Pelizaeus-Merzbacher Disease

WAINUA™ approved with launch underway; on track for EU and Canada approval decisions this year Positive Phase 3 olezarsen and donidalorsen data, preparing regulatory submissions for FCS and HAE, respectively Olezarsen granted Breakthough Therapy designation by the FDA for FCS Ionis provides full year 2024 financial guidance CARLSBAD, Calif., Feb. 21, 2024 /PRNewswire/ --Ionis Pharmaceuticals, Inc. (Nasdaq: IONS) (the "Company"), today reported financial results for the fourth quarter and full year ended December 31, 2023. "This past year included many remarkable achievements as we continued to advance our vision to bring better futures to people with serious diseases. Ionis achieved two FDA approvals, delivered three positive Phase 3 data readouts, expanded our rich Phase 3 pipeline to nine medicines and advanced our next wave of wholly owned medicines as well as our technology," said Brett P. Monia, Ph.D., chief executive officer of Ionis. "In 2024, we anticipate building on our success with important catalysts and continued value creation. The WAINUA U.S. launch is underway for patients with hereditary ATTR polyneuropathy, and we expect additional approvals in other countries this year. We plan to present positive Phase 3 data for olezarsen in familial chylomicronemia syndrome and donidalorsen in hereditary angioedema, positioning Ionis to independently launch these two medicines. We also anticipate additional readouts from multiple mid-stage programs that, if positive, would advance into Phase 3 development, further strengthening our ability to deliver a steady cadence of potentially transformational medicines for years to come." Fourth Quarter and Full Year 2023 Summary Financial Results(1): Financial Highlights Revenue more than doubled for the fourth quarter of 2023 compared to the same period in the prior year and increased 34% for the full year, driven by the successful progression of Ionis' pipeline and technology platform Operating expenses increased compared to the prior year, primarily due to strategic investments to bring eplontersen, olezarsen and donidalorsen to patients 2023 operating loss significantly improved over prior year due to substantial revenue earned during the year Cash and short-term investments of $2.3 billion as of December 31, 2023 enables continued investments to drive increasing value, including supporting our potential upcoming launches Recent Marketed Medicines Highlights WAINUA approved in the U.S., resulting in a $50 million milestone payment from AstraZeneca; launch underway for treatment of adults with polyneuropathy of hereditary transthyretin-mediated amyloidosis (ATTRv-PN) SPINRAZA continued to be the global market leader for the treatment of spinal muscular atrophy (SMA) with global sales of $1.7 billion in 2023 Recent Late-Stage Pipeline Highlights Eplontersen granted Fast Track designation by the FDA for the treatment of patients with ATTR cardiomyopathy (ATTR-CM) Olezarsen granted Breakthrough Therapy designation by the FDA for the treatment of patients with familial chylomicronemia syndrome (FCS) Olezarsen granted orphan drug designation by the FDA for the treatment of patients with FCS Achieved multiple milestones with donidalorsen for the treatment of patients with hereditary angioedema (HAE): Reported positive topline data from the Phase 3 OASIS-HAE study in patients treated every four weeks or every eight weeks; preparing to submit NDA Licensed European donidalorsen commercialization rights to Otsuka; Otsuka preparing to submit MAA Donidalorsen granted orphan drug designation by EMA Reported positive Phase 2 data from the open label extension study in patients with HAE treated for two years Bepirovirsen granted fast track designation by the FDA for the treatment of patients with chronic hepatitis B (CHB) Recent Other Pipeline Highlights Achieved multiple milestones with ION582 (BIIB121) for the treatment of patients with Angelman syndrome: Completed enrollment in the Phase 1/2 HALOS study in patients with Angelman syndrome; on track for data readout in mid-2024 Presented positive clinical update from ongoing HALOS study at the FAST (Foundation for Angelman Syndrome Therapeutics) Summit Extended the long-term extension portion of HALOS study Sapablursen and ION356 granted fast track designation by the FDA for the treatment of patients with polycythemia vera (PV) and Pelizaeus-Merzbacher disease (PMD), respectively Initiated the Phase 1/2 PrPro of ION717 in patients with Prion disease AstraZeneca licensed ION826 for the treatment of heart failure, resulting in a $36 million payment from AstraZeneca Recent Technology Advancement Highlights Licensed Vect-Horus' blood-brain barrier crossing technology for the development of RNA-targeted neurological disease medicines Fourth Quarter, Full Year 2023 Financial Results and 2024 Financial Guidance "In 2023, we earned substantial revenues due to continued success with our pipeline and technology. As a result, we exceeded our 2023 revenue guidance, which drove a smaller than anticipated operating loss," said Elizabeth L. Hougen, chief financial officer of Ionis. "In 2024, with WAINUA's launch for ATTRv-PN underway, we are adding a new stream of royalty revenue to our substantial and sustained revenues. We will continue to deploy our capital resources toward growth opportunities that can enable Ionis to unlock next-level value. This includes continuing to make significant investments in near-term commercial opportunities, the expansion of our wholly owned pipeline, and advancing our technology, all of which should empower future growth." Revenue Ionis' revenue was comprised of the following: Commercial revenues in 2023 were comparable to 2022. Commercial revenue for 2023 included $240 million from SPINRAZA royalties, which was comparable to 2022. Ionis' commercial revenue in 2023 also included royalties from QALSODY U.S. product sales. R&D revenue significantly increased in 2023 compared to 2022 primarily due to continued success with Ionis' pipeline and technology. As a result, Ionis earned significant partner