Memory Disorders

-New testing method highlights link between protofibrils and biomarkers for neurodegeneration- -Patient and caregiver perspectives on five-year treatment with lecanemab - - Utilization of blood biomarkers to predict brain amyloid accumulation in AHEAD study of preclinical AD- TOKYO and CAMBRIDGE, Mass., Oct. 30, 2024 /PRNewswire/ -- Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, "Eisai") and Biogen Inc. (Nasdaq: BIIB, Corporate headquarters: Cambridge, Massachusetts, CEO: Christopher A. Viehbacher, "Biogen") announced today that the latest findings for lecanemab-irmb (U.S. brand name: LEQEMBI®), an anti-amyloid beta (Aβ) protofibril* antibody for the treatment of early Alzheimer's disease (AD), were presented at the Clinical Trials for Alzheimer's Disease Conference (CTAD), held in Madrid, Spain, and virtually. Benefits of Continued Treatment with Lecanemab for People with Early AD In July 2024 at the Alzheimer's Association International Conference (AAIC) 2024, results from the open-label long-term extension study (OLE) following the core study of the lecanemab Phase 3 Clarity AD study were presented, showing that the mean change from baseline in CDR-SB (global cognitive and functional scale) in the lecanemab treated group relative to the placebo group was -0.45 at 18 months, and at 36 months, this expanded to -0.95 compared to a prespecified natural history** cohort of AD. There was a 30% reduction in the relative risk of progressing to the next disease stage In addition, the tau PET substudy of the lecanemab Phase 3 Clarity AD clinical study showed that with three (3) years of continuous treatment with lecanemab, 59% of patients with no or low tau accumulation in the brain (no tau/low tau) at baseline showed improvement or no decline, and 51% showed improvement from baseline on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) global cognitive and functional scale.1 Clarity AD data presented at CTAD expand on these initial results to include additional measurements resulting from three (3) years of continuous lecanemab treatment in patients with low levels of amyloid accumulation in the brain at baseline (less than 60 Centiloids: low amyloid). These data show that 46% of patients improved or had no decline, and 33% showed improvement from baseline on the CDR-SB. On the ADAS-Cog14 measurement scale, 46% of patients showed improvement or no decline and 43% showed improvement. On the ADCS MCI-ADL, 51% of patients showed improvement or no decline and 48% showed improvement. These results – from no tau/low tau population and low amyloid populations – suggest that earlier initiation of lecanemab treatment may have a positive impact on disease progression of early AD patients and may provide continued benefits to patients with early AD over the long term.2 No new safety findings were observed with continued lecanemab treatment over three (3) years. Most amyloid-related imaging abnormalities (ARIA) occurred in the first six (6) months of treatment. After the first six (6) months, ARIA rates were low and similar to ARIA rates on placebo during the placebo-controlled period. With regards to the incidence of ARIA by ApoEε4 status during the continuous treatment, the incidence was higher in ApoE4 homozygotes than in heterozygotes or non-carriers, but rates of new ARIA were decreased after the completion of the 18 months core study as treatment continued, regardless of ApoEε4 status.2 Correlation between Protofibrils and Biomarkers for Neurodegenerative Disease i n the AD Brain Dual-acting lecanemab is the only early AD treatment available to support neuronal function by clearing the highly toxic protofibrils that continue to cause neuronal injury and death even after plaques have been cleared from the brain. Protofibrils accumulate early in the AD brain and lead to nerve cell function loss, abnormal nerve processes, inflammation, and memory loss. In non-clinical studies, antibodies against protofibrils prevented protofibril-mediated neuronal dysfunction and memory loss. Accurately quantifying the amount of protofibrils in human cerebrospinal fluid (CSF) has been challenging due to their low concentration. As such, a new measurement method was developed by researchers at Eisai to accurately quantify protofibrils in CSF. Utilizing this new method of measurement, the amount of protofibrils in AD CSF correlated more strongly with neurodegenerative disease biomarkers (CSF total tau and neurogranin) than with CSF Aβ42, a biomarker associated with Aβ plaques accumulation, indicating that protofibrils are closely related to synaptic dysfunction. Furthermore, it was observed that protofibrils, unlike plaques, are diffusible. These results suggest that protofibrils induce synaptic dysfunction, playing an important role in neurodegeneration in AD brains.3 Lecanemab Treatment for Early AD: Insights from Long-Term U.S. Clinical Studies Dr. Marwan Noel Sabbagh, Moreno Family Chair for Alzheimer's Research and Vice Chairman for Research and Professor, Department