Leukodystrophy NOS

– Accelerating value creation with numerous commercial, regulatory and pipeline milestones – – Ionis outlines clear path to sustained positive cash flow – CARLSBAD, Calif., Jan. 13, 2025 /PRNewswire/ -- Ionis Pharmaceuticals, Inc. (Nasdaq: IONS) today announced highlights from the Company's 2024 achievements and previewed important milestones expected in 2025. Ionis will provide a business update at the 42nd Annual J.P. Morgan Healthcare Conference on Wednesday, January 15 at 10:30am PT; the presentation is available today on the Ionis website. "With last month's U.S. approval and launch of TRYNGOLZA™ (olezarsen) as the first-ever therapy for familial chylomicronemia syndrome and the potential approval of donidalorsen in hereditary angioedema later this year, Ionis has entered a new chapter as a fully integrated commercial-stage biotechnology company that independently brings our innovative medicines to patients," said Brett P. Monia, Ph.D., chief executive officer, Ionis. "TRYNGOLZA is the first of four independent Ionis product launches anticipated over the next three years. We also expect four key launches from important partnered programs within this timeframe. Collectively, these medicines stand to help millions of patients with serious diseases and create substantial value for all our stakeholders. To that end, we expect increasing product and royalty revenue to enable Ionis to achieve our goal of being cash flow positive." 2025 Anticipated Highlights Include: Launch TRYNGOLZA, Ionis' first independent product and the first-ever therapy for U.S. patients with familial chylomicronemia syndrome (FCS): U.S. Food and Drug Administration (FDA) Approval for FCS on December 19, 2024 Potential European Medicines Agency (EMA) approval for FCS Phase 3 results and U.S. regulatory submission for olezarsen in severe hypertriglyceridemia, a large patient population with high unmet need Phase 3 topline data for CORE, CORE 2 and ESSENCE Phase 3 trials expected in second half of 2025 Potential approval of donidalorsen, a first-in-class RNA-targeted medicine for hereditary angioedema and Ionis' second anticipated independent launch: U.S. FDA action date of August 21, 2025 U.S. commercial field team scale-up and launch Continue progress with WAINUA™ (eplontersen), Ionis' first U.S. co-commercialized medicine in collaboration with AstraZeneca: Continued positive performance in U.S. launch for polyneuropathy of hereditary transthyretin-mediated amyloidosis (ATTRv-PN) OUS approvals for ATTRv-PN Continuing the fully enrolled, landmark CARDIO-TTRansform trial in ATTR cardiomyopathy, with data expected in the second half of 2026 Advance the next wave of wholly owned medicines for serious neurological diseases, including seven clinical-stage therapies: Phase 3 trial start in first half of 2025 for ION582 for Angelman syndrome Phase 3 data for zilganersen in Alexander disease, a rare leukodystrophy with no approved disease-modifying therapies Phase 2 data for ION464 (SNCA) in multiple system atrophy Continue momentum with key partnered programs, including: Phase 3 data for pelacarsen, a potentially groundbreaking medicine for Lp(a)-driven cardiovascular disease (Novartis) Continue advancing next-generation technologies for RNA-targeted medicines Achieve clinical proof of concept for Mesyl Phosphoramidate (MsPA) backbone and siRNA platforms Advance first Bicycle-siRNA into clinical development Select first clinical candidate engineered to cross the blood brain barrier INDICATION for TRYNGOLZA™ (olezarsen) TRYNGOLZA™ (olezarsen) was approved by the U.S. Food and Drug Administration as an adjunct to diet to reduce triglycerides in adults with familial chylomicronemia syndrome (FCS). IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS TRYNGOLZA is contraindicated in patients with a history of serious hypersensitivity to TRYNGOLZA or any of the excipients in TRYNGOLZA. Hypersensitivity reactions requiring medical treatment have occurred. WARNINGS AND PRECAUTIONS Hypersensitivity Reactions Hypersensitivity reactions (including symptoms of bronchospasm, diffuse erythema, facial swelling, urticaria, chills and myalgias) have been reported in patients treated with TRYNGOLZA. Advise patients on the signs and symptoms of hypersensitivity reactions and instruct patients to promptly seek medical attention and discontinue use of TRYNGOLZA if hypersensitivity reactions occur. ADVERSE REACTIONS The most common adverse reactions (incidence >5% of TRYNGOLZA-treated patients and >3% higher frequency than placebo) were injection site reactions, decreased platelet count and arthralgia. Please see full Prescribing Information for TRYNGOLZA. 