Vitamin A

WAINUATM U.S. launch progressing well; approved in UK; positive CHMP opinion Olezarsen FCS PDUFA December 19, 2024 Donidalorsen HAE PDUFA August 21, 2025; EU regulatory submission in process On track to achieve 2024 P&L financial guidance; increased 2024 cash guidance CARLSBAD, Calif., Nov. 6, 2024 /PRNewswire/ -- Ionis Pharmaceuticals, Inc. (Nasdaq: IONS) (the "Company") today reported financial results for the third quarter of 2024. "Today, we stand on the cusp of a new era for Ionis, with our first co-commercialization launch proceeding well with WAINUA, our first planned independent launch fast approaching and continued strong progress across our rich pipeline. With an upcoming December FDA action date, we are ready to independently bring olezarsen to people with familial chylomicronemia syndrome, a serious rare disease with no approved treatments in the U.S. We are similarly well positioned for our second independent launch for donidalorsen, which we believe could become a preferred treatment choice for people with hereditary angioedema, with an FDA action date of August 21, 2025," said Brett P. Monia, Ph.D., chief executive officer of Ionis. "In parallel, we are making great progress across the rest of our rich Phase 3 pipeline. We expect Phase 3 results supporting olezarsen's second indication in severe hypertriglyceridemia and pelacarsen in Lp(a)-driven cardiovascular disease next year, as well as Phase 3 results supporting eplontersen's second indication in ATTR cardiomyopathy in the second half of 2026. We are also advancing our next wave of potentially transformational wholly owned medicines, including ION582 for Angelman syndrome, which we expect to enter Phase 3 development in the first half of next year following our positive end of Phase 2 discussion with the FDA. Our recent achievements, together with our advancing and expanding pipeline, position Ionis to deliver on our goal to bring a steady cadence of transformational medicines to people with serious diseases." Third Quarter 2024 Summary Financial Results(1): Financial Highlights Revenue for the three and nine months ended September 30, 2024 decreased by 7% and increased by 3% compared to the same periods last year, respectively. Ionis continued to generate revenue from diverse sources, including a new source of royalty revenue with the launch of WAINUA in the U.S in the first quarter Operating expenses for the three and nine months ended September 30, 2024 increased as planned compared to the same periods last year, excluding certain one-time costs in 2023, reflecting continued investments in late-stage development, including WAINUA for ATTR cardiomyopathy (ATTR-CM) and olezarsen for severe hypertriglyceridemia (sHTG), and commercialization efforts for WAINUA, olezarsen and donidalorsen Reaffirmed 2024 P&L financial guidance, increased cash guidance to $2.2 billion reflecting proceeds from equity offering Recent Marketed Medicines Highlights WAINUA (WAINZUA in Europe) for the treatment of adults with polyneuropathy of hereditary transthyretin-mediated amyloidosis (ATTRv-PN) achieved multiple commercial and regulatory milestones: Generated sales of $23 million and $44 million resulting in royalty revenue of $5 million and $10 million in the three and nine months ended September 30, 2024, respectively Received positive Committee for Medicinal Products for Human Use (CHMP) opinion from European Medicines Agency (EMA) for the treatment of hereditary transthyretin-mediated amyloidosis in adult patients with stage 1 or stage 2 polyneuropathy Approved in UK by the Medicines and Healthcare products Regulatory Agency (MHRA) with an accelerated National Institute for Health and Care Excellence (NICE) recommendation; earning $30 million from AstraZeneca Launch underway in Canada, following approval and reimbursement from Health Canada SPINRAZA® (nusinersen) for the treatment of spinal muscular atrophy (SMA) generated global sales of $381 million and $1.2 billion resulting in royalty revenue of $57 million and $152 million in the three and nine months ended September 30, 2024, respectively Positive Phase 2/3 DEVOTE study data presented from higher dose nusinersen; global regulatory applications planned QALSODY® (tofersen) granted marketing approval in China for the treatment of SOD1-ALS Recent Late-Stage Pipeline Highlights Olezarsen positioned to potentially treat two patient populations with