Alexander Disease

Olezarsen Phase 3 data showed significant triglyceride lowering, substantial reductions in acute pancreatitis attacks and favorable safety and tolerability in patients with FCS; on track for regulatory filings in early 2024 Eplontersen marketing applications accepted for review in the EU and Canada; potential U.S. approval in December 2023 On track to achieve 2023 financial guidance CARLSBAD, Calif., Nov. 2, 2023 /PRNewswire/ -- Ionis Pharmaceuticals, Inc. (Nasdaq: IONS) (the "Company"), today reported financial results for the third quarter of 2023. "We continue to successfully execute on our strategy to deliver a steady cadence of potentially transformational medicines to patients," said Brett P. Monia, Ph.D., chief executive officer of Ionis. "Eplontersen is on track for its first potential approval in the U.S. and is under regulatory review in the EU and Canada. We believe the positive efficacy and safety data coupled with an attractive self-administration dosing profile positions eplontersen to be the preferred therapy in the largely underserved hereditary ATTR polyneuropathy population. We reported positive data from the olezarsen Phase 3 Balance study in patients with familial chylomicronemia syndrome, showing statistically significant triglyceride lowering, substantial reductions in acute pancreatitis attacks and favorable safety and tolerability, positioning olezarsen to be our first independent commercial launch. We also made additional progress across our wholly owned and partnered pipeline, and further expanded our rich Phase 3 pipeline with the advance of zilganersen for patients with Alexander disease into Phase 3 development. Looking ahead, we expect to continue our positive momentum with the potential approval and launch of eplontersen and the Phase 3 data readout of donidalorsen in hereditary angioedema." Third Quarter 2023 Summary Financial Results: Financial Highlights Revenue continued to be substantial and sustained, with revenues of $144 million and $463 million in the three and nine months ended September 30, 2023, reflecting a 10% decrease and 6% increase compared to the same periods last year, respectively, driven by the timing of certain partner payments Operating expenses increased in the three and nine months ended September 30, 2023 compared to the same periods last year, primarily due to strategic investments to bring eplontersen, olezarsen and donidalorsen to patients Cash and short-term investments of $2.2 billion as of September 30, 2023 enables continued investments to drive increasing value Reaffirmed 2023 financial guidance Near-Term Commercial Opportunities and Late-Stage Pipeline Highlights Achieved multiple milestones with eplontersen: Eplontersen is under regulatory review by the European Medicines Agency (EMA) and Health Canada for the treatment of hereditary ATTR polyneuropathy (ATTRv-PN) The EMA granted orphan drug designation to eplontersen for the treatment of ATTR in the EU Published positive data from the Phase 3 NEURO-TTRansform study in patients with ATTRv-PN in the Journal of the American Medical Association (JAMA) showing eplontersen halted measures of disease progression and continuously improved quality of life at 35-, 66- and 85-weeks Presented positive new data showing continued benefit in secondary endpoints from the Phase 3 NEURO-TTRansform study in patients with ATTRv-PN at the European ATTR Amyloidosis (EU-ATTR) meeting Presented positive exploratory data from a pre-defined cardiac sub-population of patients in NEURO-TTRansform showing improvement in cardiac function and structure compared to external placebo at the Heart Failure Society of America (HFSA) Annual Scientific Meeting Completed enrollment of the Phase 3 CARDIO-TTRansform study of eplontersen in patients with ATTR cardiomyopathy (ATTR-CM), the largest study ever conducted in ATTR-CM; on track for data readout as early as H1:2025 Reported positive data from the Phase 3 Balance study of olezarsen in patients with familial chylomicronemia syndrome (FCS) Olezarsen demonstrated robust, dose-dependent reductions in APOCIII, statistically significant reductions in triglycerides, substantial reductions in acute pancreatitis attacks and a favorable safety and tolerability profile On track to file for regulatory approval in the U.S. and EU in early 2024 The FDA granted orphan drug designation to donidalorsen for the treatment of patients with hereditary angioedema (HAE); on track for data readout in the Phase 3 OASIS-HAE study in H1:2024 Advanced zilganersen (GFAP) into Phase 3 development for the treatment of patients with Alexander disease The FDA granted orphan drug designation to ulefnersen (FUS) for the treatment of patients with FUS-ALS Partnered Program Highlights GSK reported positive data from the Phase 2b B-Together study of bepirovirsen followed by pegylated interferon in patients with chronic hepatitis