payments, including $50 million from AstraZeneca for the FDA approval of WAINUA for ATTRv-PN in the U.S., $36 million from AstraZeneca for licensing ION826 and payments from Ionis' new collaborations with Otsuka, Roche and Novartis. Operating Expenses Ionis' operating expenses increased for the year ended December 31, 2023 compared to 2022 primarily due to certain one-time costs, including a non-cash charge associated with a lease exit and the license fee Ionis paid to Vect-Horus. As Ionis advanced its robust pipeline, study costs increased compared to the same periods in 2022 as many of the Company's Phase 3 studies are either fully enrolled or approaching full enrollment, resulting in higher R&D expenses year over year. R&D expenses for the fourth quarter of 2023 were lower compared to the fourth quarter of 2022, primarily due to the $80 million upfront payment Ionis paid to Metagenomi in 2022. Ionis' SG&A expenses increased year over year primarily due to launch preparation activities for WAINUA, olezarsen and donidalorsen. Balance Sheet As of December 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 and significant partner payments throughout 2023. Ionis' working capital also increased over the same period primarily due to the Company's higher cash and short-term investments balance. In 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. 2024 Financial Guidance The Company's 2024 guidance reflects its plan to deploy its capital resources toward growth opportunities, including continued investments in its near-term commercial opportunities, expanding its wholly owned pipeline and advancing its technology platform. Additionally, the Company expects to continue earning substantial revenue from its commercial portfolio and partnered programs. Webcast Management will host a conference call and webcast to discuss Ionis' fourth quarter and full year 2023 results at 11:30 a.m. Eastern time on Wednesday, February 21, 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 fourth quarter and full year 2023 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 Ionispharma.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, 2022, and most recent Form 10-Q, which are on 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. WAINUATM is a registered trademark of the AstraZeneca group of companies. *In October 2022, Ionis entered into a sale and leaseback transaction for several of its real estate assets. As a result, the Company recognized a $150 million gain on sale of real estate assets in the fourth quarter of 2022. The Company excluded the gain on sale of real estate assets and the related tax effect from its non-GAAP amounts for the applicable periods. Reconciliation of GAAP to Non-GAAP Basis As illustrated in the Selected Financial Information in this press release, non-GAAP operating expenses, non-GAAP income (loss) from operations, and non-GAAP net income (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. In 2022, Ionis' non-GAAP net loss excluded the gain on real estate assets related to the sale and leaseback transaction and the related tax effects. 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) Company Codes: NASDAQ-NMS:IONS

PALO ALTO, Calif., Sept. 20, 2022 /PRNewswire/ -- Koji Tanabe of I Peace, Inc. () and a researcher Hiroko Nobuta of the University of California, San Francisco (currently assistant professor at Rutgers University) successfully achieved the direct reprogramming: the direct and rapid transformation of Dermal fibroblasts into Oligodendrocyte precursor cells by inducing four genes into the cells. This research was jointly conducted with Prof. Wernig at Sanford University and Prof. Rowitch at UCSF. The research was published in the online edition of an academic journal "Development" on June 24th. Continue Reading Oligodendrocytes are cells that form myelin around the axons of neurons, which act as insulators surrounding the neurons and accelerate the rate at which electrical signals flow. Abnormalities in oligodendrocytes cause cerebral leukodystrophy. The production of a large number of oligodendrocytes is necessary for understanding its pathology, drug discovery, and transplantation medicine. The conventional method of inducing differentiation of human iPS cells or ES cells into oligodendrocytes is inefficient and requires a long time for differentiation induction. Therefore, it has required high cost for the transplantation medicine and the clarification of the pathology, which hinder the development for early treatment and drug discovery. In addition, transplantation treatment has accompanied with problems such as the possibility of tumor formation due to contamination of undifferentiated cells. In this study, we have successfully transformed dermal cells into oligodendrocyte precursors without undergoing the stem cell state. Surprisingly, oligodendrocyte precursors produced directly from dermal cells finally differentiated into functional oligodendrocytes that wrapped around neurons to form myelin sheaths both in vitro and in vivo mouse brain after transplantation. Furthermore, we successfully reproduced the clinical condition in vitro using oligodendrocyte precursors cells generated from dermal cells of a patient with Pelizaeus-Merzbacher disease (PMD), a type of congenital myelination failure. PMD is a developmental disorder that occurs in children and is caused by an abnormality in the oligodendrocyte specific gene PLP1. It is known that the gene abnormality causes oligodendrocytes to die in the brain during differentiation, which prevents myelination. At present, there is no fundamental treatment for the disease, with only palliative treatment for symptoms such as movement impairment, spastic paralysis, and epilepsy. The direct reprogramming from this study successfully reproduced the pathological condition within a significantly reduced production time, which will surely accelerate drug discovery and development in the future. The oligodendrocyte precursor cells produced in this study have been proven to engraft in the mouse brain after transplantation and wrap around neurons. Therefore, they