of Neurology, Barrow Neurological Institute, presented outcomes of an analysis of the use of lecanemab treatment between January 6, 2023, and July 30, 2024, based on payment claims data from the Komodo Research Database, a medical database in the U.S. In the U.S., lecanemab is used in accordance with the US FDA-approved indication, dosing, and monitoring guidelines. The analysis found that access to lecanemab treatment is expanding and highlighted opportunities to improve access in rural areas and educational outreach for underserved populations.4 Dr. David Watson of the Alzheimer's Research and Treatment Center reported on patients who continued to receive lecanemab treatment following the Phase II Study 201 and Phase III Clarity AD study. A total of 136 patients participated in both studies at this center, and 66 patients chose to continue lecanemab therapy, with 13 patients receiving treatment for more than five (5) years and 40 patients receiving treatment for more than three (3) years. More than half of the patients (15/24) who continued treatment with lecanemab for more than three (3) years after the core phase remained in their initial stage of disease. Further, in a survey of 11 patients (or their caregivers) who received lecanemab treatment for more than five (5) years, all patients responded that they were "very satisfied" or "satisfied" with lecanemab treatment. In addition, between 45% and 73% of patients responded that lecanemab treatment made them feel more positive about their daily life, social activities, memory, etc. "frequently" or "very often."5 No new long-term safety findings were observed in these multi-year studies.5 Progress in the AHEAD 3-45 Study: Improving Screening Eligibility Using Blood Biomarkers and Completing Patient Enrollment AHEAD 3-45 is a Phase 3 clinical study for individuals with preclinical AD, meaning they are clinically unimpaired but have intermediate or elevated levels of amyloid in their brains. In the study, blood tests, cognitive function tests (PACC-5***), amyloid PET, MRI, and tau PET were used for screening. Based on the amount of Aβ accumulation in the brain as determined by amyloid PET, subjects were assigned to two (2) trials with different dose settings: the A3 trial, for those with borderline Aβ levels in the brain, and the A45 trial, for those with positive Aβ levels in the brain.6 Screening with blood biomarker tests was important to improve eligibility for amyloid PET testing in subjects without cognitive impairment. Using plasma Aβ42/40 ratio and p-tau217/tau217 ratio in the initial screening reduced screening failure on amyloid PET from more than 70% to less than 30%. In particular, plasma p-tau217 was shown to correlate with amyloid PET, supporting its role as a useful blood biomarker to identify elevated amyloid in the brain.6 Enrollment for the AHEAD 3-45 study was completed in October 2024. Lifetime Achievement Award Presented to Professor Lannfelt Professor Emeritus Lars Lannfelt of Uppsala University received the CTAD Lifetime Achievement Award in recognition of his pioneering work in scientific discovery and drug development in AD. As part of this award ceremony, he delivered a keynote speech outlining the discovery of the arctic mutation in familial AD, its application to therapeutic strategies targeting protofibrils for AD treatment, and the development of lecanemab. Eisai serves as the lead for lecanemab's development and regulatory submissions globally with both Eisai and Biogen co-commercializing and co-promoting the product and Eisai having final decision-making authority. *Protofibrils are believed to contribute to the brain injury that occurs with AD and are considered to be the most toxic form of Aβ, having a primary role in the cognitive decline of this progressive, debilitating condition.7 Protofibrils cause injury to neurons in the brain which, in turn, can negatively impact cognitive function through multiple mechanisms, not only increasing the development of insoluble Aβ plaques but also increasing direct damage to brain cell membranes and the connections that transmit signals between nerve cells or nerve cells and other cells. It is believed the reduction of protofibrils may prevent the progression of AD by reducing damage to neurons in the brain and cognitive dysfunction.8 **ADNI is a clinical research project launched in 2005 to develop methods to predict the onset of AD and to confirm the effectiveness of treatments. The ADNI observational cohort was pre-specified and used during the design of Clarity AD. The cohort represents the exact population of those in Clarity AD study; matched ADNI participants show similar degree of decline to placebo group out to 18 months. ***PACC-5 is a composite measure that provides a highly sensitive measure of changes in cognitive function in individuals with preclinical AD. Please see full Prescribing Information for LEQEMBI, including Boxed WARNING. U.S. INDICATION LEQEMBI® [(lecanemab-irmb) 100 mg/mL injection for intravenous use] is