B virus (HBV) Reported positive interim data from the ongoing Phase 2 study of IONIS-FB-LRx in patients with immunoglobulin A nephropathy (IgAN) Biogen reported positive data from the Phase 1/2 study of IONIS-MAPTRx (BIIB080) in patients with Alzheimer's disease Completed enrollment in the Phase 1/2 HALOS study of ION582 (BIIB121) in patients with Angelman syndrome Entered a new agreement with Roche to advance two novel RNA-targeted programs for Alzheimer's disease and Huntington's disease Third Quarter 2023 Financial Results "Our year-to-date financial results keep us on track to achieve our 2023 guidance as we execute on a strategy to unlock next-level value," said Elizabeth L. Hougen, chief financial officer of Ionis. "Our strong financial foundation includes more than $2B in cash, significant royalty revenue with SPINRAZA, and substantial and sustained R&D revenue from multiple partners. We are well positioned to continue investing in our key priorities to drive future positive cash flow, including advancing our go-to-market activities, growing our wholly owned pipeline and optimizing new cutting-edge technologies for future medicines. We look forward to the potential U.S. eplontersen ATTRv-PN approval next month followed closely by launch. Together with our partner, AstraZeneca, we believe we are well positioned to identify new patients to further grow the market and become the treatment of choice for this population that remains largely underserved by current therapies." Revenue Ionis' revenue was comprised of the following: Commercial revenue for the three and nine months ended September 30, 2023 included $67 million and $179 million from SPINRAZA royalties, respectively, which were essentially flat compared to the same periods last year reflecting SPINRAZA's resilience against emerging competition. Ionis' commercial revenue in the three and nine months ended September 30, 2023 also included royalties from the U.S. launch of QALSODY. R&D revenue decreased for the three months ended September 30, 2023 and increased for the nine months ended September 30, 2023 compared to the same periods last year due to the timing of certain partner payments, including the $35 million license fee for IONIS-FB-LRx that Ionis earned from Roche in the three months ended September 30, 2022. Operating Expenses Ionis' operating expenses increased in the three and nine months ended September 30, 2023 compared to the same periods in 2022, consistent with expectations. As Ionis advanced its robust pipeline, study costs increased compared to the same periods in 2022 as most of the Company's Phase 3 studies are either fully enrolled or approaching full enrollment, resulting in higher R&D expenses year over year. Ionis' SG&A expenses also increased year over year primarily due to launch preparation activities for eplontersen, olezarsen and donidalorsen. Balance Sheet As of September 30, 2023, Ionis' cash, cash equivalents and short-term investments increased to $2.2 billion compared to $2.0 billion at December 31, 2022 primarily due to the $500 million Ionis received from Royalty Pharma in January 2023. Ionis' working capital also increased over the same period primarily due to the Company's higher cash and short-term investments balance. In the first quarter of 2023, the Company recorded a long-term liability for future royalties due to Royalty Pharma. In June 2023, Ionis issued $575 million of senior convertible notes due in June 2028 with an interest rate of 1.75%. The Company used the majority of the proceeds to repurchase $504 million of its 0.125% convertible notes. Webcast Management will host a conference call and webcast to discuss Ionis' third quarter 2023 results at 11:30 a.m. Eastern time on Thursday, November 2, 2023. Interested parties may access the webcast here. A webcast replay will be available for a limited time at the same address. To access the Company's third quarter 2023 earnings slides click here. About Ionis Pharmaceuticals, Inc. For more than 30 years, Ionis has been a leader in RNA-targeted therapy, pioneering new markets and changing standards of care. Ionis currently has four marketed medicines and a promising late-stage pipeline highlighted by cardiovascular and neurological franchises. Our scientific innovation began and continues with the knowledge that sick people depend on us, which fuels our vision to become the leader in genetic medicine, utilizing a multi-platform approach to discover, develop and deliver life-transforming therapies. To learn more about Ionis visit or follow us on Twitter @ionispharma. Ionis' Forward-looking Statement This press release includes forward-looking statements regarding Ionis' business, financial guidance and the therapeutic and commercial potential of QALSODY (tofersen), SPINRAZA (nusinersen), TEGSEDI (inotersen), WAYLIVRA (volanesorsen), eplontersen, olezarsen, donidalorsen, zilganersen, ulefnersen, pelacarsen, bepirovirsen, IONIS-FB-LRx, Ionis' technologies and Ionis' other products in development. 