Eplontersen

Additional clinical and real-world data from the industry’s largest amyloidosis pipeline will advance understanding of underlying mechanisms of disease and unmet needs WILMINGTON, Del.--(BUSINESS WIRE)-- AstraZeneca and Alexion, AstraZeneca Rare Disease, will showcase 14 studies, including real-world evidence (RWE), from their portfolio and pipeline of investigational amyloidosis therapies at the International Symposium on Amyloidosis (ISA), in Rochester, MN from May 26–30, 2024. Presentations will include a new subgroup analyses of the Phase 3 NEURO-TTRansform study of WAINUATM (eplontersen), which was approved by the US Food and Drug Administration (FDA) in December 2023 for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults, commonly referred to as hATTR-PN or ATTRv-PN.1 Additionally, clinical data will be presented on ALXN2220 and anselamimab, which are being evaluated in Phase III clinical trials for ATTR and light chain (AL) amyloidosis, respectively. Sarah Walters, Vice President, US Cardiovascular, Renal & Metabolic Diseases, AstraZeneca, said: “AstraZeneca is dedicated to advancing the science and improving the lives of patients that are impacted by this devastating disease. Our data at the 2024 International Symposium on Amyloidosis demonstrate the leadership commitment AstraZeneca, Alexion and our partners Ionis and Neuroimmune have to develop best in class treatment options to serve a broad range of amyloidosis patients.” Christophe Hotermans, Senior Vice President, Head of Global Medical Affairs, Alexion, said: “With the largest and fastest-growing pipeline of investigational amyloidosis therapies, we are working to advance multiple modalities with the potential to halt, reduce or reverse organ damage. Key presentations at the ISA Annual Meeting include live-cell imaging and Phase I clinical data evaluating the ability of ALXN2220 to remove amyloid from cardiac tissue, to support its further study as a potential treatment for advanced ATTR cardiomyopathy. Additionally, findings on epidemiology and patient renal outcomes will reinforce the urgency for differentiated amyloidosis diagnosis and additional treatment options in AL amyloidosis.” Robust evidence program increases understanding of amyloidosis patient characteristics and treatment effectiveness. In addition to sub-analyses of the NEURO-TTRansform data, AstraZeneca will present US patient characteristics data, preliminary data from the OverTTuRe study measuring prevalence and characteristics of phenotypes in patients with ATTR amyloidosis in the United States and Japan; as well as the MaesTTRo study design, part of a global, multi-study, real-world evidence program designed to fill the evidence gaps of the effectiveness of treatments for ATTR. WAINUA is currently being evaluated in the Phase 3 CARDIO-TTRansform study for adults with cardiomyopathy of transthyretin-mediated amyloidosis (ATTR-CM), a systemic, progressive and fatal condition that typically leads to progressive heart failure and often death within three-to-five years from disease onset.2-5 The CARDIO-TTRansform Phase 3 study is fully enrolled with more than 1,400 patients–making it the largest study in this patient population to date.6 As part of a global development and commercialization agreement, AstraZeneca and Ionis are commercializing WAINUA for the treatment of hATTR-PN in the US and are seeking regulatory approval in Europe and other parts of the world.6 Novel investigational amyloid depleter assets demonstrate potential to improve outcomes for amyloidosis patients High-resolution live-cell imaging will offer new insight into the underlying cellular mechanism of antibody-mediated amyloid removal with ALXN2220. Results will show the addition of ALXN2220 to ATTR patient-derived cardiac tissue triggered phagocytosis, including recruitment of macrophages to amyloid deposits, detachment, internalization and degradation of ATTR amyloid. An encore poster presentation will report results from the first-in-human study of ALXN2220. Initial treatment with ALXN2220 was well tolerated with a transient increase in C-reactive proteins, suggesting initial targeted immune activation and recruitment of phagocytic immune cells. Additionally, an encore poster presentation will describe the pharmacokinetic and pharmacodynamic (PK/PD) model used for the selection of the dose range, dose escalation, dosing interval and study duration. Further, a poster will outline the baseline demographics and characteristics of the 406 participants of the Alexion CARES clinical program evaluating anselamimab in patients with Mayo Stage IIIa