indicated for the treatment of Alzheimer's disease (AD). Treatment with LEQEMBI should be initiated in patients with mild cognitive impairment (MCI) or mild dementia stage of disease, the population in which treatment was initiated in clinical trials. IMPORTANT SAFETY INFORMATION CONTRAINDICATION LEQEMBI is contraindicated in patients with serious hypersensitivity to lecanemab-irmb or to any of the excipients of LEQEMBI. Reactions have included angioedema and anaphylaxis. WARNINGS AND PRECAUTIONS AMYLOID-RELATED IMAGING ABNORMALITIES LEQEMBI can cause ARIA-E and ARIA-H, which can occur together. ARIA-E can be observed on magnetic resonance imaging (MRI) as brain edema or sulcal effusions and ARIA-H as microhemorrhage and superficial siderosis. ARIA can occur spontaneously in patients with AD. With this class of medications, ARIA-H generally occurs in association with ARIA-E. Reported ARIA symptoms may include headache, confusion, visual changes, dizziness, nausea, and gait difficulty. Focal neurologic deficits may also occur. Symptoms usually resolve over time. Incidence of ARIA Symptomatic ARIA occurred in 3% (29/898) and serious ARIA symptoms in 0.7% (6/898) with LEQEMBI. Clinical ARIA symptoms resolved in 79% (23/29) of patients during the period of observation. ARIA, including asymptomatic radiographic events, was observed: LEQEMBI, 21% (191/898); placebo, 9% (84/897). ARIA-E was observed: LEQEMBI, 13% (113/898); placebo, 2% (15/897). ARIA-H was observed: LEQEMBI, 17% (152/898); placebo, 9% (80/897). No increase in isolated ARIA-H was observed for LEQEMBI vs placebo. ApoE ε4 Carrier Status and Risk of ARIA Of the patients taking LEQEMBI, 16% (141/898) were ApoE ε4 homozygotes, 53% (479/898) were heterozygotes, and 31% (278/898) were noncarriers. With LEQEMBI, the incidence of ARIA was higher in ApoE ε4 homozygotes (LEQEMBI: 45%; placebo: 22%) than in heterozygotes (LEQEMBI: 19%; placebo: 9%) and noncarriers (LEQEMBI: 13%; placebo: 4%). Symptomatic ARIA-E occurred in 9% of ApoE ε4 homozygotes vs 2% of heterozygotes and 1% of noncarriers. Serious ARIA events occurred in 3% of ApoE ε4 homozygotes and in ~1% of heterozygotes and noncarriers. The recommendations on management of ARIA do not differ between ApoE ε4 carriers and noncarriers. Radiographic Findings The majority of ARIA-E radiographic events occurred within the first 7 doses, although ARIA can occur at any time, and patients can have >1 episode. Maximum radiographic severity of ARIA-E with LEQEMBI was mild in 4% (37/898), moderate in 7% (66/898), and severe in 1% (9/898) of patients. Resolution of ARIA-E on MRI occurred in 52% of patients by 12 weeks, 81% by 17 weeks, and 100% overall after detection. Maximum radiographic severity of ARIA-H microhemorrhage with LEQEMBI was mild in 9% (79/898), moderate in 2% (19/898), and severe in 3% (28/898) of patients; superficial siderosis was mild in 4% (38/898), moderate in 1% (8/898), and severe in 0.4% (4/898) of patients. With LEQEMBI, the rate of severe radiographic ARIA-E was highest in ApoE ε4 homozygotes (5%; 7/141) vs heterozygotes (0.4%; 2/479) or noncarriers (0%; 0/278). With LEQEMBI, the rate of severe radiographic ARIA-H was highest in ApoE ε4 homozygotes (13.5%; 19/141) vs heterozygotes (2.1%; 10/479) or noncarriers (1.1%; 3/278). Intracerebral Hemorrhage Intracerebral hemorrhage >1 cm in diameter was reported in 0.7% (6/898) with LEQEMBI vs 0.1% (1/897) with placebo. Fatal events of intracerebral hemorrhage in patients taking LEQEMBI have been reported. Concomitant Antithrombotic Medication: In Clarity AD, baseline use of antithrombotic medication (aspirin, other antiplatelets, or anticoagulants) was allowed if the patient was on a stable dose. The majority of exposures to antithrombotic medications were to aspirin. Antithrombotic medications did not increase the risk of ARIA with LEQEMBI. The incidence of intracerebral hemorrhage was 0.9% (3/328) in patients taking LEQEMBI with a concomitant antithrombotic medication at the time of the event vs 0.6% (3/545) in those who did not receive an antithrombotic. Patients taking LEQEMBI with an anticoagulant alone or combined with an antiplatelet medication or aspirin had an incidence of intracerebral hemorrhage of 2.5% (2/79) vs none in patients receiving placebo. Caution should be exercised when considering the administration of anticoagulants or a thrombolytic agent (e.g., tissue plasminogen activator) to a patient already being treated with LEQEMBI. Other Risk Factors for Intracerebral Hemorrhage: Patients were excluded from enrollment in Clarity AD for findings on neuroimaging that indicated an increased risk for intracerebral hemorrhage. These included findings suggestive of cerebral amyloid angiopathy (prior cerebral hemorrhage >1 cm in greatest diameter, >4 microhemorrhages, superficial siderosis, vasogenic edema) or other lesions (aneurysm, vascular malformation). The presence of an ApoE ε4 allele is also associated with cerebral amyloid angiopathy. Caution should be exercised when considering the