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 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 six 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 Statements This press release includes forward-looking statements regarding Ionis' business and the therapeutic and commercial potential of TRYNGOLZA, Ionis' technologies and other products in development. Any statement describing Ionis' goals, expectations, financial or other projections, intentions or beliefs is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain risks and uncertainties, including but not limited to those related to our commercial products and the medicines in our pipeline, and particularly those inherent in the process of discovering, developing and commercializing medicines that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such medicines. Ionis' forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause its results to differ materially from those expressed or implied by such forward-looking statements. Although Ionis' forward-looking statements reflect the good faith judgment of its management, these statements are based only on facts and factors currently known by Ionis. 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 Dec. 31, 2023, and most recent Form 10-Q, which are on file with the SEC. Copies of these and other documents are available at . Ionis Pharmaceuticals® and TRYNGOLZA™ are trademarks of Ionis Pharmaceuticals, Inc. WAINUA™ is a registered trademark of the AstraZeneca plc. Ionis Investor Contact: D. Wade Walke, Ph.D. [email protected] 760-603-2331 Ionis Media Contact: Hayley Soffer [email protected] 760-603-4679 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

STRASBOURG, France--( BUSINESS WIRE )--BrainTale, a medtech deciphering white matter to enable better brain care, spin-off of the Paris Region Greater Hospitals, announced today the enrollment of the first patient in the CALDIFF, investigator-sponsored clinical trial, sponsored by the Paris Region Greater Hospitals (Assistance Publique - Hôpitaux de Paris) and led by Professor Fanny Mochel (APHP220801, NCT05911919). The study has been designed to clinically demonstrate the potential of a BrainTale-developed biomarker to predict in the early phase the progression of X-linked cerebral adrenoleukodystrophy (X-ALD). " There is an urgent need for new methods of early diagnosis in X-ALD to enable faster and more effective therapeutic interventions ," declares Prof. Fanny Mochel, Head of the Neurometabolic Diseases and Leukodystrophies Reference Center at the Pitié-Salpêtrière Hospital (AP-HP) and principal investigator. “ This biomarker has great potential for improving patient follow-up and detecting signs of the disease to enable appropriate care .” CALDIFF is an investigator-sponsored prospective multi-centric study planned in 12 centers using the BrainTale platform for analyzing and exploiting diffusion MRI (magnetic resonance imaging) data. It aims at clinically demonstrating the potential of a BrainTale-developed biomarker to predict in the early phase the progression of X-linked cerebral adrenoleukodystrophy, a white matter orphan disease. The results of this study could transform the patient care by supporting the decision and implementation of an allogeneic bone marrow transplant at an early stage of the disease, the only treatment today to halt or even reverse the demyelinating lesions of the disease, thus reducing the associated morbidity and mortality. “ The launch of this trial is a key step in demonstrating the clinical usefulness of this biomarker, which could optimize the care of X-ALD patients ,” comments Prof. Damien Galanaud, neuroradiologist (AP-HP), co-founder of BrainTale and scientific leader of the study. This clinical validation of a biomarker developed on BrainTale's technology platform paves the way for precision neurology. The biomarkers developed by BrainTale support the research and development of new treatments by optimizing clinical trials, in particular by homogenizing patient populations and demonstrating the efficacy of drug candidates through higher sensitivity monitoring of diseases progression. BrainTale aims at accelerating the development of new therapies for patients suffering from X-ALD as well as other white matter diseases such as leukodystrophies and multiple sclerosis. What is X-linked cerebral adrenoleukodystrophy? X-linked adrenoleukodystrophy (X-ALD) is a rare and serious genetic disorder, mainly affecting males. With an incidence of 1 per 17,000 births, it is the most common leukodystrophy. This metabolic disease affects the brain, spinal cord and peripheral nerves, as well as the adrenal glands and testes. X-ALD can appear at different ages and in different clinical forms. It occurs in all populations and ethnic groups with similar frequencies. The true incidence may be underestimated, not least because of the lack of systematic neonatal screening. About BrainTale BrainTale is an innovative European medtech company measuring the brain through white matter quantification and standardization based on a commercially available software medical device solution. This regulatory-cleared AI software offers quality controlled, non-invasive, reliable and clinically validated reports after diffusion tensor MRI data processing. BrainTale enables drug developers, leading academic researchers, and physicians to improve patient care by understanding neuroinflammatory and neurodegenerative conditions, assess brain lesions evolutions and take appropriate decisions in the clinic and during drug development. BrainTale empowers the scientific and medical community with objective measure to transform brain care. Because brain diseases have become the medical issue of our time, we can no longer wait. At BrainTale, we strongly believe that by exploring better, we can treat faster, together. For more information, please visit www.braintale.eu