and IIIb AL amyloidosis, which includes the largest prospective AL amyloidosis study to date in advanced stage AL amyloidosis. Advancing understanding of the amyloidosis landscape A retrospective chart analysis from the US EMR TriNetX database will report outcomes in AL amyloidosis patients with renal involvement receiving bortezomib or daratumumab. Only half of patients were renal-responders and few achieved renal complete response (renCR, proteinuria ≤200 mg/day), underscoring the unmet medical need for this patient subset. Retrospective analyses will also be presented across three posters on the incidence and prevalence of AL and ATTR amyloidosis, reinforcing the importance of timely diagnosis of amyloidosis and continued monitoring. A comprehensive list of AstraZeneca key abstracts to be presented at the 2024 International Symposium on Amyloidosis includes7: Lead author Abstract title Presentation details Poster presentation session 1: 10:00-10:30 Poster presentation session 2: 14:45-15:45 Eplontersen Gillmore JD, Davis M, Hahn K, Smith G, Shivappa N, Papas M, Folkvaljon F, Pao C, Sundin AK, L Wittbrodt E, Grogan M Prospective, Real-World Data on the Characteristics, Treatment Patterns, and Outcomes of Patients With Transthyretin Amyloidosis: Design of the MaesTTRo Study Date: Wednesday, May 29 Abstract ID: 204 Waddington Cruz M, Berk J, Parman Y, Gertz M, Khella S, Weiler M, Kwoh J, Chen J, Reicher B, Nåtman J, Dasgupta N Eplontersen for Hereditary Transthyretin Amyloidosis With Polyneuropathy: An Exploratory Analysis of Treatment Effect in Male and Female Patients Date: Wednesday, May 29 Abstract ID: 202 Gillmore JD, Adams D, Weiler M, Masri A, Obici L, Kwoh J, Reicher B, Chen J, Waddington Cruz M, Natman J, Gertz M Eplontersen for Hereditary Transthyretin Amyloidosis With Polyneuropathy: An Exploratory Analysis in Patients With the V30M TTR variant and Early-onset or Late-onset Disease Date: Wednesday, May 29 Abstract ID: 230 Wixner J, Conceição I, Berk J, Adams D, Polydefkis M, Attarian S, Gillmore J, Dyck J, Coelho T, Chen J, Hardy E, Kwoh J, Nåtman J, Waddington Cruz M Neuropathy Impairment and Nutritional Status With Eplontersen in Patients With Hereditary Transthyretin-Mediated Amyloidosis Date: Wednesday, May 29 Abstract ID: 174 Alexander K, Alvarez C, Kumar N, Pao C, Wittbrodt E, Kohsaka S Prevalence and Descriptive Characteristics of Clinical Phenotypes in Patients With ATTR amyloidosis in the United States and Japan: Preliminary Results from the OverTTuRe Study Date: Monday, May 27 Abstract ID: 198 Bazell C, Alston M, Kumar N, Huang J, Venditto J, Grillis D, Eisenberg S, Nativi-Nicolau J Descriptive Characteristics of Patients Diagnosed With Transthyretin Amyloidosis in the Commercial and Medicare Populations Date: Wednesday, May 29 Abstract ID: 518 ALXN 2220 Michalon A, Huy, Mercuri M, Kahr P, Hock C, Grimm J ALXN2220: High-resolution Live-cell Imaging of Antibody-mediated Cardiac ATTR Amyloid Depletion Date: Tuesday, May 28 Abstract ID: 226 Michalon A, Renaud L, Machacek M, Cortijo C, Udaata C, Mercuri M, Buller F, Hock C, Nitsch R, Kahr P, Grimm J Prediction of Cardiac ATTR Depletion by NI006 Using Mechanistic PK/PD Modeling Date: Wednesday, May 29 Abstract ID: 291 Aus dem Siepen F, Van der Meer P, Damy T, Garcia-Pavia P, Donal E, Lairez O, Blank A, Kristen A, Quarta CC, Buchele G, Mercuri M, Hock C, Michalon A, Kahr P, Rey S, Tichy M ALXN2220: Targeted Immune Activation in Patients Undergoing Antibody-mediated Cardiac ATTR Amyloid Depletion Date: Wednesday, May 29 Abstract ID: 227 Amyloidosis Incidence and Analyses Laires PA, Evans J, Thompson J, Manwani R, Mudumby P, Field M, Fang S Prevalence, Incidence, and Characterization of Light Chain Amyloidosis in the USA: A Real-World Analysis Utilizing Electronic Health Records (EHR) Date: Monday, May 27 Abstract ID: 65 Manwani R, Yang F, Zhang Y, Laires PA Outcomes in Patients With AL Amyloidosis With Renal Involvement: Findings from the TriNetX Database Date: Monday, May 27 Abstract ID: 113 Laires PA, Li SXL, Uday A, Kumar P, Silva AM, Quarta C Prevalence and Incidence of ATTR Amyloidosis in the United States: Insights from Claims Database and Electronic Health Records Date: Tuesday, May 28 Abstract ID: 68 Laires PA, Zhang Y, Manwani R, Silva AM, Catini J, Thompson J, Dozier M, Yang F Subtype Distribution of Amyloidosis in the United States: Insights from an Electronic Health Records Database Analysis Date: Tuesday, May 28 Abstract ID: 112 The full list of ISA 2024 congress abstracts are available online. INDICATION for WAINUATM (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 WAINUATM (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 US Full Prescribing Information for WAINUA. Notes NEURO-TTRansform NEURO-TTRansform is a global, open-label, randomized trial evaluating the efficacy and safety of eplontersen in patients with hATTR-PN.8,9 The trial enrolled adult patients with hATTR-PN Stage 1 or Stage 2 compared to the external placebo group from the NEURO-TTR registrational trial that Ionis completed in 2017.8,9 The comparison of efficacy and safety for WAINUA versus external placebo was based on data up to week 66, and all patients were followed on treatment until week 85, when they had the option to transition into an open-label extension study, which is still ongoing.8,9 WAINUA WAINUATM (eplontersen) is a ligand-conjugated antisense oligonucleotide (LICA) medicine designed to reduce the production of transthyretin, or TTR protein.9,10 WAINUA has been approved in the US for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults (also referred to as hATTR-PN).1 AstraZeneca in amyloidosis Amyloidosis is a group of complex rare diseases caused by abnormal proteins that misfold and clump together to form toxic amyloids that deposit in tissues or organs, including the heart, kidneys and peripheral nerves.11-12 The build-up of these toxic amyloids can result in significant organ damage and organ failure that can severely impact quality of life and ultimately be fatal.11-12 AstraZeneca and its Rare Disease Unit, Alexion, are developing and evaluating multiple modalities with the potential to halt and reduce organ damage across various types of amyloidosis. The Company is uniquely positioned to lead therapeutic and diagnostic advances for people living with amyloidosis with the largest and fastest-growing pipeline of investigational amyloidosis therapies to address the spectrum of patient needs. Alexion Alexion, AstraZeneca Rare Disease, is focused on serving patients and families affected by rare diseases and devastating conditions through the discovery, development and delivery of life-changing medicines. A pioneering leader in rare disease for more than three decades, Alexion was the first to translate the complex biology of the complement system into transformative medicines, and today it continues to build a diversified pipeline across disease areas with significant unmet need, using an array of innovative modalities. As part of AstraZeneca, Alexion is continually expanding its global geographic footprint to serve more rare disease patients around the world. It is headquartered in Boston, MA, US. About AstraZeneca AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines in Oncology, Rare Diseases and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries, and its innovative medicines are used by millions of patients worldwide. For more information, please visit and follow us on social media @AstraZeneca. References WAINUATM (eplontersen) [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2023. Viney N, et al. Ligand conjugated antisense oligonucleotide for the treatment of transthyretin amyloidosis: preclinical and phase 1 data. ESC Heart Failure. 2021;8:652-661. Rintell D, et al. Patient and family experience with transthyretin amyloid cardiomyopathy (ATTR-CM) and polyneuropathy (ATTR-PN) amyloidosis: results of two focus groups. Orphanet J Rare Dis. 2021;16:70. Columbia University Irving Medical Center [Internet]. Drug Reduces Death from Underdiagnosed Form of Heart Failure [last accessed 11 December 2023]. Available from: . ClinicalTrials.gov. CARDIO-TTRansform: A Study to Evaluate the Efficacy and Safety of Eplontersen (Formerly Known as ION-682884, IONIS-TTR-LRx and AKCEA-TTR-LRx) in Participants With Transthyretin-Mediated Amyloid Cardiomyopathy (ATTR CM) [last accessed 21 May 2024] Available from: . Ionis Pharmaceuticals [Internet]. WAINUA™ (eplontersen) granted regulatory approval in the U.S. for the treatment of adults with polyneuropathy of hereditary transthyretin-mediated amyloidosis [last accessed 16 May 2024]. Available from: . Mayo Clinic. International Symposium on Amyloidosis: Abstracts/Posters [last accessed 21 May 2024] Available from: . Coelho T, et al. Design and Rationale of the Global Phase 3 NEURO-TTRansform Study of Antisense Oligonucleotide AKCEA-TTR-LRx(ION-682884-CS3) in Hereditary Transthyretin-Mediated Amyloid Polyneuropathy. Nerol Ther. 2021 Jun;10(1):375-389. Coelho T, et al. Eplontersen for Hereditary Transthyretin Amyloidosis With Polyneuropathy. JAMA. 2023;330(15):1448–1458. Coelho T, et al. Characteristics of Patients with Hereditary Transthyretin Amyloidosis-Polyneuropathy (ATTRv-PN) in NEURO-TTRansform, an Open-label Phase 3 Study of Eplontersen. Neurol Ther. 2023;12:267–287. Cleveland Clinic. Amyloidosis. Cleveland Clinic website. Accessed May 21, 2024. . Mayo Clinic. Amyloidosis. Mayo Clinic website. Accessed May 21, 2024. . US-89473 Last Updated 5/24