urgent unmet need, familial chylomicronemia syndrome (FCS) and severe hypertriglyceridemia (sHTG): NDA for patients with FCS under FDA Priority Review with a PDUFA date of December 19, 2024 Marketing authorization application (MAA) under regulatory review by the EMA Ongoing pivotal development program for sHTG on track for data in H2:2025 Donidalorsen Phase 3 data position it to potentially launch next year as the first RNA-targeted prophylactic treatment for people with hereditary angioedema (HAE): FDA accepted the NDA for patients with HAE with a PDUFA date of August 21, 2025; Otsuka, Europe and Asia Pacific partner, preparing to submit MAA Presented positive Phase 2 open label extension (OLE) study data in patients treated up to three years with every four weeks or every eight weeks dosing Zilganersen Phase 3 study fully enrolled as a potential treatment for Alexander disease; on track for data in 2025 Granted Fast Track designation by the FDA ION582 achieved important clinical and regulatory milestones enabling initiation of Phase 3 development in Angelman syndrome (AS) in H1:2025: Presented positive Phase 1/2 data in patients with AS at Angelman Syndrome Foundation (ASF) Family Conference Completed positive End-of-Phase 2 discussion with FDA, included alignment on Phase 3 design Reported positive data from the Phase 2 study of IONIS-FB-LRx in patients with immunoglobulin A nephropathy (IgAN); Roche continues to advance IONIS-FB-LRx in the Phase 3 IMAGINATION study Recent Other Pipeline Updates Sapablursen for the treatment of polycythemia vera granted orphan drug designation by FDA; enrollment complete in Phase 2 IMPRSSION study with data expected in 2025 IONIS-MAPTRx (BIIB080) enrollment complete in Phase 2 CELIA study in patients with early Alzheimer's disease (AD); data expected in 2026 Initiated first in human studies with multiple medicines from neurological disease pipeline: Phase 1/2 Orbit study of ION356 (PLP1) in patients with Pelizaeus-Merzbacher disease (PMD) Phase 1/2 HERO study of ION269 (APP), for the potential treatment of Alzheimer's disease (AD), which is initially being evaluated in patients with Down syndrome (DS) who have a genetic risk for developing AD Phase 1/2 ATTUNE study of ION440 (MECP2) in patients with MECP2 duplication syndrome Third Quarter 2024 Financial Results "This year has been marked by strong delivery on our pipeline and business goals, which position Ionis to deliver on our vision of bringing a steady cadence of innovative medicines to patients in need. Fully realizing these significant opportunities requires substantial investment. As a result, we recently executed an equity offering that extends our cash runway, enabling us to continue to invest in the numerous attractive opportunities ahead of us, including our near-term commercial launches with multi-billion-dollar revenue potential and our rich late and mid-stage pipeline," said Elizabeth L. Hougen, chief financial officer of Ionis. "Looking beyond this year, we will continue to invest in go-to-market preparations for our planned olezarsen and donidalorsen launches. Additionally, with our increased confidence in the potential of WAINUA and olezarsen to address broader patient populations, we plan to scale our capabilities in line with the significant potential of these important medicines. At the same time, we are investing in our next wave of medicines, including pre-commercialization activities and Phase 3 development for ION582 for Angelman syndrome and zilganersen for Alexander disease. We expect our investments today will position Ionis for sustainable growth for years to come." Revenue Ionis' revenue was comprised of the following: Commercial revenue for the three and nine months ended September 30, 2024 included a new source of royalty revenue with the launch of WAINUA in the U.S. in late January 2024. Ionis' commercial revenue for the three and nine months ended September 30, 2024 and 2023 also included royalties from the net sales of QALSODY, which Biogen launched in the U.S. in the second quarter of 2023 and in the EU in the second quarter of 2024. SPINRAZA product sales for the three months ended September 30, 2024 compared to the same period last year increased slightly in the U.S. and decreased outside of the U.S. primarily due to an annual order from a single country that did not recur in 2024. R&D revenue was relatively consistent for the three