are expected to be technically applied to transplantation regenerative medicine for other congenital myelination failure disorders and myelinopathy (multiple sclerosis, optic neuromyelitis, etc.) which effective treatments are rare. The link to the article published in the journal Development is as follows: The Rowitch and Wernig labs have declared no financial interest in the company and that the company did not fund the research. Researcher Hiroko Nobuta established a laboratory at Rutgers University in New Jersey in September 2020. She works for drug discovery and regeneration research for myelin diseases using oligodendrocytes created by the direct programming. I Peace, inc. I Peace, inc. globally develops sales of GMP iPS cell and entrusted manufacturing services of medical grade cells. The company was founded in 2015 by Koji Tanabe, a graduate of Professor Shinya Yamanaka's laboratory at Kyoto University and the second author of the paper that reported the successful establishment of the world's first human iPS cell line. Tanabe has been involved in iPS cell research since the early days of its development, and is daily working on innovative technical development to make iPS cells accessible to everyone through I Peace, inc. Our unique technology enables us to produce multiple donor-derived iPS cells in parallel without contamination concerns and to provide a large number of iPS cells at a reasonable price. We support drug discovery and cell medicine development by providing our iPS cell and other cell products as high-quality cell products that meet PMDA and FDA standards to pharmaceutical companies and cell medicine development companies. We are also promoting the production of iPS cells for individuals so that everyone in the world can prepare for the future by possessing his or her own iPS cells. We support pharmaceutical companies and cell medicine development companies so that cell medicine will be within the reach of patients as soon as possible. We aim the soonest prevalence of the regenerative medicine by establishing iPS cell banking services for individuals. I Peace, Inc. Founder・CEO：Koji Tanabe Established：2015 Headquarter：Palo Alto, California, U.S.A. Subsidiary in Japan：I Peace, Ltd., Kyoto iPS cell manufacturing base : Peace Engine Kyoto, Kyoto Website : Media contact：[email protected] SOURCE I Peace, Inc.

A rare but potentially debilitating brain disorder finally has a definitive cause, thanks to research teams working on opposite sides of the globe. A mutation in the gene that manages the transportation out of cells of zinc, an essential dietary micronutrient, is responsible for the disorder, called hypomyelinating leukodystrophy. A rare but potentially debilitating brain disorder finally has a definitive cause, thanks to research teams working on opposite sides of the globe. A mutation in the gene that manages the transportation out of cells of zinc, an essential dietary micronutrient, is responsible for the disorder, called hypomyelinating leukodystrophy. The research, jointly led by Dr. Quasar Padiath at the University of Pittsburgh and Dr. Anju Shukla at the Kasturba Medical College in India, is reported in the journal Brain. This is the first time that a mutation in a zinc transporter gene -- in this case, TMEM163 -- has been definitively linked to the development of any brain disorder, and it has the potential to provide insights into the role of zinc in normal brain development, injury and disease. "Discovering a new gene responsible for causing a disease is always exciting; that feeling never gets old," said Padiath, associate professor of human genetics and neurobiology at Pitt. "And finding out that a zinc transporter is really important for proper myelin development could have many clinical implications and offer new ways of treating other related neurological conditions." Hypomyelinating leukodystrophies are rare and often fatal neurological disorders caused by defects in genes involved in growth or maintenance of myelin, the fatty layer of insulation surrounding nerves that helps them transmit electrical impulses. As the myelin layer gradually gets thinner and is lost in these patients, nerve signals slow to a crawl, ushering in a slew of neurological problems, including impaired movement and balance control, muscle wasting, problems with vision, and hearing and memory loss. While genes have been linked to leukodystrophies, the genetic underpinnings for the majority of cases are still unknown. To identify the root cause of a patient's condition and recommend the most appropriate therapy, clinical neurologists often turn to researchers like Padiath. By combing through patients' genomes, Padiath looks for mutations and analyzes the effect of these mutations in cells and animal models, such as mice. Such an analysis is no small feat. To definitively link a new gene mutation to disease symptoms, multiple independent patient cases that share the same gene defect and clinical presentation have to be identified. For rare diseases, such as hypomyelinating leukodystrophies, finding such cases is possible only by tapping a network of scientific and clinical collaborators from all over the world. In this study, the first patient sample came from Shukla, a professor of medical genetics at Manipal in southwest India. Inquiries to other groups in the U.S. and the Netherlands identified additional families who also carried mutations in the same gene. A series of in-depth lab studies showed that the TMEM163 mutations impair the transporter's ability to effectively shunt zinc from inside the cell, causing reduced production of proteins responsible for synthesis and maintenance of myelin and increasing cell death. "Understanding how genes cause rare diseases is the first step in the process of finding treatments," said Padiath. "It is important to remember that diseases that are rare in the global context are very important and real for patients and their families. Studying these diseases helps find cures and give hope to patients and valuable insights into therapeutic targets essential for normal cell functioning."