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QALSODY approved for SOD1-ALS; MAA under review in EU Reported positive Phase 3 eplontersen ATTRv-PN data; December 22, 2023 PDUFA date On track to achieve 2023 financial guidance CARLSBAD, Calif., May 3, 2023 /PRNewswire/ -- Ionis Pharmaceuticals, Inc. (Nasdaq: IONS) (the "Company"), today reported financial results for the first quarter of 2023. Financial results are summarized below: Financial Highlights Revenue for the first quarter of 2023 was in line with expectations and included revenue from numerous diverse sources Operating expenses increased in the first quarter of 2023 compared to the prior year as planned, reflecting investments in advancing Ionis' pipeline, technology and go-to-market activities for eplontersen, olezarsen and donidalorsen Cash and short-term investments of $2.3 billion at March 31, 2023 enables continued investment in creating future growth opportunities Reaffirmed 2023 financial guidance "2023 is off to a strong start. With QALSODY's approval, it joins SPINRAZA as a new groundbreaking medicine to treat a devastating neurological disease, further validating our RNA-targeting therapeutic platform. We also achieved another important milestone with our recent positive eplontersen Phase 3 data. We believe the positive efficacy and safety data, and the attractive self-administered dosing profile, position eplontersen to be an important treatment for ATTRv-PN patients, who today are underserved. We look forward to the first potential approval of eplontersen in the U.S. in December," said Brett P. Monia, Ph.D., chief executive officer of Ionis. "In addition, we further expanded our industry-leading late-stage pipeline to seven programs across nine indications following the start of GSK's bepirovirsen hepatitis B program. In the second half, we plan to report results from our olezarsen Phase 3 FCS study, which if positive, positions us for our first independent commercial launch. These recent achievements, together with our upcoming milestones, continue to build value for Ionis stakeholders." Recent Late-Stage Pipeline Highlights FDA granted Biogen accelerated approval of QALSODY (tofersen) for patients with SOD1-ALS FDA accepted eplontersen NDA for patients with polyneuropathy caused by hereditary TTR amyloidosis (ATTRv-PN) with a PDUFA date of December 22, 2023 Presented positive week-35 and week-66 data from the Phase 3 NEURO-TTRansform study of eplontersen in patients with ATTRv-PN GSK advanced bepirovirsen into Phase 3 development in patients with chronic hepatitis B Recent Additional Pipeline Updates Biogen presented data demonstrating IONIS-MAPTRx (BIIB080) substantially reduced tau protein in patients with early-stage Alzheimer's disease Continued to focus R&D efforts by discontinuing two programs that did not meet Ionis' target product profile, cimdelirsen for acromegaly and sapablursen for beta-thalassemia. Ionis continues to advance the Phase 2 sapablursen study for polycythemia vera First Quarter 2023 Financial Results "Our first quarter results were in line with our expectations. We generated meaningful revenue while continuing to invest in key growth opportunities across our business. These results keep us on track to achieve our 2023 financial guidance," said Elizabeth L. Hougen, chief financial officer of Ionis. "We plan to continue investing in areas with the greatest potential to drive growth. As such, we expect our investments to grow modestly as we advance and expand our late-stage pipeline and move our near-term commercial opportunities toward the market. Additionally, as we keep more programs for ourselves, we expect a greater proportion of commercial revenues compared to R&D revenues, and our commercial revenues to be the primary driver of future revenue growth." Revenue Ionis' revenue was comprised of the following: Ionis continued to derive its revenue for the first quarter of 2023 from diverse sources, with approximately half coming from commercial products and half from numerous partnered programs. Commercial revenue for the first quarter of 2023 included $50 million from SPINRAZA royalties. Global SPINRAZA product sales of $443 million decreased six percent in the first quarter of 2023, compared to the same period last year primarily due to the impact from foreign currency, fewer new patient starts in the U.S. and channel dynamics. R&D revenue for the first quarter of 2023 included $24 million from AstraZeneca for its share of the global Phase 3 development costs for eplontersen, $20 million from Biogen for advancing several neurology disease programs and $15 million from GSK for advancing bepirovirsen into Phase 3 development. Already in the second quarter, the Company earned $16 million in a milestone payment from Biogen when QALSODY was approved in the U.S. Operating Expenses Ionis' operating expenses increased in the first quarter of 2023 compared to the same period in 2022, consistent with expectations. As Ionis advanced its robust pipeline, study costs increased as most of the Company's Phase 3 studies were either fully enrolled or approaching full enrollment resulting in higher R&D expenses year over year. Additionally, as Ionis prepares to launch eplontersen, olezarsen and donidalorsen, the Company's SG&A expenses also increased year over year. Balance Sheet As of March 31, 2023, Ionis' cash, cash equivalents and short-term investments increased to $2.3 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. Additionally, the Company recorded a long-term liability for future royalties due to Royalty Pharma in the first quarter of 2023. Webcast Management will host a conference call and webcast to discuss Ionis' first quarter 2023 results at 11:30 a.m. Eastern time on Wednesday, May 3, 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 first 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, ION363, pelacarsen, bepirovirsen, 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, 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, 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. QALSODY™ 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. 2023 Key Value Driving Events(1) SOURCE Ionis Pharmaceuticals, Inc.