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 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, 2022, and most recent Form 10-Q, which are on file with the Securities and Exchange Commission. Copies of these and other documents are available from the Company. In this press release, unless the context requires otherwise, "Ionis," "Company," "we," "our" and "us" all refer to Ionis Pharmaceuticals and its subsidiaries. Ionis Pharmaceuticals® is a registered trademark of Ionis Pharmaceuticals, Inc. Akcea Therapeutics® is a registered trademark of Akcea Therapeutics, Inc. TEGSEDI® is a registered trademark of Akcea Therapeutics, Inc. WAYLIVRA® is a registered trademark of Akcea Therapeutics, Inc. QALSODYTM is a trademark of Biogen. SPINRAZA® is a registered trademark of Biogen. Reconciliation of GAAP to Non-GAAP Basis As illustrated in the Selected Financial Information in this press release, non-GAAP operating expenses, non-GAAP loss from operations, and non-GAAP net loss were adjusted from GAAP to exclude compensation expense related to equity awards and the related tax effects. Compensation expense related to equity awards are non-cash. These measures are provided as supplementary information and are not a substitute for financial measures calculated in accordance with GAAP. Ionis reports these non-GAAP results to better enable financial statement users to assess and compare its historical performance and project its future operating results and cash flows. Further, the presentation of Ionis' non-GAAP results is consistent with how Ionis' management internally evaluates the performance of its operations. Key 2023 Value Driving Events(1) SOURCE Ionis Pharmaceuticals, Inc.

Accelerated approval marks a scientific advancement in treatment of superoxide dismutase 1 (SOD1)-amyotrophic lateral sclerosis (ALS) Approval based on reduction of neurofilament, a biomarker associated with neuronal damage in ALS QALSODY joins SPINRAZA® as Ionis-discovered medicine approved for treatment of a rare and fatal neurodegenerative disease CARLSBAD, Calif., April 25, 2023 /PRNewswire/ -- Ionis Pharmaceuticals, Inc. (Nasdaq: IONS) today announced that its partner Biogen has received U.S. Food and Drug Administration (FDA) approval of QALSODY™ (tofersen) 100 mg/15mL injection for the treatment of amyotrophic lateral sclerosis (ALS) in adults who have a mutation in the superoxide dismutase 1 (SOD1) gene. This indication is approved under accelerated approval based on a reduction in plasma neurofilament light chain (NfL) observed in patients treated with QALSODY. Continued approval for this indication may be contingent upon verification of clinical benefit from ongoing trial(s). The ongoing Phase 3 ATLAS study of tofersen in people with presymptomatic SOD1-ALS will serve as the confirmatory study. QALSODY is the first and only approved treatment to target a genetic cause of ALS and the latest Ionis-discovered medicine to gain market approval. Neurofilaments are proteins that are released from neurons when they are damaged, making them a marker of neurodegeneration. "Today's approval of QALSODY represents a scientific advancement for the ALS community. We thank the people with SOD1-ALS whose participation in the clinical studies made this day possible. We are proud of the Ionis scientists whose dedication made the discovery of this medicine possible, and we are appreciative of our partners at Biogen for their ongoing commitment to ALS," said Brett P. Monia, Ph.D., chief executive officer of Ionis. "The QALSODY approval highlights our significant progress advancing RNA-based treatments targeting severe neurological diseases." Warnings and precautions associated with QALSODY were serious neurologic events, including myelitis and or radiculitis; papilledema and elevated intracranial pressure; and aseptic meningitis. If symptoms consistent with myelitis, radiculitis papilledema, elevated intracranial, or aseptic meningitis develop, diagnostic workup and treatment should be initiated according to the standard of care. Management may require interruption or discontinuation of QALSODY. The most common adverse reactions that occurred in ≥10% of QALSODY treated participants and more than the placebo arm were pain, fatigue, arthralgia, CSF white blood cell increased, and myalgia. The efficacy of QALSODY was assessed in a 28-week randomized, double-blind, placebo-controlled clinical study in patients 23 to 78 years of age with weakness attributable to ALS and a SOD1 mutation confirmed by a central laboratory. One hundred eight (108) patients were randomized 2:1 to receive treatment with either QALSODY 100 mg (n=72) or placebo (n=36) for 24 weeks (3 loading doses followed by 5 maintenance doses). Concomitant riluzole and/or edaravone use was permitted for