months ended September 30, 2024 compared to the same period last year. R&D revenue increased for the nine months ended September 30, 2024 compared to the same period last year primarily due to the amortization of upfront payments from the new collaborations with Roche and Novartis that Ionis entered into during the second half of last year. In addition, license fees increased year over year as a result of new collaborations Ionis entered into during the second quarter of 2024, including the expanded donidalorsen licensing agreement with Otsuka, which now includes the Asia-Pacific region in addition to Europe. These increases were partially offset by the decrease in WAINUA joint development revenue, which decreased as development activities relating to ATTRv-PN wound down with the launch of WAINUA for this indication. Operating Expenses Ionis' operating expenses, excluding one-time costs associated with a lease exit in the third quarter of 2023, increased for the three and nine months ended September 30, 2024 compared to the same periods in 2023, consistent with expectations. SG&A expenses increased year over year primarily due to the launch of WAINUA in the U.S. and launch preparation activities for olezarsen and donidalorsen, including establishing the field team for olezarsen in the second quarter of 2024. R&D expenses were essentially flat for the three and nine months ended September 30, 2024 compared to the same periods last year as several late-stage studies have ended. Balance Sheet As of September 30, 2024, Ionis' cash, cash equivalents and short-term investments increased to $2.5 billion compared to $2.3 billion at December 31, 2023. In September 2024, Ionis issued 11.5 million shares of its common stock at a public offering price of $43.50 per share that generated gross proceeds of $500 million, before deducting underwriting discounts and commissions and other offering expenses payable by Ionis. The Company plans to continue deploying its capital resources toward growth opportunities, and projects to end 2024 with $2.2 billion in cash, cash equivalents and short-term investments. Ionis' working capital also increased over the same period primarily due to the Company's higher cash and short-term investments balance. As a result of Ionis' advancing pipeline that has delivered several positive data readouts, Ionis expects to make increased investments in the years ahead with the goal to realize the value of these opportunities, with a focus on its wholly owned late-stage and next wave of innovative medicines. Webcast Management will host a conference call and webcast to discuss Ionis' third quarter 2024 results at 11:30 a.m. Eastern time on Wednesday, November 6, 2024. 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 2024 earnings slides click here. For more information about SPINRAZA and QALSODY, visit and , respectively. QALSODY is approved under accelerated approval based on reduction in plasma neurofilament light chain (NfL) observed in patients treated with QALSODY. Continued approval may be contingent upon verification of clinical benefit in confirmatory trial(s). INDICATION for WAINUA™ (eplontersen) WAINUA injection, for subcutaneous use, 45 mg is indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. IMPORTANT SAFETY INFORMATION for WAINUA™ (eplontersen) WARNINGS AND PRECAUTIONS Reduced Serum Vitamin A Levels and Recommended Supplementation WAINUA leads to a decrease in serum vitamin A levels. Supplement with recommended daily allowance of vitamin A. Refer patient to an ophthalmologist if ocular symptoms suggestive of vitamin A deficiency occur. ADVERSE REACTIONS Most common adverse reactions (≥9% in WAINUA-treated patients) were vitamin A decreased (15%) and vomiting (9%). Please see link to U.S. Full Prescribing Information for WAINUA. About Ionis Pharmaceuticals, Inc. For three decades, Ionis has invented medicines that bring better futures to people with serious diseases. Ionis currently has five marketed medicines and a leading pipeline in neurology, cardiology, and other areas of high patient need. As the pioneer in RNA-targeted medicines, Ionis continues to drive innovation in RNA therapies in addition to advancing new approaches in gene editing. A deep understanding of disease biology and industry-leading technology propels our work, coupled with a passion and urgency to deliver life-changing advances for patients. To learn more about Ionis, visit Ionis.com and follow us on X (Twitter), LinkedIn and Instagram. Ionis' Forward-looking Statement This press release includes forward-looking statements regarding Ionis' business, financial guidance and the therapeutic and commercial potential of our commercial medicines, additional medicines in development and technologies. 