- Continued, progressive improvement in motor function and achievement of motor milestones at 12-months post-treatment represents an important and statistically significant change, in contrast to the disease course observed in BridgeBio’s ongoing CANinform natural history comparator study - Significant and sustained reductions in N-acetylaspartate (NAA) levels in urine, cerebrospinal fluid (CSF), and brain in all participants who received low dose; encouraging trends of further reduction in urine NAA in participants who received high dose BBP-812 - If approved, BridgeBio’s gene therapy for Canavan disease could be the first therapeutic option for children born with this fatal neurodevelopmental disorder PALO ALTO, Calif., Oct. 24, 2024 (GLOBE NEWSWIRE) -- BridgeBio Pharma, Inc. (Nasdaq: BBIO) (BridgeBio ), a commercial-stage biopharmaceutical company focused on genetic diseases, presented positive preliminary data from eleven participants dosed in the CANaspire Phase 1/2 clinical trial of BBP-812, an investigational intravenous (IV) adeno-associated virus serotype 9 (AAV9) gene therapy in development for the treatment of Canavan disease. Preliminary results from the study were presented in an invited, peer reviewed talk by the study’s principal investigator, Dr. Florian Eichler, M.D., director of the leukodystrophy service at Massachusetts General Hospital, Center for Rare Neurological Disease and principal investigator of CANaspire, today at the 31st Annual Congress of the European Society of Gene and Cell Therapy (ESGCT) in Rome, Italy. “We continue to be encouraged by the results children are achieving in the CANaspire trial of BBP-812,” said Dr. Eichler. “Compared to the natural course of Canavan disease, in which most children do not achieve developmental milestones beyond that of a 6-month old, the fact that some children are sitting independently, taking steps, or even walking post-dosing is truly remarkable.” CANaspire is a Phase 1/2 open-label study designed to evaluate the safety, tolerability, and pharmacodynamic activity of BBP-812, in pediatric patients with Canavan disease. CANinform is an ongoing natural history study of more than 60 patients with Canavan disease, which was designed as a robust comparator for the CANaspire study in accordance with FDA’s guidance on the design and conduct of externally controlled trials. Highlights of the results presented at ESGCT 2024 include: Rapid and sustained reduction of NAA in urine and brain of participants post BBP-812 dosing Urine NAA was reduced to levels associated with mild Canavan disease (average reduction of 64% +/- 14% twelve months after receiving low dose and 73% +/- 13% three months after the high dose)NAA in CSF was reduced an average of 70% +/- 10% twelve months after receiving the low dose. Lower urine NAA levels have been maintained for nearly 3 years in the earliest dosed participants Improved myelination on T-2-weighted magnetic resonance imaging (MRI) observed in the majority of participants dosed with BBP-812Progressive and continued post-dose improvement in gross motor function (measured by Gross Motor Function Measure (GMFM)-88) and achievement of motor milestones (measured by Hammersmith Infant Neurological Examination (HINE)-2) This trajectory of progressive improvement stands in stark contrast to the characterized natural history of the disease, where the trajectory over this time period is essentially flatIn the low-dose cohort, these divergent trajectories result in statistically significant improvements in achieved motor function and milestones at 12-months after treatment with BBP-812, compared to what is observed in and predicted by the natural history of the disease; data from the high dose cohort are not yet available All participants demonstrated progress on administered developmental/motor assessments as measured by the GMFM-88, HINE-2, CDC milestones, or the Canavan Disease Rating ScaleBBP-812 continues to be generally well-tolerated, with a safety profile consistent with other systemically administered AAV9 gene therapies BBP-812 has been granted Regenerative Medicine Advanced Therapy (RMAT), Orphan Drug, Rare Pediatric Disease (RPDD), and Fast Track Designations from the FDA, as well as Orphan Drug Designation from the European Medicines Agency. With RPDD, if approved, BridgeBio may qualify for a PRV. About CANaspireCANaspire is a Phase 1/2 open-label study designed to evaluate the safety, tolerability, and pharmacodynamic activity of BridgeBio’s AAV9 gene therapy candidate, BBP-812, in pediatric patients with Canavan disease. Each eligible patient will receive a single IV infusion of BBP-812. The primary outcomes of the study are safety, as well as change from baseline of urine and central nervous system NAA levels. Motor function and development will also be assessed. For more information about the CANaspire trial, visit TreatCanavan.com or ClinicalTrials.gov (NCT04998396). About Canavan DiseaseAffecting approximately 1,000 children in the U.S. and European Union, Canavan disease is an ultra-rare, disabling and fatal disease with no approved therapy. Most children are not able to meet developmental milestones, are unable to crawl, walk, sit or talk, and die at a young age. The disease is caused by an inherited mutation of the ASPA gene that codes for aspartoacylase, a protein that breaks down a compound called NAA. Deficiency of aspartoacylase activity results in accumulation of NAA, and ultimately results in toxicity to myelin in ways that are not currently well understood. Myelin insulates neuronal axons, and without it, neurons are unable to send and receive messages as they should. The current standard of care for Canavan disease is limited to supportive therapy. About BridgeBio Pharma, Inc.BridgeBio Pharma, Inc. (BridgeBio) is a commercial-stage biopharmaceutical company founded to discover, create, test and deliver transformative medicines to treat patients who suffer from genetic diseases. BridgeBio’s pipeline of development programs ranges from early science to advanced clinical trials. BridgeBio was founded in 2015 and its team of experienced drug discoverers, developers and innovators are committed to applying advances in genetic medicine to help patients as quickly as possible. For more information visit bridgebio.com and follow us on LinkedIn, Twitter and Facebook. BridgeBio Pharma, Inc. Forward-Looking Statements This press release contains forward-looking statements. Statements BridgeBio makes in this press release may include statements that are not historical facts and are considered forward-looking within the meaning of Section 27A of the Securities Act of 1933, as amended (the “Securities Act”), and Section 21E of the Securities Exchange Act of 1934, as amended (the “Exchange Act”), which are usually identified by the use of words such as “anticipates,” “believes,” “continues,” “estimates,” “expects,” “hopes,” “intends,” “may,” “plans,” “projects,” “remains,” “seeks,” “should,” “will,” and variations of such words or similar expressions. BridgeBio intends these forward-looking statements to be covered by the safe harbor provisions for forward-looking statements contained in Section 27A of the Securities Act and Section 21E of the Exchange Act. These forward-looking statements, including statements relating to expectations, plans and prospects regarding BridgeBio’s regulatory approval process for BBP-812, the ability of BBP-812 to be the first therapeutic treatment option for children born with Canavan disease and eligibility for a PRV, reflect BridgeBio’s current views about its plans, intentions, expectations, strategies and prospects, which are based on the information currently available to BridgeBio and on assumptions BridgeBio has made. Although BridgeBio believes that its plans, intentions, expectations, strategies and prospects as reflected in or suggested by those forward-looking statements are reasonable, BridgeBio can give no assurance that the plans, intentions, expectations or strategies will be attained or achieved. Furthermore, actual results may differ materially from those described in the forward-looking statements and will be affected by a number of risks, uncertainties and assumptions, including, but not limited to, BridgeBio’s ability to continue and complete its Phase 1/2 clinical trial of BBP-812 for the treatment of Canavan disease, BridgeBio’s ability to advance BBP-812 in clinical development according to its plans, the ability of BBP-812 to treat Canavan disease, the ability of BBP-812 to retain Fast Track Designation, RPDD, RMAT and Orphan Drug Designation from the FDA and Orphan Drug Designation from the European Medicines Agency, and potential adverse impacts due to global health emergencies, including delays in regulatory review, manufacturing and supply chain interruptions, adverse effects on healthcare systems and disruption of the global economy, the impacts of current macroeconomic and geopolitical events, including changing conditions from hostilities in Ukraine and in Israel and the Gaza Strip, increasing rates of inflation and rising interest rates, on our business operations and expectations as well as those risks set forth in the Risk Factors section of BridgeBio’s most recent Annual Report on Form 10-K, and BridgeBio’s other filings with the U.S. Securities and Exchange Commission. Moreover, BridgeBio operates in a very competitive and rapidly changing environment in which new risks emerge from time to time. These forward-looking statements are based upon the current expectations and beliefs of BridgeBio’s management as of the date of this press release and are subject to certain risks and uncertainties that could cause actual results to differ materially from those described in the forward-looking statements. Except as required by applicable law, we assume no obligation to update publicly any forward-looking statements, whether as a result of new information, future events or otherwise. BridgeBio Contact:Vikram Balicontact@bridgebio.com(650)-789-8220