Development of BIIB105, an investigational antisense oligonucleotide for amyotrophic lateral sclerosis (ALS), will be discontinued based on data from the Phase 1/2 ALSpire study Biogen and Ionis continue their long-standing commitment to developing therapies for ALS given the devastating impact of this progressive, fatal neurodegenerative condition CARLSBAD, Calif. and CAMBRIDGE, Mass., May 16, 2024 /PRNewswire/ -- Ionis Pharmaceuticals, Inc. (Nasdaq: IONS) and Biogen Inc. (Nasdaq: BIIB) announced the decision to terminate development of BIIB105 (ION541) an investigational antisense oligonucleotide (ASO) for amyotrophic lateral sclerosis (ALS) based on topline results from the Phase 1/2 ALSpire study. BIIB105 was designed to reduce expression of ataxin-2 (ATXN2) protein and demonstrated statistically significant cerebrospinal fluid (CSF) ATXN2 protein reductions in the study. However, over the 6-month placebo-controlled period, treatment with BIIB105 did not result in a reduction in levels of plasma neurofilament light chain (NfL), a marker of neurodegeneration and neuronal damage. Additionally, BIIB105 did not demonstrate an impact on clinical outcome measures of function, breathing and strength. Continue Reading Biogen logo (PRNewsfoto/Biogen Inc.,Ionis Pharmaceuticals, Inc.) "While BIIB105 lowered ATXN2 protein, it did not reduce neurofilament, which gives us confidence that BIIB105 did not slow the disease process," said Stephanie Fradette, Pharm.D., Head of the Neuromuscular Development Unit at Biogen. "We are deeply grateful for the contributions of the study participants and remain committed to developing treatments that can meaningfully change the disease trajectory for people living with ALS." "We are very appreciative of the people with ALS and investigators who participated in this study and were critical to advancing our scientific understanding of ALS," said Frank Bennett, Ph.D., executive vice president and chief scientific officer of Ionis. "Ionis continues to be committed to the ALS community and is advancing our Phase 3 ulefnersen program for people with the genetic form of the disease known as FUS-ALS." Longer-term biomarker and efficacy data from the open-label-extension were similar to those seen during the 6-month placebo-controlled treatment period, with sustained reductions in ATXN2 but no impact on NfL or clinical outcome measures over 40+ weeks of follow up. No evidence of benefit was observed in any subgroup evaluated, including those participants with a Poly-CAG expansion in the ATXN2 gene. The Phase 1/2 study was a randomized, placebo-controlled, dose-escalating trial to evaluate BIIB105 administered intrathecally to adults (n=99) with ALS. Participants were randomized to receive BIIB105 or placebo (3:1 or 2:1 ratio) for 3 to 6 months. Participants who completed the placebo-controlled period were eligible to enroll in the open-label extension. During the 6-month placebo-controlled portion of the study, the most common adverse events (AEs) in BIIB105 treated participants were procedural pain, headache and fall. AEs leading to study discontinuation were higher in the BIIB105 group (8.3%) compared with the placebo group (3.6%). Analyses of data from the study are ongoing to further understanding of the underlying disease process and effects of BIIB105. The companies will present the BIIB105 Phase 1/2 data at the upcoming European Network to Cure ALS (ENCALS) meeting in Stockholm, Sweden in June. About Ionis' Neurology Franchise Ionis' neurology franchise addresses all major brain regions and central nervous system cell types and currently has three Phase 3 studies ongoing with 11 therapies in clinical development, several of which Ionis plans to commercialize directly. Ionis is discovering and developing potential treatments for many neurological diseases for which there are few or no disease modifying treatments, including common diseases like Alzheimer's and Parkinson's as well as rare diseases such as amyotrophic lateral sclerosis (ALS) and Alexander disease. Ionis has discovered and developed three commercially available neurological disease medicines, including SPINRAZA® (nusinersen), the first approved treatment for spinal muscular atrophy, WAINUATM (eplontersen), a medicine to treat hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN), and QALSODY® (tofersen) for SOD1-ALS. 