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. 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 Form 10-K for the year ended December 31, 2023, 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. SPINRAZA® and QALSODY® are registered trademarks of Biogen. WAINUATM is a registered trademark of the AstraZeneca group of companies. Ionis Investor Contact: D. Wade Walke, Ph.DD. [email protected] 760-603-2331 Ionis Media Contact: Hayley Soffer [email protected] 760-603-4679 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 2024 Value Driving Events(1) SOURCE Ionis Pharmaceuticals, Inc. WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

Oral gildeuretinol demonstrated a statistically significant reduction in the geographic atrophy (GA) lesion growth rate of 15.3% from 6 to 24 months (p=0.047) in a pre-specified analysis. Gildeuretinol is the first investigational oral therapy to demonstrate a functional benefit in low luminance visual acuity (LLVA) over 24 months (p=0.031), a key secondary endpoint. Gildeuretinol showed a clinically meaningful reduction in GA lesion growth rate of 13.4% from baseline to 24 months (p=0.075), the study’s primary endpoint. Results indicate that slowing the formation of toxic vitamin A dimers could help address the high unmet need for oral therapies in multiple retinal diseases. Gildeuretinol demonstrated a favorable safety and tolerability profile. Among participants at risk of developing Choroidal Neovascularization (CNV) or wet AMD, only 11% in the gildeuretinol group experienced these adverse events compared to 44% in the placebo group, as reported by clinical investigators. CAMBRIDGE, Mass., Oct. 23, 2024 (GLOBE NEWSWIRE) -- Alkeus Pharmaceuticals, Inc., a biopharmaceutical company dedicated to preserving the sight of individuals impacted by retinal diseases, today announced that patients with geographic atrophy (GA) secondary to age-related macular degeneration (AMD) treated with investigational oral therapy gildeuretinol (ALK-001) showed a statistically significant reduction in the GA lesion growth rate of 15.3% vs. placebo from 6 to 24 months (p=0.047). Gildeuretinol also demonstrated a statistically significant visual function improvement, showing 4.4 fewer letters lost (p=0.031) in low luminance visual acuity (LLVA) over 24 months. Gildeuretinol showed a clinically meaningful trend in slowing GA growth rate of 13.4% from baseline to 24 months (p=0.075), the study’s primary endpoint. A trend toward functional benefit in best corrected visual acuity (BCVA) was demonstrated with 3.3 fewer letters lost (p=0.099). Topline results of the SAGA study of gildeuretinol for the treatment of GA secondary to AMD were presented by Alexander Melamud, M.D., M.A., retina specialist and vitreoretinal surgeon with the Retina Group of Washington and a principal investigator in the SAGA study during the 128th Annual Meeting of the American Academy of Ophthalmology (AAO) held in Chicago October 18-21, 2024. “These data indicate a significant slowing of the growth rate of GA lesions, as well as reducing visual function decline,” said Seemi Khan, M.D., M.P.H., M.B.A., Chief Medical Officer of Alkeus Pharmaceuticals. “It takes a couple of months for gildeuretinol to replace vitamin A and achieve a therapeutic effect. Therefore, we are encouraged by the sensitivity analysis measuring the effect starting at six months of treatment. These data represent the first clinical demonstration that slowing vitamin A dimerization could be a target in the treatment of GA secondary to AMD. By slowing dimerization with gildeuretinol’s unique mechanism, we could reduce further damage to the retina at more advanced stages and possibly delay or prevent the onset of GA. We are excited by the potential of gildeuretinol as an oral therapy with functional benefits in GA, in addition to its potential to be the first therapy for Stargardt disease. We would like to thank the patients, investigators and trial sites for their participation in this study, as well as the National Institutes of Health National Eye Institute