use of LEQEMBI in patients with factors that indicate an increased risk for intracerebral hemorrhage and in patients who need to be on anticoagulant therapy. ARIA Monitoring and Dose Management Guidelines Obtain a recent baseline brain MRI prior to initiating treatment with LEQEMBI and prior to the 5th, 7th, and 14th infusions. Enhanced clinical vigilance for ARIA is recommended during the first 14 weeks of treatment with LEQEMBI. Depending on ARIA-E and ARIA-H clinical symptoms and radiographic severity, use clinical judgment when considering whether to continue dosing or to temporarily or permanently discontinue LEQEMBI. If a patient experiences ARIA symptoms, clinical evaluation should be performed, including MRI if indicated. If ARIA is observed on MRI, careful clinical evaluation should be performed prior to continuing treatment. HYPERSENSITIVITY REACTIONS Hypersensitivity reactions, including angioedema, bronchospasm, and anaphylaxis, have occurred with LEQEMBI. Promptly discontinue the infusion upon the first observation of any signs or symptoms consistent with a hypersensitivity reaction and initiate appropriate therapy. INFUSION-RELATED REACTIONS (IRRs) IRRs were observed—LEQEMBI: 26% (237/898); placebo: 7% (66/897)—and the majority of cases with LEQEMBI (75%, 178/237) occurred with the first infusion. IRRs were mostly mild (69%) or moderate (28%) in severity. IRRs resulted in discontinuation of LEQEMBI in 1% (12/898). Symptoms of IRRs included fever and flu-like symptoms (chills, generalized aches, feeling shaky, and joint pain), nausea, vomiting, hypotension, hypertension, and oxygen desaturation. In the event of an IRR, the infusion rate may be reduced or the infusion may be discontinued and appropriate therapy initiated as clinically indicated. Consider prophylactic treatment prior to future infusions with antihistamines, acetaminophen, nonsteroidal anti-inflammatory drugs, or corticosteroids. ADVERSE REACTIONS The most common adverse reaction leading to discontinuation of LEQEMBI was ARIA-H microhemorrhages that led to discontinuation in 2% (15/898) with LEQEMBI vs <1% (1/897) with placebo. The most common adverse reactions reported in ≥5% with LEQEMBI (N=898) and ≥2% higher than placebo (N=897) were IRRs (LEQEMBI: 26%; placebo: 7%), ARIA-H (LEQEMBI: 14%; placebo: 8%), ARIA-E (LEQEMBI: 13%; placebo: 2%), headache (LEQEMBI: 11%; placebo: 8%), superficial siderosis of central nervous system (LEQEMBI: 6%; placebo: 3%), rash (LEQEMBI: 6%; placebo: 4%), and nausea/vomiting (LEQEMBI: 6%; placebo: 4%). [Notes to editors] 1. About lecanemab (LEQEMBI®) Lecanemab is the result of a strategic research alliance between Eisai and BioArctic. It is a humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against aggregated soluble (protofibril) and insoluble forms of amyloid-beta (Aβ). Lecanemab is approved in the U.S.,9 Japan,10 China,11 South Korea,12 Hong Kong,13 Israel,14 the United Arab Emirates15 and Great Britain.16 Eisai has also submitted applications for approval of lecanemab in 10 countries and regions, including the European Union (EU). LEQEMBI's approvals in these countries were based on Phase 3 data from Eisai's, global Clarity AD clinical trial, in which it met its primary endpoint and all key secondary endpoints with statistically significant results. The primary endpoint was the global cognitive and functional scale, Clinical Dementia Rating Sum of Boxes (CDR-SB). In the Clarity AD clinical trial, treatment with lecanemab reduced clinical decline on CDR-SB by 27% at 18 months compared to placebo.17,18 The mean CDR-SB score at baseline was approximately 3.2 in both groups. The adjusted least-squares mean change from baseline at 18 months was 1.21 with lecanemab and 1.66 with placebo (difference, −0.45; 95% confidence interval [CI], −0.67 to −0.23; P<0.001). In addition, the secondary endpoint from the AD Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL), which measures information provided by people caring for patients with AD, noted a statistically significant benefit of 37% compared to placebo. The adjusted mean change from baseline at 18 months in the ADCS-MCI-ADL score was −3.5 in the lecanemab group and −5.5 in the placebo group (difference, 2.0; 95% CI, 1.2 to 2.8; P<0.001). The ADCS MCI-ADL assesses the ability of patients to function independently, including being able to dress, feed themselves and participate in community activities. The most common adverse events (>10%) in the lecanemab group were infusion reactions, ARIA-H (combined cerebral microhemorrhages, cerebral macrohemorrhages, and superficial siderosis), ARIA-E (edema/effusion), headache, and fall. In July 2024 Eisai presented 36-month data from the Phase 3 Clarity AD Open-Label Extension Study demonstrating that LEQEMBI-treated patients continued to show benefit at 36 months of treatment. In the 18-month core study of Clarity AD, there was a statistically significant difference in global cognition and function as measured by CDR-SB between the LEQEMBI and placebo groups. The separation in CDR-SB between the group that continued to receive LEQEMBI (early start group) and the group who switched from placebo to LEQEMBI (delayed start group) was maintained during the 6-month OLE following the core study. This indicates that similar disease trajectory for both early and delayed start groups occurred with LEQEMBI administration. The blood biomarker results (plasma Aβ42/40 ratio, ptau181, GFAP and NfL) showed improvement even after delayed initiation of treatment with LEQEMBI. Since July 2020 the Phase 3 clinical study (AHEAD 3-45) for individuals with preclinical AD, meaning they are clinically normal and have intermediate or elevated levels of amyloid in their brains, is ongoing. AHEAD 3-45 is conducted as a public-private partnership between the Alzheimer's Clinical Trial Consortium that provides the infrastructure for academic clinical trials in AD and related dementias in the U.S, funded by the National Institute on Aging, part of the National Institutes of Health, Eisai, and Biogen. Since January 2022, the Tau NexGen clinical study for Dominantly Inherited AD (DIAD), that is conducted by Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU), led by Washington University School of Medicine in St. Louis, is ongoing and includes lecanemab as the backbone anti-amyloid therapy. 2 . About the Collaboration between Eisai and Biogen for AD Eisai and Biogen have been collaborating on the joint development and commercialization of AD treatments since 2014. Eisai serves as the lead of lecanemab development and regulatory submissions globally with both companies co-commercializing and co-promoting the product and Eisai having final decision-making authority. 3 . About the Collaboration between Eisai and BioArctic for AD Since 2005, Eisai and BioArctic have had a long-term collaboration regarding the development and commercialization of AD treatments. Eisai obtained the global rights to study, develop, manufacture and market lecanemab for the treatment of AD pursuant to an agreement with BioArctic in December 2007. The development and commercialization agreement on the antibody back-up was signed in May 2015. 4 . About Eisai Co., Ltd. Eisai's Corporate Concept is "to give first thought to patients and people in the daily living domain, and to increase the benefits that health care provides." Under this Concept (also known as human health care (hhc) Concept), we aim to effectively achieve social good in the form of relieving anxiety over health and reducing health disparities. With a global network of R&D facilities, manufacturing sites and marketing subsidiaries, we strive to create and deliver innovative products to target diseases with high unmet medical needs, with a particular focus in our strategic areas of Neurology and Oncology. In addition, we demonstrate our commitment to the elimination of neglected tropical diseases (NTDs), which is a target (3.3) of the United Nations Sustainable Development Goals (SDGs), by working on various activities together with global partners. For more information about Eisai, please visit (for global headquarters: Eisai Co., Ltd.), and connect with us on X, LinkedIn and Facebook. The website and social media channels are intended for audiences outside of the UK and Europe. For audiences based in the UK and Europe, please visit and Eisai EMEA LinkedIn. 5 . 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. The company routinely posts information that may be important to investors on its website at . Follow Biogen on social media – Facebook, LinkedIn, X, YouTube. Biogen Safe Harbor This news release contains forward-looking statements, including about the potential clinical effects of lecanemab; the potential benefits, safety and efficacy of lecanemab; potential regulatory discussions, submissions and approvals and the timing thereof; the treatment of Alzheimer's disease; the anticipated benefits and potential of Biogen's collaboration arrangements with Eisai; the potential of Biogen's commercial business and pipeline programs; including lecanemab; 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 the medicine; 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. References Sperling, R., Selkoe, D., Reyderman, L., Youfang, C., Van Dyck, C. (2024, July 28 - August 1). Does the Current Evidence Base Support Lecanemab Continued Dosing for Early Alzheimer's Disease? [Perspectives Session] Alzheimer's Association International Conference, Philadelphia, PA, United States. Van Dyck, C. (2024, October 29-November 1). Does the Current Evidence Base Support Lecanemab Continued Dosing for Early Alzheimer's Disease? [Symposium on Lecanemab Continued Dosing] Clinical Trials for Alzheimer's Disease, Madrid, Spain. De Simone, F., Buitrago, L., Benina, N., et al. (2024, October 29-November 1). The use of plasma biomarkers for the prediction of Amyloid positivity. [Oral Presentation] Clinical Trials for Alzheimer's Disease, Madrid, Spain. Sabbagh, M., Zhao, C., Mahendran, M. et al. (2024, October 29-November 