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. Biogen's Continuous Commitment to ALS For over a decade, Biogen has been committed to advancing ALS research to provide a deeper understanding of all forms of the disease. The company has continued to invest in and pioneer research despite making the difficult decision to discontinue a late-stage ALS asset in 2013. Biogen has applied important learnings to its portfolio of assets for genetic and other forms of ALS, with the goal of increasing the probability of bringing a potential therapy to patients in need. These applied learnings include evaluating genetically validated targets in defined patient populations, pursuing the most appropriate modality for each target and employing sensitive clinical endpoints. In addition to QALSODY, the first treatment to target a genetic cause of ALS, which was discovered by Ionis, the company has a robust discovery pipeline including efforts to address TDP43 pathology for the broad ALS population. TDP43 pathology is seen in 97% of ALS cases and is considered a hallmark of the disease. About Biogen Founded in 1978, Biogen is a leading biotechnology company that pioneers innovative science to deliver new medicines to transform patients' lives and to create value for shareholders and our communities. We apply deep understanding of human biology and leverage different modalities to advance first-in-class treatments or therapies that deliver superior outcomes. Our approach is to take bold risks, balanced with return on investment to deliver long-term growth. We routinely post information that may be important to investors on our website at . Follow us on social media - Facebook, LinkedIn, X, YouTube. Ionis Forward-looking Statements 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. QALSODY® is a registered trademark of Biogen. WAINUATM is a registered trademark of the AstraZeneca group of companies. Biogen Safe Harbor This news release contains forward-looking statements, about the treatment of ALS; the anticipated benefits and potential of Biogen's collaboration arrangements with Ionis; the potential of Biogen's commercial business and pipeline programs; and risks and uncertainties associated with drug development and commercialization. These statements may be identified by words such as "aim," "anticipate," "believe," "could," "estimate," "expect," "forecast," "intend," "may," "plan," "possible," "potential," "will," "would" and other words and terms of similar meaning. Drug development and commercialization involve a high degree of risk, and only a small number of research and development programs result in commercialization of a product. Results in early-stage clinical studies may not be indicative of full results or results from later stage or larger scale clinical studies and do not ensure regulatory approval. You should not place undue reliance on these statements. These statements involve risks and uncertainties that could cause actual results to differ materially from those reflected in such statements, including without limitation unexpected concerns that may arise from additional data, analysis or results obtained during clinical studies; the occurrence of adverse safety events; risks of unexpected costs or delays; the risk of other unexpected hurdles; regulatory submissions may take longer or be more difficult to complete than expected; regulatory authorities may require additional information or further studies, or may fail or refuse to approve or may delay approval of Biogen's drug candidates, including lecanemab; actual timing and content of submissions to and decisions made by the regulatory authorities regarding lecanemab; uncertainty of success in the development and potential commercialization of lecanemab; failure to protect and enforce Biogen's data, intellectual property and other proprietary rights and uncertainties relating to intellectual property claims and challenges; product liability claims; and third party collaboration risks, results of operations and financial condition. The foregoing sets forth many, but not all, of the factors that could cause actual results to differ from Biogen's expectations in any forward-looking statement. Investors should consider this cautionary statement as well as the risk factors identified in Biogen's most recent annual or quarterly report and in other reports Biogen has filed with the U.S. Securities and Exchange Commission. These statements speak only as of the date of this news release. Biogen does not undertake any obligation to publicly update any forward-looking statements. SOURCE Ionis Pharmaceuticals, Inc.