for providing funding for this study.” SAGA was a 24-month, double-masked, randomized, placebo-controlled trial to investigate the safety, pharmacokinetics, tolerability and efficacy in patients with GA secondary to AMD. The study enrolled 198 patients. The primary efficacy endpoint was the growth rate of GA lesions from baseline to 24 months as assessed by Fundus Autofluorescence (FAF). The first key secondary endpoint was the change in LLVA from baseline to 24 months. A favorable safety and tolerability pro demonstrated by gildeuretinol, consistent with prior clinical studies of gildeuretinol in Stargardt disease. Additionally, among participants at risk of developing Choroidal Neovascularization (CNV) or wet AMD, only 11% in the gildeuretinol group experienced these adverse events compared to 44% in the placebo group, as reported by the retina specialist investigators. “These data are meaningful and changing the conversation in the space about what might be possible with next generation treatments for patients with GA and earlier stages of AMD,” said Charles Wykoff, M.D., Ph.D., retina specialist and Director of Research at Retina Consultants of Texas. “While the primary endpoint was not met, the anatomic efficacy signal appears real, and most interestingly there appears to be a consistent signal of functional preservation with treatment. This patient population could benefit tremendously from a safe and effective systemic treatment option.” GA is a serious, progressive condition that causes irreversible loss of central vision. It is estimated that the median time of progression to severe visual impairment is slightly over six years. There is no oral therapy approved by the FDA to treat GA. The prevalence of GA in the United States is estimated to be over 1 million people, with 160,000 new cases occurring each year. “One of the most exciting aspects of these results is that gildeuretinol is the first oral medication to show a meaningful positive effect on low luminance visual acuity in macular degeneration,” Dr. Melamud said. “One of the first things patients lose in macular degeneration is low light vision, which can have a dramatic impact on daily living. The positive effect demonstrated on LLVA is significant. Based on these results, this therapy would definitely have a place in the overall strategy of treating AMD and slowing the decline observed in our patients. The favorable safety pro warrant treatment as early as possible.” About Gildeuretinol Acetate (ALK-001) Oral gildeuretinol acetate (ALK-001) is a new chemical entity designed to reduce the dimerization of vitamin A without modulating the visual cycle. In preclinical studies, gildeuretinol decreased vitamin A dimerization down to the normal rate and prevented retinal degeneration and loss of visual function in animals with Stargardt disease. A randomized, placebo-controlled, double-masked clinical trial of gildeuretinol in late-stage Stargardt patients (TEASE-1) showed clinically and statistically significant slowing of the growth of retinal lesions over two years of treatment. Additional clinical trials of gildeuretinol in Stargardt disease are ongoing. Gildeuretinol has received breakthrough therapy designation and orphan drug designation for Stargardt disease from the U.S. Food and Drug Administration. A study (SAGA) of gildeuretinol in 198 patients with geographic atrophy (GA) secondary to age-related macular degeneration (AMD) demonstrated a meaningful trend in the reduction of lesion growth rate and demonstrated a functional benefit in low luminance visual acuity (LLVA). In studies, gildeuretinol demonstrated a favorable safety and tolerability profile. About Alkeus Pharmaceuticals Alkeus Pharmaceuticals, Inc. is a private biopharmaceutical company with headquarters in Cambridge, Mass., backed by institutional investors led by Bain Capital Life Sciences. Founded in 2010, Alkeus is developing therapies for serious diseases of the eye with high unmet need, with the purpose to protect the sight of individuals impacted by retinal diseases. Alkeus’ breakthrough-designated lead candidate, gildeuretinol acetate (ALK-001), is a new chemical entity currently being evaluated in clinical trials for the treatment of Stargardt disease and for geographic atrophy (GA) secondary to age-related macular degeneration (AMD). For further information, please contact: Media Relations media@alkeuspharma.com Website: