Angelman Syndrome

Press Release Dr. Paulo Fontoura, MD, PhD, joins STALICLA as Chief Scientific and Clinical Development Advisor Geneva, Switzerland – September 19, 2024 – STALICLA SA, a Swiss neuro precision biotech company dedicated to developing precision medicine-based treatments for neurodevelopmental disorders, announced today that Dr. Paulo Fontoura will be joining their drug development team as Chief Scientific and Clinical Development Advisor. Dr. Fontoura will work to support STALICLA’s mission to transform the treatment landscape for neurodevelopmental disorders. Lynn Durham, CEO of STALICLA, said: “We are delighted and humbled to welcome Paulo to the STALICLA team. With his unparalleled insight and unique understanding of CNS drug development and neurodevelopmental disorders, he is strengthening STALICLA’s position as a pioneer in precision neuropsychiatry. Paulo’s expertise will be instrumental in helping us achieve our next milestones, notably our entry into two Phase 2 clinical trials in subgroups of patients with autism spectrum disorder (ASD), each with expected readouts in the coming 24 months.” Dr. Paulo Fontoura is a pioneer in innovative clinical development strategies. During his 16-year tenure at Roche, he served as the Global Head of Neuroscience Clinical Development; he was instrumental in the launch of several groundbreaking medications targeting neurological conditions, including Multiple Sclerosis (MS), Spinal Muscular Atrophy (SMA), and Neuromyelitis Optica Spectrum Disorder (NMOSD), as well as pioneering work on Alzheimer's, Parkinson's, Huntington's disease, and several psychiatric and neurodevelopmental disorders. Specifically, he and his team spearheaded the clinical development of new therapies for Fragile X, Down's and Angelman's syndromes, and the first pharmacological treatment for core symptoms of ASD which reached Phase 3 clinical trials in both adults and children. Additionally, his team co-led the Autism Innovative Medicine Studies (AIMS) including EU-AIMS and AIMS-2-TRIALS public private partnership. Dr. Fontoura has also had an illustrious academic career. He held multiple faculty positions at the New University of Lisbon and Stanford University, where he earned his MD and a PhD in Neuroimmunology and trained as a clinical neurologist. In recognition of his exceptional achievements in the field of neuroscience, he was elected as a Fellow of the American Academy of Neurology in 2022. He currently serves as a visiting professor at the New University of Lisbon and lectures at the European Center of Pharmaceutical Medicine in Basel. Paulo Fontoura MD, PhD, Chief Scientific and Clinical Development Advisor, said: “I am thrilled to join the STALICLA team and help them develop therapies for people with neurodevelopmental disorders. Their approach promises to bring real breakthroughs in this area of great medical need.” About STALICLA: STALICLA SA is a Swiss clinical-stage biopharmaceutical company, revolutionizing the treatment of neurodevelopmental disorders. The company has developed a clinically validated neuro precision development platform, successfully delivering stratified patient subgroups and advancing tailored treatment options. Its lead NDD asset, STP1, and a second NDD asset are set to enter Phase 2 trials with expected readouts within 24 months. STP7 (Mavoglurant), is also being advanced for Phase 3 trials, fully funded by the US government. For more information, please visit: www.stalicla.com. Contacts: STALICLA SALynn Durham Founder & Chief Executive Officerlynn.durham@stalicla.com Media & InvestorsChris MaggosCohesion Bureauchris.maggos@cohesionbureau.com+41 79 367 6254 Attachment 20240918 Paulo Fontoura PR_final

Second quarter total revenue of $147 million, Crysvita® revenue of $114 million and Dojolvi® revenue of $19 million Increased 2024 expected total revenue guidance to $530 million to $550 million NOVATO, Calif., Aug. 01, 2024 (GLOBE NEWSWIRE) -- Ultragenyx Pharmaceutical Inc. (NASDAQ: RARE), a biopharmaceutical company focused on the development and commercialization of novel therapies for serious rare and ultrarare genetic diseases, today reported its financial results for the quarter ended June 30, 2024. “Our strong financial performance in the second quarter was driven by growing revenue across our commercial therapies from increasing global demand, leading us to raise our total revenue guidance for this year,” said Emil D. Kakkis, M.D., Ph.D., chief executive officer and president of Ultragenyx. “In the quarter, we also reported positive data from our Phase 1/2 study in Angelman syndrome, our Phase 2/3 study in osteogenesis imperfecta, and our Phase 3 study in GSDIa. We are in an excellent position to achieve additional key milestones in the second half of the year including initiating our Phase 3 Angelman study and filing for accelerated approval for UX111 in Sanfilippo syndrome type A.” Second Quarter 2024 Selected Financial Data Tables and Financial Results Revenues (dollars in thousands), (unaudited) Three Months Ended June 30, Six Months Ended June 30, 2024 2023 2024 2023 Crysvita Product sales$40,449 $16,884 $76,690 $38,118 Revenue in Profit-Share Territory 67,045 61,314 107,447 111,220 Royalty revenue in European Territory 6,176 4,816 12,118 9,698 Total Crysvita Revenue 113,670 83,014 196,255 159,036 Dojolvi 19,355 16,491 35,717 30,794 Mepsevii 6,145 8,439 12,756 16,919 Evkeeza 7,856 365 11,131 577 Daiichi Sankyo — — — 1,479 Total revenues$147,026 $108,309 $255,859 $208,805 Total RevenuesUltragenyx reported $147 million in total revenue for the second quarter of 2024, which represents 36% growth compared to the same period in 2023. Second quarter 2024 Crysvita revenue was $114 million, which represents 37% growth compared to the same period in 2023. This includes product sales of $40 million from Latin America and Turkey, which represents 140% growth compared to the same period in 2023. Dojolvi revenue in the second quarter 2024 was $19 million, which represents 17% growth compared to the same period in 2023. Evkeeza revenue in the second quarter 2024 was $8 million, as demand continues to build in the company’s territories outside of the United States. Selected Financial Data (dollars in thousands, except per share amounts), (unaudited) Three Months Ended June 30, Six Months Ended June 30, 2024 2023 2024 2023 Total revenues$147,026 $108,309 $255,859 $208,805 Operating expenses: Cost of sales 21,280 9,914 38,813 22,171 Research and development 161,503 164,949 339,990 330,647 Selling, general and administrative 80,604 81,403 158,764 158,049 Total operating expenses 263,387 256,266 537,567 510,867 Net loss$(131,598) $(159,828) $(302,282) $(323,800)Net loss per share, basic and diluted$(1.52) $(2.25) $(3.54) $(4.58) Operating Expenses Total operating expenses for the second quarter of 2024 were $263 million, including non-cash stock-based compensation of $39 million. In 2024, annual operating expenses are expected to be stable or to decrease as the company continues to manage its costs and focus its investment on advancing multiple Phase 3 programs and executing on commercial product launches. Net Loss For the second quarter of 2024, Ultragenyx reported net loss of $132 million, or $1.52 per share basic and diluted, compared with a net loss for the second quarter of 2023 of $160 million, or $2.25 per share basic and diluted. Net Cash Used in Operations and Cash BalanceFor the three months ended June 30, 2024, net cash used in operations was $77 million and for the six months ended June 30, 2024 it was $268 million. Cash, cash equivalents, and marketable debt securities were $874 million as of June 30, 2024, which includes $381 million of net proceeds from issuance of common stock and pre-funded warrants in connection with an underwritten public offering in June 2024. 2024 Full Year Financial Guidance Total revenue guidance increased to be in the range of $530 million to $550 million (previously $500 million to $530 million)Crysvita revenue expected to be towards the upper end of the range of $375 million to $400 million. This includes all regions where Ultragenyx will recognize revenue: product sales in Latin America and Turkey, royalties in Europe, which have been ongoing, and royalties in North America, which began in April 2023.Dojolvi revenue in the range of $75 million to $80 millionNet Cash Used in Operations less than $400 million Recent Updates and Clinical Milestones UX143 (setrusumab) monoclonal antibody for Osteogenesis Imperfecta (OI): 14-month data resulted in a large, sustained 67% reduction in annualized fracture rate and persistent median annualized fracture rate of 0.00 (p=0.0014)Positive 14-month results from the Phase 2 portion of the ongoing Phase 2/3 Orbit study demonstrated that, as of the May 24, 2024 data cut-off date, treatment with setrusumab continued to significantly reduce incidence of fractures in patients with OI. Treatment with setrusumab also resulted in ongoing and meaningful improvements in lumbar spine bone mineral density (BMD) at month 12 without evidence of plateau. The median annualized rate of radiologically confirmed fractures across all 24 patients in the 2 years prior to treatment was 0.72. Following a mean treatment duration period of 16 months, the median annualized fracture rate was reduced 67% to 0.00 (p=0.0014; n=24). The reduction in annualized fracture rates was associated with continued, clinically meaningful increases in BMD. Treatment with setrusumab at 12-month demonstrated a mean increase in lumbar spine BMD from baseline of 22% (p<0.0001, n=19) and an improvement of mean baseline lumbar spine BMD Z-score from -1.73 to -0.49 at 12 months. The improvements in BMD and Z-scores were significant and consistent across all OI sub-types studied. As of the data cut-off, there were no treatment-related serious adverse events observed in the study and there were no reported hypersensitivity reactions related to setrusumab. More detailed 14-month data will be presented at a future scientific meeting. GTX-102 antisense oligonucleotide for Angelman syndrome: Successful End-of-Phase 2 (EOP2) meeting with Food and Drug Administration (FDA); on track to initiate Phase 3 by the end of the yearIn July 2024, Ultragenyx completed a successful EOP2 meeting with the FDA supporting the pivotal Phase 3 Aspire study design, which will be a global, randomized, double-blind, sham-controlled trial and will include a 48-week primary efficacy analysis period enrolling approximately 120 patients with Angelman syndrome with a genetically confirmed diagnosis of full maternal UBE3A gene deletion. The primary endpoint will be improvement in cognition assessed by Bayley-4 cognitive raw score. The key secondary endpoint will be the Multi-domain Responder Index (MDRI) across all five domains of cognition, receptive communication, behavior, gross motor function, and sleep. Individual secondary endpoints were also discussed and aligned on with the FDA for the domains of communication, behavior, motor function and sleep. Additionally, the company plans to initiate Aurora, an open-label clinical study, to evaluate the safety and efficacy of GTX-102 for the treatment of patients with other Angelman syndrome genotypes and in other age groups. The company has also participated in a PRIME meeting with the European Medicines Agency, receiving acceptance of the overall Phase 3 study design, dosing and evaluations and has met with Japan’s Pharmaceuticals and Medical Devices Agency to inform and discuss its Phase 3 study design. The company expects the pivotal Phase 3 Aspire study to start by the end of 2024 and the Aurora study to start in 2025. UX701 AAV gene therapy for Wilson disease: Last patient in Cohort 3 dosed; expect interim Stage 1 data in the second half of 2024All patients in the three dose-escalation cohorts of Stage 1 have been dosed. During Stage 1, the safety and efficacy of UX701 will be evaluated and a dose will be selected for further evaluation in Stage 2, which is the pivotal, randomized, placebo-controlled stage of the study. Data from Stage 1 are expected in the second half of 2024, which will be followed by dose selection and initiation of Stage 2. UX111 AAV gene therapy for Sanfilippo syndrome type A (MPS IIIA): Agreement reached with FDA that cerebral spinal fluid (CSF) heparan sulfate (HS) can be used as a reasonable surrogate endpoint for accelerated approvalIn June 2024, Ultragenyx announced a successful meeting with the FDA during which the company reached agreement with the FDA that CSF HS is a reasonable surrogate endpoint that could support submission of a biologics license application, or BLA, seeking accelerated approval for UX111. As discussed with the FDA, the BLA filing will be based on the available data including from the ongoing pivotal Transpher A study evaluating the safety and efficacy of UX111 in children with MPS IIIA. The details of a BLA will be finalized with the FDA in a pre-BLA meeting that is expected to happen in the second half of 2024, with the intent to file the application late this year or early next year. DTX401 AAV gene therapy for Glycogen Storage Disease Type Ia (GSDIa): Positive top-line results from Phase 3 Study resulted in a statistically significant reduction in daily cornstarch intake at Week 48 (p<0.0001) with maintenance of glucose control In May 2024, Ultragenyx announced positive topline results from the Phase 3 GlucoGene study for the treatment of patients aged eight years and older. The study achieved its primary endpoint, demonstrating that treatment with DTX401 resulted in a statistically significant and clinically meaningful reduction in daily cornstarch intake compared with placebo at Week 48. The mean percent reduction was 41.3% in the DTX401 group (n=20) compared with 10.3% in the placebo group (n=24) at Week 48 (p<0.0001). Across patients treated with DTX401, the mean reduction in cornstarch continued to decline over the 48-week period. In the treatment group, all patients achieved a reduction in cornstarch, with 68% achieving ≥30% reduction and 37% achieving ≥50% reduction compared to the placebo group, which achieved the same reductions in 13% and 4% of patients, respectively, at Week 48. The study also successfully met key secondary endpoints of reduction in the number of cornstarch doses per day and maintenance of glucose control at Week 48. Full 48 Week data from the Phase 3 study will be presented at a scientific conference later this year. These results will be discussed with regulatory authorities to support a marketing application in 2025. DTX301 AAV gene therapy for Ornithine Transcarbamylase (OTC) Deficiency: Phase 3 study dosing patients; expect enrollment to be completed in the second half of 2024Ultragenyx is randomizing and dosing patients in the ongoing Phase 3 study. The pivotal, 64-week study will include approximately 50 patients, randomized 1:1 to DTX301 or placebo. The primary endpoints are response as measured by removal of ammonia-scavenger medications and protein-restricted diet and change in 24-hour ammonia levels. Enrollment is currently expected to be completed in the second half of 2024. Conference Call and Webcast Information Ultragenyx will host a conference call today, Thursday, August 1, 2024, at 2 p.m. PT/5 p.m. ET to discuss the second quarter 2024 financial results and provide a corporate update. The live and replayed webcast of the call will be available through the company’s website at https://ir.ultragenyx.com/events-presentations. The replay of the call will be available for one year. About Ultragenyx Ultragenyx is a biopharmaceutical company committed to bringing novel therapies to patients for the treatment of serious rare and ultrarare genetic diseases. The company has built a diverse portfolio of approved medicines and treatment candidates aimed at addressing diseases with high unmet medical need and clear biology, for which there are typically no approved therapies treating the underlying disease. The company is led by a management team experienced in the development and commercialization of rare disease therapeutics. Ultragenyx’s strategy is predicated upon time- and cost-efficient drug development, with the goal of delivering safe and effective therapies to patients with the utmost urgency. For more information on Ultragenyx, please visit the company's website at: www.ultragenyx.com. Forward-Looking Statements and Use of Digital Media Except for the historical information contained herein, the matters set forth in this press release, including statements related to Ultragenyx's expectations and projections regarding its future operating results and financial performance, anticipated cost or expense reductions, the timing, progress and plans for its clinical programs and clinical studies, future regulatory interactions, and the components and timing of regulatory submissions are forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements involve substantial risks and uncertainties that could cause our clinical development programs, collaboration with third parties, future results, performance or achievements to differ significantly from those expressed or implied by the forward-looking statements. Such risks and uncertainties include, among others, the uncertainty of clinical drug development and unpredictability and lengthy process for obtaining regulatory approvals, risks related to serious or undesirable side effects of our product candidates, the company’s ability to achieve its projected development goals in its expected timeframes, risks related to reliance on third party