of cases occur in childhood Prevalence: ~1 in 1-3 million (~300 people in the U.S.); accounts for ~2-8% of leukodystrophies
Page 10
Innovative Pivotal Study Designed to Assess ZANVASTRO in People with Alexander Disease 1,2 10 A global, randomized, double-blind, placebo-controlled study in ~50 patients with Alexander disease (AxD) 2-65 years old An open-label sub-study in patients <2 years old conducted at certain sites Primary endpoint: Percentage change in gait speed as assessed by the 10-Meter Walk Test (10MWT) at Week 61 DESIGN PRIMARY OBJECTIVE 60 week: OL treatment ZANVASTRO (50mg) ZANVASTRO (50mg) SCREENING Patients with AxD + documented genetic mutation in GFAP Open-label sub-study in patients <2 years old ZANVASTRO (50mg) ZANVASTRO (50mg) 60 week: Controlled treatment (Ph1 FIH) ZANVASTRO (25mg) Control R 2:1 OL QUARTERLY DOSING ZANVASTRO (50mg) Control R 2:1 60 week: Controlled treatment (Pivotal) 120 week: LTE Assessing motor function with age-appropriate measures R, randomized; OL, open-label; LTE, long-term extension. 1. Clinicaltrials.gov/NCT04849741. 2. An extended LTE of up to 240 weeks added for patients outside the U.S.
Page 11
ZANVASTRO: Primary Endpoint Assessing Gross Motor Function Statistically Significant in Pivotal Study1 11 1. ZANVASTRO is now approved in the U.S.; see Full Prescribing Information. 2. Meters per second. 3. ANCOVA model. Better Worse ZANVASTRO showed a statistically significant and clinically meaningful stabilization in gait speed as measured by the 10-Meter Walk Test (10MWT) in patients ≥ 5 years old Primary Endpoint (10MWT) ZANVASTRO (50mg) n=17 Pooled Control n=13 Baseline (m/s) Mean 1.2 1.1 % Change at Week 61 Mean -1.0 -36.9 Least Squares Mean (LSM) (95% CI) -2.1 (-23.0, 18.8) -35.4 (-59.3, -11.5) LSM Difference (95% CI) 33.3 (1.4, 65.3) P-value3 p = 0.041
Page 12
Secondary and Exploratory Endpoints Consistently Supported ZANVASTRO for the Treatment of Alexander Disease1 12 1. ZANVASTRO is now approved in the U.S.; see Full Prescribing Information. Gross Motor Function Measure-88 (GMFM-88) • GMFM-88: Age-appropriate measure of motor function in patients 2-4 years old • 22.9 least square mean difference at week 61 between ZANVASTRO 50 mg and control (nominal p = 0.034) • Plasma GFAP: evidence of target engagement and modulation of the underlying cause of disease in ZANVASTRO treated patients • 33.6% least square geometric mean ratio lower at week 61 from baseline compared to control (nominal p = 0.003) Change in Plasma GFAP from Baseline
Page 13
Favorable Safety and Tolerability Observed in the ZANVASTRO Pivotal Trial1 13 1. ZANVASTRO is now approved in the U.S.; see Full Prescribing Information. • Most adverse reactions were mildor moderate • Most common adverse reactions were vomiting, back pain, cough, headache, and post-lumbar puncture syndrome • Serious adverse reactions occurred less frequently with ZANVASTRO vs. control • One serious adverse reaction of aseptic meningitis occurred in a ZANVASTRO-treated patient • Not associated with clinical signs or symptoms • Resolved with treatment • Did not lead to treatment discontinuation ZANVASTRO: Favorable Safety and Tolerability Profile
Page 14
The first and only disease modifying therapy approved by the FDA for the treatment of pediatric and adult patients with Alexander disease NOW APPROVED 1. ZANVASTRO is now approved in the U.S.; see Full Prescribing Information.
Page 15
Kyle Jenne Chief Global Product Strategy Officer Accelerating Value through Commercial Execution
Page 16
ZANVASTRO: Ionis’ First Independent Neurology Launch 1 16 ZANVASTRO indication enables treatment for children and adults with Alexander disease Broad Label Strategy to Reach Patients Identification, diagnosis and treatment management Strong partnership with the Alexander disease patient community Well-Established Patient Community Education, access and support Substantial Unmet Need Expanding global access through Recordati2 Alexander disease: An ultra-rare, progressive and often fatal neurological disorder First approved disease modifying treatment 1. ZANVASTRO is now approved in the U.S.; see Full Prescribing Information. 2. Assuming approval.
Page 17
BB Initial ZANVASTRO Launch Strategy1 171. ZANVASTRO is now approved in the U.S.; see Full Prescribing Information. Transition patients to commercial drug from clinical study and EAP Initiate treatment with ZANVASTRO in patients already diagnosed with AxD Broaden disease awareness to drive new patient identification Work with payers to ensure access to ZANVASTRO for patients diagnosed with Alexander disease
Page 18
IONIS EVERY STEP: Designed Specifically to Meet the Unique Needs of the Alexander Disease Community 18 Disease education, treatment support and connection to key resources Financial assistance and reimbursement support programs1 Access and reimbursement support Dedicated patient support from Patient Education Managers TM 1. For commercially covered patients only. Medicare, Medicaid, TRICARE, Department of Defense, or Veterans Administration, or any other state or federal government-funded patients are not eligible.
Page 19
Advancing our Goal of Delivering a Steady Cadence of New Transformational Medicines1 191. ZANVASTRO is now approved in the U.S.; see Full Prescribing Information. 2. Assuming approval. Multiple Future Commercial Opportunities2 Establishing Foundation for Future Neurology Launches2 Expanding Commercial Capabilities in Neurology
Page 20
Brett Monia, Ph.D. Chief Executive Officer Delivering a Steady Cadence of Transformational Medicines for Serious Diseases
Page 21
The first and only disease modifying therapy approved by the FDA for the treatment of pediatric and adult patients with Alexander disease NOW APPROVED 1. ZANVASTRO is now approved in the U.S.; see Full Prescribing Information.
Page 22
Q&A
Page 23
23 Breakthrough Therapies Driving Accelerating Growth