patients and at baseline 62% of patients were taking riluzone, and 8% of patients were taking edaravone. Over 28 weeks in VALOR, participants in the primary analysis population (n=60) treated with QALSODY experienced less decline from baseline as measured by the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) compared to placebo, though the results were not statistically significant (QALSODY-placebo adjusted mean difference [95% CI]: 1.2 [-3.2, 5.5]). In the overall intent-to-treat population (n=108), QALSODY-treated participants experienced a 55% reduction in plasma NfL compared to a 12% increase in placebo-treated participants (difference in geometric mean ratios for QALSODY to placebo: 60%; nominal p<0.0001). Additionally, levels of CSF SOD1 protein, an indirect measure of target engagement, were reduced by 35% in the QALSODY-treated group compared to 2% in the corresponding placebo group (difference in geometric mean ratios for QALSODY to placebo: 34%; nominal p<0.0001). At an interim analysis at 52 weeks of participants who had completed VALOR and enrolled in an open-label extension (OLE) study, reductions in NfL were seen in participants previously receiving placebo and who initiated QALSODY in the OLE, similar to the reductions seen in participants treated with QALSODY in VALOR. Earlier initiation of QALSODY compared to placebo/delayed-start of QALSODY was associated with trends for reduction in decline on measures of clinical function (ALSFRS-R), respiratory strength (slow vital capacity percent-predicted), and muscle strength (hand-held dynamometry megascore), though they were not statistically significant. QALSODY was also associated with a non-statistically significant trend towards reduction of the risk of death or permanent ventilation. These exploratory analyses should be interpreted with caution given the limitations of data collected outside of controlled study, which may be subject to confounding. The approval of QALSODY was supported by 12-month integrated results from VALOR and its OLE comparing earlier initiation of tofersen (at the start of VALOR) to delayed initiation of tofersen (six months later, in the OLE), that were published in The New England Journal of Medicine. What is QALSODY? QALSODY™ (tofersen) is a prescription medicine used to treat adults with amyotrophic lateral sclerosis (ALS) associated with a mutation in the superoxide dismutase 1 (SOD1) gene. This indication is approved under accelerated approval based on reduction in plasma neurofilament light chain (NfL) observed in patients treated with QALSODY. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trial(s). IMPORTANT SAFETY INFORMATION What is the most important information that I should know about QALSODY? QALSODY can cause serious side effects, including: Inflammation of the spinal cord (myelitis) and/ or irritation of the nerve roots (radiculitis), including serious cases, have been reported in patients treated with QALSODY. Contact your healthcare provider to learn more about symptoms associated with myelitis or radiculitis, and/ or if you believe you are experiencing either of these conditions. QALSODY may need to be interrupted or discontinued. Swelling of the optic nerve (papilledema) and increased pressure inside the skull (elevated intracranial pressure), including serious cases, have been reported in patients treated with QALSODY. Contact your healthcare provider to learn more about symptoms associated with papilledema or elevated intracranial pressure, and/ or if you believe you are experiencing either of these conditions. Inflammation of the brain linings (aseptic meningitis), including serious cases, have been reported in patients treated with QALSODY. Contact your healthcare provider to learn more about symptoms associated with aseptic meningitis, and/ or if you believe you are experiencing this condition. What should I tell my HCP before I start using QALSODY? Before taking QALSODY, tell your healthcare provider if you are pregnant, plan to become pregnant, or are breastfeeding or plan to breastfeed. What are the possible side effects of QALSODY? The most common adverse reactions reported in patients treated with QALSODY were pain (back pain, pain in arms or legs), feeling tired, muscle and joint pain and increased white blood cell count in the cerebrospinal fluid (CSF). This information is not intended to replace discussions with your healthcare provider. These are not all the possible side effects of QALSODY. Please talk to your healthcare provider if you experience any of these symptoms, or other new symptoms that concern you. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Please see full Prescribing Information. For more details on QALSODY, visit . About QALSODY™ (tofersen) QALSODY is an antisense oligonucleotide (ASO) designed to bind to SOD1 mRNA to reduce SOD1 protein production. QALSODY is indicated for the treatment of ALS in adults who have a mutation in the SOD1 gene in the U.S. This indication is approved under accelerated approval based on reduction in plasma NfL observed in patients treated with QALSODY. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trial(s). QALSODY is administered intrathecally as three loading doses administered at 14-day intervals followed by maintenance doses administered once every 28 days thereafter. In people with SOD1-ALS, mutations in their SOD1 gene cause their bodies to create a toxic misfolded form of SOD1 protein. This toxic protein causes motor neurons to degenerate, resulting in progressive muscle weakness, loss of function, and eventually, death. Biogen licensed tofersen from Ionis under a collaborative development and license agreement. In addition to the ongoing OLE of VALOR, QALSODY is being studied in the Phase 3, randomized, placebo-controlled ATLAS study to evaluate whether QALSODY can delay clinical onset when initiated in presymptomatic individuals with a SOD1 genetic mutation and biomarker evidence of disease activity (elevated plasma NfL). The primary efficacy endpoint is the proportion of participants with emergence of clinically manifest ALS. ATLAS is currently more than 50 percent enrolled with clinical trial sites in 14 countries worldwide with an estimated primary completion date in 2026. More details about ATLAS (NCT04856982) can be found at clinicaltrials.gov. About Amyotrophic Lateral Sclerosis and SOD1-ALS Amyotrophic lateral sclerosis (ALS) is a rare, progressive and fatal neurodegenerative disease that results in the loss of motor neurons in the brain and the spinal cord that are responsible for controlling voluntary muscle movement. People with ALS experience muscle weakness and atrophy, causing them to lose independence as they steadily lose the ability to move, speak, eat, and eventually breathe. Average life expectancy for people with ALS is three to five years from time of symptom onset. Multiple genes have been implicated in ALS. Genetic testing helps determine if a person's ALS is associated with a genetic mutation, even in individuals without a known family history of the disease. Currently, there are no genetically targeted treatment options for ALS. SOD1-ALS is diagnosed in approximately 2% of all ALS cases, impacting about 330 people in the United States. While there are medications approved for broad ALS, no available treatments target a genetic mutation associated with ALS. Approximately 5-10% of people with ALS are thought to have a genetic form of the disease; however, they may not have a known family history of the disease. About Ionis' Neurology Franchise Ionis' neurology franchise addresses all major brain regions and central nervous system cell types and currently has three Phase 3 studies ongoing with 12 therapies in clinical development, several of which Ionis plans to commercialize directly. Ionis is discovering and developing potential treatments for many neurological diseases for which there are few or no disease modifying treatments, including common diseases like Alzheimer's and Parkinson's as well as rare diseases such as amyotrophic lateral sclerosis (ALS) and Alexander disease. Ionis has discovered and developed three commercially available neurological disease medicines, including the first approved treatment for spinal muscular atrophy, a medicine to treat hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN), and now QALSOLDY for SOD1-ALS. About Ionis Pharmaceuticals, Inc. For more than 30 years, Ionis has been a leader in RNA-targeted therapy, pioneering new markets and changing standards of care with its novel antisense technology. Ionis currently has three marketed medicines and a promising late-stage pipeline highlighted by cardiovascular and neurological franchises. Our scientific innovation began and continues with the knowledge that sick people depend on us, which fuels our vision to become the leader in genetic medicine, utilizing a multi-platform approach to discover, develop and deliver life-transforming therapies. To learn more about Ionis visit and follow us on Twitter @ionispharma. Ionis' Forward-looking Statement This press release includes forward-looking statements regarding Ionis' business and the therapeutic and commercial potential of QALSODY (tofersen), Ionis' technologies and Ionis' other products in development. 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 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 Dec. 31, 2022, which is on file with the Securities and Exchange Commission. Copies of this and other documents are available from the Company. In this press release, unless the context requires otherwise, "Ionis," "Company," "we," "our" and "us" all refer to Ionis Pharmaceuticals and its subsidiaries. Ionis Pharmaceuticals® is a registered trademark of Ionis Pharmaceuticals. SOURCE Ionis Pharmaceuticals, Inc.