partners to conduct certain activities on the company’s behalf, our limited experience in generating revenue from product sales, risks related to product liability lawsuits, our dependence on Kyowa Kirin for the commercial supply of Crysvita, fluctuations in buying or distribution patterns from distributors and specialty pharmacies, the transition back to Kyowa Kirin of our exclusive rights to promote Crysvita in the United States and Canada and unexpected costs, delays, difficulties or adverse impact to revenue related to such transition, smaller than anticipated market opportunities for the company’s products and product candidates, manufacturing risks, competition from other therapies or products, and other matters that could affect sufficiency of existing cash, cash equivalents and short-term investments to fund operations, the company’s future operating results and financial performance, the timing of clinical trial activities and reporting results from same, and the availability or commercial potential of Ultragenyx’s products and drug candidates. Ultragenyx undertakes no obligation to update or revise any forward-looking statements. For a further description of the risks and uncertainties that could cause actual results to differ from those expressed in these forward-looking statements, as well as risks relating to the business of Ultragenyx in general, see Ultragenyx's Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) on May 3, 2024, and its subsequent periodic reports filed with the SEC. In addition to its SEC filings, press releases and public conference calls, Ultragenyx uses its investor relations website and social media outlets to publish important information about the company, including information that may be deemed material to investors, and to comply with its disclosure obligations under Regulation FD. Financial and other information about Ultragenyx is routinely posted and is accessible on Ultragenyx’s Investor Relations website (https://ir.ultragenyx.com/) and LinkedIn website (https://www.linkedin.com/company/ultragenyx-pharmaceutical-inc-/mycompany/). Contacts Ultragenyx Pharmaceutical Inc.InvestorsJoshua Higair@ultragenyx.com Ultragenyx Pharmaceutical Inc.Selected Statement of Operations Financial Data(in thousands, except share and per share amounts)(unaudited) Three Months Ended June 30, Six Months Ended June 30, 2024 2023 2024 2023 Statement of Operations Data: Revenues: Product sales$73,805 $42,179 $136,294 $86,408 Royalty revenue 73,221 46,331 119,565 51,213 Collaboration and license — 19,799 — 71,184 Total revenues 147,026 108,309 255,859 208,805 Operating expenses: Cost of sales 21,280 9,914 38,813 22,171 Research and development 161,503 164,949 339,990 330,647 Selling, general and administrative 80,604 81,403 158,764 158,049 Total operating expenses 263,387 256,266 537,567 510,867 Loss from operations (116,361) (147,957) (281,708) (302,062)Change in fair value of equity investments (3,991) 261 (245) (73)Non-cash interest expense on liabilities for sales of future royalties (15,960) (15,375) (31,807) (31,011)Other income, net 5,572 3,975 12,791 10,573 Loss before income taxes (130,740) (159,096) (300,969) (322,573)Provision for income taxes (858) (732) (1,313) (1,227)Net loss$(131,598) $(159,828) $(302,282) $(323,800)Net loss per share, basic and diluted$(1.52) $(2.25) $(3.54) $(4.58)Shares used in computing net loss per share, basic and diluted 86,580,516 70,897,991 85,433,443 70,639,015 Ultragenyx Pharmaceutical Inc.Selected Activity included in Operating Expenses(in thousands)(unaudited) Three Months Ended June 30, Six Months Ended June 30, 2024 2023 2024 2023 Non-cash stock-based compensation$39,363 $34,653 $76,297 $66,592 UX143 clinical milestone — $9,000 — $9,000 Ultragenyx Pharmaceutical Inc.Selected Balance Sheet Financial Data(in thousands)(unaudited) June 30, December 31, 2024 2023 Balance Sheet Data: Cash, cash equivalents, and marketable debt securities $874,490 $777,110 Working capital 691,774 451,747 Total assets 1,618,437 1,491,013 Total stockholders' equity 432,418 275,414