1). Lecanemab Treatment in Real World Settings in the United States. [Late Breaking Symposium 2]. Clinical Trials for Alzheimer's Disease, Madrid, Spain. Watson, D., Neam, M., Stafford, M. et al. (2024, October 29-November 1). Transitioning from Clinical Trial to Clinical Practice for Long-Term Lecanemab Treatment in Early Alzheimer's Disease: Perspectives from an Alzheimer's Disease Treatment Center. [Poster Presentation]. Clinical Trials for Alzheimer's Disease, Madrid, Spain. Sperling, RA., Rissman, R., Johnson, KA., et al. (2024, October 29-November 1). Screening Plasma Biomarkers, Amyloid and Tau PET Imaging in the AHEAD 3-5 Study. [Late Breaking Symposium 1]. Clinical Trials for Alzheimer's Disease, Madrid, Spain. Amin L, Harris DA. Aβ receptors specifically recognize molecular features displayed by fibril ends and neurotoxic oligomers. Nat Commun. 2021;12:3451. doi:10.1038/s41467-021-23507-z Ono K, Tsuji M. Protofibrils of Amyloid-β are Important Targets of a Disease-Modifying Approach for Alzheimer's Disease. Int J Mol Sci. 2020;21(3):952. doi: 10.3390/ijms21030952. PMID: 32023927; PMCID: PMC7037706. U.S. Food and Drug Administration. 2023. FDA Converts Novel Alzheimer's Disease Treatment to Traditional Approval. Last accessed: October 2024. Reuters. 2023. Japan approves Alzheimer's treatment Leqembi by Eisai and Biogen. Last accessed: October 2024. The Pharma Letter. 2024. Brief - Alzheimer drug Leqembi now approved in China. Last accessed: October 2024. Pharmaceutical Technology. 2024. South Korea's MFDS approves Eisai-Biogen's LEQEMBI for Alzheimer's. Last accessed: October 2024. Pharmaceutical Technology. 2024. Hong Kong approves Leqembi for Alzheimer's treatment. Last accessed: October 2024. BioSpace. 2024. Leqembi approved for the treatment of Alzheimer's disease in Israel. Last accessed: October 2024. United Arab Emirates Ministry of Health & Prevention. 2024. Registered Medical Product Directory. Leqembi. Last accessed: October 2024. BioSpace. 2024. Leqembi authorized for early Alzheimer's disease in Great Britain. Last accessed: October 2024. Eisai presents full results of lecanemab Phase 3 confirmatory Clarity AD study for early Alzheimer's disease at Clinical Trials on Alzheimer's Disease (CTAD) conference. Available at: van Dyck, C., et al. Lecanemab in Early Alzheimer's Disease. New England Journal of Medicine. 2023;388:9-21. . SOURCE Eisai Inc. 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Dose-dependent increase in neuroprotective APOE2 expression in all participants with ongoing durability at 12 months Consistent reductions across CSF tau biomarkers and tau PET in majority of participants LX1001 well tolerated across all dose cohorts with no reports of amyloid-related imaging abnormalities (ARIA) Company to host webcast today at 7:00 AM ET NEW YORK, Oct. 30, 2024 (GLOBE NEWSWIRE) -- Lexeo Therapeutics, Inc. (Nasdaq: LXEO), a clinical stage genetic medicine company dedicated to pioneering treatments for genetically defined cardiovascular diseases and APOE4-associated Alzheimer’s disease, today announced positive interim results from the Phase 1/2 study of LX1001 (NCT03634007) for the treatment of APOE4-associated Alzheimer’s disease (AD). Treatment with LX1001 led to dose-dependent increases in APOE2 protein expression and improvements in AD-associated tau biomarkers, measures which have been closely correlated with cognitive outcomes. LX1001 also demonstrated a favorable safety profile with no reports of ARIA1. The data were presented today in a late-breaking oral presentation at the Clinical Trials on Alzheimer’s Disease (CTAD) conference in Madrid, Spain and expand the body of evidence on LX1001 as a potential therapy for the more progressive course of Alzheimer’s seen in APOE4 homozygotes. “APOE4 homozygotes are approximately 15 times more likely to develop Alzheimer’s disease than the general population, have faster disease progression, and have an increased risk of ARIA with currently available therapies that can cause serious complications,” said Dr. Kim Johnson, Division Chief, Memory Disorders at the Department of Neurology of Duke University School of Medicine and a principal investigator in the Phase 1/2 study. “Today’s results suggest the potential of LX1001, which based on available data is well tolerated without reports of ARIA. The study also resulted in notable reductions in tau biomarkers, which suggest a possible effect on Alzheimer’s disease pathology.” LX1001 is an AAVrh10-based gene therapy candidate designed to deliver the protective APOE2 allele into the central nervous system of APOE4 homozygous patients, who have two copies of the toxic APOE4 allele. APOE2 is associated with a significantly lower risk of Alzheimer’s onset and slower disease progression. In the Phase 1/2 study, which completed enrollment in Q4 2023, fifteen patients with mild cognitive impairment (MCI) or mild or moderate AD were dosed with LX1001 in four dose-ascending cohorts. The study’s primary objective was to assess safety and tolerability, with