CARLSBAD, Calif., March 29, 2023. Ionis Pharmaceuticals, Inc. today reported that its partner Biogen presented new Phase 1b clinical data showing that IONIS-MAPTRx (BIIB080) reduced soluble tau protein in cerebrospinal fluid (CSF) in a dose-dependent and sustained manner in patients with early-stage Alzheimer's disease (AD). IONIS-MAPTRx also reduced aggregated tau pathology, as measured by positron emission tomography (PET) in all brain composites assessed. The primary endpoint of the Phase 1b study (25 weeks) and open-label long-term extension study (through week 100) was safety and tolerability, with biomarker data as an exploratory endpoint. The results were presented today at the International Conference on Alzheimer's and Parkinson's Diseases (AD/PD) 2023). In patients with AD, tau protein can form "tangles" that progressively accumulate in brain regions involved in cognition. The accumulation of pathological tau tangles has been shown to promote neuronal damage and death. IONIS-MAPTRx is an investigational antisense medicine discovered by Ionis that is being developed by Biogen. It is designed to target microtubule-associated protein tau (MAPT) mRNA and prevent production of tau protein. "This Phase 1b clinical study of IONIS-MAPTRx is the first to demonstrate this magnitude of a reduction of tau pathology across important brain regions. These encouraging findings are the latest example of the potential of the Ionis RNA-targeting platform to selectively modulate proteins linked to CNS disease," said Eugene Schneider, M.D., executive vice president and chief clinical development officer at Ionis. "Ionis is pioneering potential therapies for serious neurological diseases with high unmet need. In addition to Alzheimer's disease, our clinical stage neurology programs include ATTR polyneuropathy, ALS, Alexander disease, Parkinson's disease and Angelman syndrome." The Phase 1b trial and its open-label long-term extension (LTE) were designed to evaluate the safety and tolerability of multiple dose levels of IONIS-MAPTRx in patients with mild AD (n=46). In this study, the majority of adverse events were mild or moderate in severity, of which the most common were headache, back pain, and post-lumbar puncture syndrome (PLPS). The results showed that IONIS-MAPTRx reduced biomarkers of soluble tau in CSF (t-tau and p-tau181) in a dose-dependent and sustained manner, with all dose groups showing approximately a 60% reduction from baseline CSF tau levels by the end of the LTE. IONIS-MAPTRx impacted aggregated tau pathology as measured by PET as early as week 25 and up to the end of the LTE at week 100, including in patients who began on placebo and received IONIS-MAPTRx treatment starting at week 25 in the LTE. By the end of the LTE, IONIS-MAPTRx reduced tau pathology relative to baseline in all dose groups across all brain composites assessed. The Phase 2 CELIA study of IONIS-MAPTRx (NCT05399888) is in progress and currently recruiting participants in the U.S. About Ionis' Neurology Franchise Ionis' neurology franchise addresses all major brain regions and central nervous system cell types and currently has three Phase 3 studies ongoing with 12 therapies in clinical development, several of which Ionis plans to commercialize directly. Ionis is discovering and developing potential treatments for many neurological diseases for which there are few or no disease modifying treatments, including common diseases like Alzheimer's and Parkinson's as well as rare diseases such as amyotrophic lateral sclerosis (ALS) and Alexander disease. Ionis' marketed neurological disease medicines include SPINRAZA®, a global foundation of care for spinal muscular atrophy (SMA), commercialized by Biogen, and TEGSEDI®, for hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN). About Ionis Pharmaceuticals, Inc. For more than 30 years, Ionis has been a leader in RNA-targeted therapy, pioneering new markets and changing standards of care. Ionis currently has three marketed medicines and a promising late-stage pipeline highlighted by cardiovascular and neurological franchises. Our scientific innovation began and continues with the knowledge that sick people depend on us, which fuels our vision to become the leader in genetic medicine, utilizing a multi-platform approach to discover, develop and deliver life-transforming therapies. Ionis' Forward-looking Statements This press release includes forward-looking statements regarding Ionis' business and the therapeutic and commercial potential of Ionis' technologies, IONIS-MAPTRx and other products in development. 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 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. 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 Dec. 31, 2022, which is on file with the Securities and Exchange Commission. Copies of this and other documents are available from the Company. SOURCE Ionis Pharmaceuticals, Inc. Posted: March 2023