WAINUATM U.S. launch progressing well; approved in Canada; EU approval decision expected this year Olezarsen PDUFA December 19, 2024 for FCS Positive Phase 3 donidalorsen data for HAE; preparing U.S. and EU regulatory submissions On track to achieve 2024 financial guidance CARLSBAD, Calif., Aug. 1, 2024 /PRNewswire/ -- Ionis Pharmaceuticals, Inc. (Nasdaq: IONS) (the "Company"), today reported financial results for the second quarter of 2024. "Over the first half of this year, we continued to deliver on our goal to bring a steady cadence of medicines to people with serious diseases. The WAINUA launch for hereditary ATTR polyneuropathy (ATTRv-PN) continues to progress well with AstraZeneca. QALSODY is now approved in the EU, expanding the number of patients who can benefit from the first approved treatment for a genetic form of ALS. And we are well positioned for our first independent launch with olezarsen, which was accepted for Priority Review with a December FDA action date for people with familial chylomicronemia syndrome (FCS), a serious and rare disease with no approved treatments in the U.S. Additionally, we completed enrollment in our Phase 3 olezarsen program for the much larger severe hypertriglyceridemia (sHTG) patient population, keeping us on track for data in the second half of next year. And based on recent positive Phase 3 results, we believe donidalorsen, our second planned independent U.S. launch, is positioned to be a preferred choice for people with hereditary angioedema (HAE)," said Brett P. Monia, Ph.D., chief executive officer of Ionis. "We also advanced our next wave of potentially transformational medicines, including announcing plans to independently advance ION582 into a Phase 3 study next year, based on positive data in Angelman syndrome; this program is poised to become the cornerstone of our robust wholly owned neurology pipeline. Our recent achievements, together with multiple upcoming catalysts, position Ionis to deliver next-level value for all stakeholders." Second Quarter 2024 Summary Financial Results(1): Financial Highlights Revenue increased for the second quarter and first half of 2024 by 20% and 8% compared to the same periods last year, respectively, primarily driven by an increase in R&D revenue reflecting the value Ionis' pipeline and technology continues to generate Operating expenses increased in the second quarter and first half of 2024 compared to the same periods last year, reflecting continued strategic investments in late-stage development, including WAINUA for ATTR cardiomyopathy and olezarsen for sHTG, and commercialization efforts for WAINUA, olezarsen and donidalorsen Reaffirmed 2024 financial guidance Recent Marketed Medicines Highlights WAINUA for the treatment of adults with polyneuropathy of hereditary transthyretin-mediated amyloidosis (ATTRv-PN) generated sales of $16 million and $21 million resulting in royalty revenue of $4 million and $5 million in the second quarter and first half of 2024, respectively WAINUA for the treatment of adults with ATTRv-PN approved in Canada SPINRAZA for the treatment of spinal muscular atrophy (SMA) generated global sales of $429 million and $770 million resulting in royalty revenue of $57 million and $95 million in the second quarter and first half of 2024, respectively QALSODY for the treatment of SOD1-ALS granted marketing approval in the EU Recent Late-Stage Pipeline Highlights Olezarsen achieved multiple clinical and regulatory milestones that support pursuit of two patient populations with urgent unmet need, familial chylomicronemia syndrome (FCS) and severe hypertriglyceridemia (sHTG): FDA accepted the NDA for patients with FCS for Priority Review with a PDUFA date of December 19, 2024 Presented positive Phase 3 Balance study data in patients with FCS with a simultaneous publication in the New England Journal of Medicine Opened Expanded Access Program (EAP) for FCS in the U.S. Completed enrollment for all Phase 3 sHTG studies: CORE pivotal study, CORE2 confirmatory pivotal study and ESSENCE supportive exposure study; on track for data across all three studies in H2:2025 Presented positive Phase 2b Bridge study data in patients with HTG and sHTG with a simultaneous publication in the New England Journal of Medicine Donidalorsen achieved multiple clinical milestones positioning it to become the first RNA-targeted prophylactic treatment for people with hereditary angioedema (HAE): Preparing to submit NDA Otsuka preparing to submit MAA; expanded Otsuka EU commercial licensing agreement to include Asia Pacific Presented positive Phase 3 OASIS-HAE study data in patients treated every four weeks or every eight weeks with a simultaneous publication in the New England Journal of Medicine