secondary outcomes including cerebrospinal fluid (CSF) APOE2 protein expression and change in tau and amyloid biomarkers. “In light of the rapid progression of Alzheimer’s disease in this population, these data highlight the therapeutic potential of delivering APOE2, which can impact multiple mechanisms of Alzheimer’s disease upstream of any specific pathway and thereby meaningfully alter the devastating course of this complex disease,” said Dr. Sandi See Tai, Chief Development Officer of Lexeo Therapeutics. “These data are highly encouraging and provide clinical evidence of the unique and targeted mechanism of LX1001 to potentially treat Alzheimer’s disease.” The interim Phase 1/2 data include follow-up through 12-months for dose Cohorts 1 through 3 and follow-up through 6-months for dose Cohort 4, demonstrating: CSF APOE2 protein expression in all participants, with dose- and time-dependent increases in expression and durability out to 12 monthsStabilization of amyloid pathology in the majority of participants, with minimal change from baseline in Aß42/40 ratio and amyloid PETConsistent reductions across CSF tau biomarkers including CSF T-tau, P-tau181, P-tau2172 and P-tau2312, in over two thirds of participants relative to baseline and natural historyReductions at 6 months in global tau PET3 SUVR in 5 of 6 participants and in regional SUVR in a majority of participants across all brain regionsParticipants with moderate AD (n=4) generally demonstrated the most improvement across various biomarker endpointsFour SAEs were reported, with three deemed unrelated to treatment and one event of mild-moderate sensorineural hearing loss assessed as possibly related to treatment with repeat audiometry pending. The Company has initiated engagement with FDA on these data and expects to provide an update on regulatory interactions and further LX1001 development plans in 2025. Conference Call InformationLexeo will host a webcast today at 7:00 AM ET to review these data and next steps for the program. To register for and access the conference call and webcast presentation, please visit https://ir.lexeotx.com/news-events/events. The webcast presentation includes slides with further analysis of the LX1001 interim data. The on-demand webcast presentation may be accessed under the News & Events tab in the Investors section of the Company’s website, and a replay will be available following the presentation. About LX1001LX1001 is an AAVrh10-based gene therapy candidate for the treatment of APOE4-homozygous Alzheimer’s disease. Individuals homozygous for APOE4, an allele of the gene APOE, are approximately 15 times more likely to develop Alzheimer’s disease than the general population, and it is estimated that there are approximately 900,000 APOE4 homozygous patients with Alzheimer’s disease in the United States. Conversely, individuals homozygous for the APOE allele APOE2 are 40% less likely to develop Alzheimer’s disease than the general population. LX1001 is designed to express the protective APOE2 gene in the central nervous system of APOE4 homozygous patients, potentially slowing or halting the progression of Alzheimer’s disease. LX1001 has been granted Fast Track designation by the FDA. About Lexeo Therapeutics Lexeo Therapeutics is a New York City-based, clinical stage genetic medicine company dedicated to transforming healthcare by applying pioneering science to fundamentally change how genetically defined cardiovascular diseases and APOE4-associated Alzheimer’s disease are treated. Using a stepwise development approach, Lexeo is leveraging early proof-of-concept functional and biomarker data to advance a pipeline of cardiovascular and APOE4-associated Alzheimer’s disease programs. Cautionary Note Regarding Forward-Looking StatementsCertain statements in this press release may constitute “forward-looking statements” within the meaning of the federal securities laws, including, but not limited to, our expectations and plans regarding our current product candidates and programs, including statements regarding the potential benefits and safety of LX1001 for the treatment of Alzheimer’s disease and the timing for receipt and announcement of data from its clinical trials, and the timing and likelihood of potential regulatory approval. Words such as “may,” “might,” “will,” “objective,” “intend,” “should,” “could,” “can,” “would,” “expect,” “believe,” “design,” “estimate,” “predict,” “potential,” “develop,” “plan” or the negative of these terms, and similar expressions, or statements regarding intent, belief, or current expectations, are forward-looking statements. While Lexeo believes these forward-looking statements are reasonable, undue reliance should not be placed on any such forward-looking statements. These forward-looking statements are based upon current information available to the company as well as certain estimates and assumptions and are subject to various risks and uncertainties (including, without limitation, those set forth in Lexeo’s filings with the U.S. Securities and Exchange Commission (SEC)), many of which are beyond the company’s control and subject to change. Actual results could be materially different from those indicated by such forward looking statements as a result of many factors, including but not limited to: risks and uncertainties related to global macroeconomic conditions and related volatility; expectations regarding the initiation, progress, and expected results of Lexeo’s preclinical studies, clinical trials and research and development programs; the unpredictable relationship between preclinical study results and clinical study results; delays in submission of regulatory filings or failure to receive regulatory approval; liquidity and capital resources; and other risks and uncertainties identified in Lexeo’s Quarterly Report on Form 10-Q for the quarterly period ended June 30, 2024, filed with the SEC on August 12, 2024, and subsequent future filings Lexeo may make with the SEC. New risks and uncertainties may emerge from time to time, and it is not possible to predict all risks and uncertainties. Lexeo claims the protection of the Safe Harbor contained in the Private Securities Litigation Reform Act of 1995 for forward-looking statements. Lexeo expressly disclaims any obligation to update or alter any statements whether as a result of new information, future events or otherwise, except as required by law. 1 Amyloid-related imaging abnormalities (ARIA) refer to MRI findings observed in patients receiving anti-amyloid therapies for Alzheimer’s disease. ARIA is most commonly observed as brain swelling and/or microhemorrhages and has a higher incidence in patients who are APOE4 allele carriers. 2 CSF P-tau217 and P-tau231 collected only in Cohorts 2, 3 and 4; all Cohort 4 samples, including 6 month and 12 month, pending analysis3 Tau PET performed only in Cohorts 3 and 4; Cohort 4 12-mth visits pending analysis Media:Media@lexeotx.com Investors:Carlo Tanzi, Ph.D.ctanzi@kendallir.com

引言 阿尔茨海默症（Alzheimer’s disease, AD）的临床前期（preclinical phase）是指患者在出现明显的认知或记忆障碍以前的阶段。尽管此时还没有显著的临床表现，但大脑中已经出现了与AD相关的病理变化，如β-淀粉样蛋白（amyloid-beta, Aβ）斑块的积聚和Tau蛋白缠结的形成。临床前期AD可以持续多年甚至数十年，最终引发一系列复杂的病理反应，导致神经退行性病变，并逐步损害记忆和认知功能【1】。 在AD进展过程中，Aβ和Tau蛋白是两种关键的异常折叠蛋白。这些蛋白在正常情况下具有特定的三维结构，但在AD进展过程中会发生错误折叠，形成病理性聚集体。这些聚集体像“种子”一样，能够诱导周围正常蛋白质发生同样的错误折叠，形成更多的聚集体，进一步加剧病理过程【2】。 然而，是什么启动了这一病理级联反应呢？基因分析表明，散发性AD的风险与主要在小胶质细胞和星形胶质细胞中表达的基因密切相关，这些细胞对Aβ的沉积有反应【3】。已确定的高危基因大多与免疫、脂质代谢和内吞途径有关，其中载脂蛋白E（APOE）及其等位基因APOE4被认为是最具风险的【4】。在健康的中枢神经系统中，APOE主要由星形胶质细胞合成，通过在脂蛋白颗粒中溶解脂质来发挥作用，并通过受体介导的内吞作用支持细胞存活、突触形成和膜扩张等过程。 除了在脂质稳态中的作用外，APOE在神经系统疾病中也起着关键作用。几乎所有包括AD在内的中枢神经系统损伤，都伴随小胶质细胞和星形胶质细胞的反应，并诱发脂质代谢途径，尤其是APOE的上调。利用小鼠模型的研究表明，APOE缺失会减少Aβ纤维状斑块的沉积，提示APOE可能参与了Aβ纤维化、稳定化或压实过程【4】。 2024年10月16日，慕尼黑工业大学Mikael Simons实验室领衔在Immunity杂志发表了题为Apolipoprotein E aggregation in microglia initiates Alzheimer’s disease pathology by seeding β-amyloidosis的研究文章。作者开发了表达HaloTag标记APOE的转基因小鼠（ApoE-Halo），并优化了APOE的纯化和检测方法，从而能够更精确地分析Aβ病变中的APOE作用。利用这一模型，作者发现APOE的纤维状聚集体在小胶质细胞的内吞-溶酶体系统中诱导了Aβ淀粉样变性，该过程受小胶质细胞脂质代谢和JAK/STAT信号通路的调控。本研究揭示了小胶质细胞内APOE的聚集可能是Aβ斑块形成和AD病理反应的初始驱动因素。 为改善APOE的可视化和纯化，作者构建了表达HaloTag标记的APOE转基因小鼠模型（ApoE-Halo），并确认了HaloTag对Aβ代谢和脂质代谢没有显著影响。将ApoE-Halo小鼠与阿尔茨海默症模型小鼠（5xFAD）交配后，作者发现APOE在Aβ纤维沉积中有显著定位，尤其在小胶质细胞中更为明显。 通过HaloTag自标记技术，研究进一步明确了APOE在Aβ斑块中的高特异性定位。随着AD的进展，Aβ斑块的纤维化加剧，APOE聚集也相应增加。Sarkosyl提取和免疫纯化分析显示，APOE聚集体呈现多聚体和纤维状形态，且部分聚集体几乎独立于Aβ存在。这一发现不仅在小鼠模型中成立，也在AD患者的脑组织中得到了验证。 为了验证APOE聚集体在Aβ斑块形成中的作用，研究人员通过将APOE聚集体注射到AD小鼠的大脑中，发现斑块生成显著增加，而去除APOE聚集体后，这一效应明显减弱。这一结果进一步证实了APOE聚集体作为Aβ斑块形成的关键辅助因子发挥了重要作用。此外，通过将APOE3和APOE4敲入小鼠与5xFAD小鼠杂交，作者发现无论是APOE3还是APOE4，都能作为Aβ斑块形成的辅助因子，但APOE4较APOE3在促进Aβ聚集和斑块生成上表现出更强的效力，表明APOE4在AD发病中的关键作用。 接下来，通过高分辨率成像和3D渲染技术发现，APOE-Halo聚集体主要位于活化的小胶质细胞内，在不同AD小鼠模型和人类AD样本中均可检测到，且小胶质细胞内存在纤维状聚集体，尤其在斑块周围。因此，APOE与小胶质细胞协同作用，共同促进了Aβ聚集体和淀粉样斑块的形成。 药物实验进一步表明，小胶质细胞的功能对于这些聚集体的形成至关重要，而溶酶体功能障碍和干扰素信号的激活则会加剧APOE聚集体的形成。不仅如此，使用JAK/STAT抑制剂进行治疗能够减少APOE依赖性聚集体和Aβ斑块的形成。因此，干扰素和免疫信号与溶酶体功能一道在APOE介导的聚集体形成中发挥了重要作用。 作者最后检测了APOE与脂质结合在小胶质细胞内聚集体形成中的作用，发现脂质化的APOE比无脂质的APOE更易被细胞摄取，并增强了聚集体的形成。此外，胆固醇合成的减少会加速APOE聚集体的形成，并促进Aβ斑块的积累。阻断小胶质细胞中的胆固醇合成也会上调APOE受体的表达，进一步加速APOE聚集体的形成。 模式图（Credit: Immunity） 综上所述，本研究揭示了阿尔茨海默症发展过程中淀粉样变性及其早期病理机制，特别是载脂蛋白E（APOE）在这一过程中扮演的关键角色。通过开发APOE-Halo小鼠模型，作者揭示了APOE聚集体在小胶质细胞的内吞-溶酶体系统中诱导了Aβ淀粉样变性，并探明了脂质代谢和免疫信号对这一过程的调控作用。本研究阐释了小胶质细胞对APOE的内吞和聚集可能是Aβ斑块形成的初始驱动因素，为理解阿尔茨海默症的病理机制提供了新的视角。 参考文献 1. Scheltens, P., et al. (2021). Alzheimer’s disease. Lancet 397, 1577–1590. 2. Jucker, M., and Walker, L.C. (2013). Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature 501, 45–51. 3. Sadick, J.S., et al. (2022). Astrocytes and oligodendrocytes undergo sub-type-specific transcriptional changes in Alzheimer’s disease. Neuron 110, 1788–1805.e10. 4. Chen, Y., et al. (2021). Apolipoprotein E: structural insights and links to Alzheimer disease pathogenesis. Neuron 109, 205–221. https://doi.org/10.1016/j.immuni.2024.09.014 责编|探索君 排版|探索君 来源|BioArt End 往期精选 围观 一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版） 热文 Cell | 是什么决定了细胞的大小？ 热文 Nature | 2024年值得关注的七项技术 热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望 热文 CRISPR技术进化史 | 24年Cell综述