Recent research suggests Relyvrio will benefit from the limited number of therapies approved to slow decline in ALS EXTON, Pa., March 9, 2023 /PRNewswire/ -- With the FDA approval of Amylyx's Relyvrio (AMX0035; sodium phenylbutyrate and taurursodiol) for amyotrophic lateral sclerosis (ALS) in September 2022, patients gained access to only the third novel molecule approved for this rare, neurodegenerative disease. Mitsubishi Tanabe's edaravone formulations (IV Radicava and oral Radicava ORS) and different riluzole formulations (generics, ITF Pharma's thickened oral suspension Tiglutik, and Mitsubishi Tanabe's oral film Exservan) are the only other approved disease-modifying therapies approved for ALS. At this early stage of launch, the majority of neurologists/neuromuscular specialists (n=68) surveyed in February 2023 reported actively discussing Relyvrio with their ALS patients, typically at their next scheduled visit with relevant candidates. Respondents consider ALS patients with early-stage disease to be the most appropriate candidates for Relyvrio, suggesting that HCPs already perceive it as a first-line therapy. However, even with these generally positive opinions on Relyvrio, reimbursement hassles and out-of-pocket costs are currently key barriers to use. Specifically, data reveal that two in five ALS patients deemed clinically appropriate for Amylyx's brand are not able to receive it due to coverage or co-pay issues. As mentioned by one neurologist unaided when queried on the biggest disadvantage of Relyvrio, " Access is absolutely ridiculous. I spent so much of my time going back-and-forth and it takes forever to get the medication." Delays in access to medications are felt especially acutely in this market and are underscored as a particularly greater barrier given the often-rapid progression of the disease and need for fast treatment. With half of neurologists never having been visited by an Amylyx sales representative, lack of familiarity is also a primary obstacle to increased Relyvrio use. Notably, only a minority of respondents consider Amylyx to be executing well on Relyvrio's launch and few feel that the manufacturer has given them the necessary information to confidently initiate patients on the brand. When asked for advice to Amylyx on Relyvrio's launch, an interviewed respondent highlighted the need for additional outreach: " The biggest thing I would recommend to them is they are not doing as great of a job getting the word out. I don't know if it's because they're still hesitant and waiting for the rest of the data to come out." Despite these obstacles, the majority of neurologists anticipate initiating trial of Relyvrio in their ALS patients over the next six months, likely in combination with other therapies, such as riluzole, in order to provide maximum therapeutic benefit for patients. Even with the noted advance that Relyvrio brings to the market, neurologists are also keen to point out that there is still a large unmet need for new and advanced treatment options. Given the large pipeline of diverse emerging therapies in ALS, including Biogen's tofersen, Apellis Pharmaceuticals' pegcetacoplan, GSK/Alector's latozinemab (GSK4527223/AL-001), Novartis' BLZ945, Sanofi's SAR443820, Ionis Pharmaceuticals' ION363, and Cytokinetics' reldesemtiv, there is hope for new options to bring relief to this underserved patient population. Spherix will continue to track the launch performance of Relyvrio in the ALS market via the Launch Dynamix™: Relyvrio (Amylyx) in ALS report series and will begin tracking the launch of tofersen in ALS if approved on its April 25th, 2023 PDUFA date. About Launch Dynamix™ Launch Dynamix: Relyvrio (Amylyx) in ALS is an independent service providing quarterly deep dives into launch benchmarks, promotional activity, barriers to uptake, and patient types gravitating to the new brand. About Spherix Global Insights Spherix Global Insights is a leading provider of market research, business intelligence and advisory services to the global life sciences industry. The company's unique service offerings are powered by deep therapeutic knowledge, the Spherix Network specialty physician panel, and commercially relevant analyses to enable strategic decision-making by our valued customers. A trusted advisor and industry thought leader, Spherix Global Insights provides specialized market expertise in six (6) focused therapeutic areas including: dermatology, gastroenterology, nephrology, neurology, rheumatology and ophthalmology. To learn more about Spherix Global Insights, visit spherixglobalinsights.com or connect through LinkedIn and Twitter. Spherix Global Insights Contacts Emma McFadden, Senior Insights Director, Neurology [email protected] Scott Upham, Corporate Communications [email protected] NOTICE: All company, brand or product names in this press release are trademarks of their respective holders. The findings and opinions expressed within are based on Spherix Global Insight's analysis and do not imply a relationship with or endorsement by any company, brand, or product aforementioned. SOURCE Spherix Global Insights