Presented positive Phase 3 OASISplus open-label extension study data in patients treated every four weeks or every eight weeks Presented positive Phase 3 OASISplus switch study data in patients previously treated with other prophylactic therapies Zilganersen (GFAP) Phase 3 study for the treatment of patients with Alexander disease fully enrolled; on track for data in 2025 Bepirovirsen Phase 3 studies for the treatment of patients with chronic hepatitis B (CHB) fully enrolled; on track for data in 2026 Recent Other Pipeline Updates Presented positive Phase 2 data for ION582 (UBE3A), our wholly owned medicine, in patients with Angelman syndrome; preparing for meetings with global regulators ahead of planned Phase 3 study start in H1:2025 Presented positive Phase 2 data for ION224 (DGAT2) in patients with metabolic dysfunction-associated steatohepatitis (MASH) Initiated the Phase 1/2 Orbit study of ION356 (PLP1) in patients with Pelizaeus-Merzbacher disease (PMD) Discontinued development of IONIS-FB-LRx for geographic atrophy (GA) and ION541 for amyotrophic lateral sclerosis (ALS) following completion of Phase 2 studies showing favorable safety profiles and good target engagement, but insufficient efficacy to advance into Phase 3 development Second Quarter 2024 Financial Results "Ionis is at a critical inflection point. We have achieved important development and regulatory milestones for WAINUA, olezarsen and donidalorsen, all of which have significant potential to help patients in need. In parallel, we continue to advance our next wave of potentially transformational medicines," said Elizabeth L. Hougen, chief financial officer of Ionis. "To drive next-level of value creation for all stakeholders, we remain focused on strategically investing our capital to fully unlock the potential of our promising near-and longer-term portfolio. Our investments are focused on go-to-market preparations for our upcoming planned olezarsen and donidalorsen launches. And with our increased confidence in the potential of WAINUA and olezarsen to address broader patient populations, we are planning additional investments to scale our capabilities in line with the significant potential that these important medicines represent. Additionally, we are investing in our next wave of medicines, including pre-commercialization activities and Phase 3 development for ION582 for Angelman syndrome, which we plan to start in the first half of next year. We expect our investments today and in the years ahead will position Ionis for sustainable growth for years to come." Revenue Ionis' revenue was comprised of the following: Commercial revenue in the second quarter and first half of 2024 included a new source of royalty revenue with the launch of WAINUA in the U.S. in late January 2024. Ionis' commercial revenue in the second quarter and first half of 2024 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. R&D revenue in the second quarter and first half of 2024 increased compared to the same periods 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 increased in the second quarter and first half of 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. R&D expenses decreased in the second quarter and were essentially flat in the first half of 2024 compared to the same periods last year as several late-stage studies have ended. Balance Sheet As of June 30, 2024, Ionis' cash, cash equivalents and short-term investments decreased to $2.1 billion compared to $2.3 billion at December 31, 2023. The Company plans to continue deploying its capital resources toward growth opportunities, and as previously guided, projects to end 2024 with $1.7 billion in cash, cash equivalents and short-term investments. Ionis' working capital also decreased over the same period primarily due to the Company's lower cash and short-term investments balance. We expect to make increased strategic investments in the years ahead, with a focus on late-stage programs, wholly owned assets, and our next wave of innovative medicines. Webcast Management will host a conference call and webcast to discuss Ionis' second quarter 2024 results at 11:30 a.m. Eastern time on Thursday, August 1, 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 second 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) and LinkedIn. 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.D. [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.