Anti-n3pglu amyloid beta antibodies and uses thereof

Abstract

To provide methods for treating human Alzheimer disease using anti-N3pG Aβ antibodies (e.g., donanemab) without causing harmful effects caused by long term chronic administration of antibodies.SOLUTION: Disclosed is a method for reducing amyloid beta (Aβ) plaque in the brain of a human Alzheimer disease (AD) subject, where the method comprises: administering to the subject three first dosages of 700 mg of an anti-N3pGlu amyloid beta antibody where each first dose is administered at a frequency of once every four weeks; and four weeks after the three first doses, administering to the subject one or more second doses of 1400 mg of the anti-N3pGlu amyloid beta antibody at a frequency of once every four weeks, where the anti-N3pG amyloid beta antibody comprises a light chain variable region (LCVR) and a heavy chain variable region each having a specific sequence.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present disclosure relates to methods of preventing or treating diseases with anti-N3pGlu Aβ antibodies, where the diseases are characterized by amyloid beta (Aβ) deposition in a subject. The present disclosure also relates to doses and dosing regimens of anti-N3pGlu Aβ antibodies useful for treating or preventing diseases characterized by Aβ deposition. Some aspects of the present disclosure relate to treating or preventing diseases characterized by Aβ deposition in a subject, where the subject is selected based on i) tau levels / burden in the entire brain (global tau), ii) tau levels / burden in portions of the brain (e.g., different lobes of the brain), and / or iii) the presence of one or two alleles of APOE4 in the subject's genome. Diseases that can be treated or prevented using the antibodies, dosing regimens, or methods disclosed herein include, for example, Alzheimer's disease (AD), Down's syndrome, and cerebral amyloid angiopathy (CAA). The present disclosure also relates to slowing disease progression in subjects with early symptomatic Alzheimer's disease, optionally in the presence of intermediate brain tau load. The present disclosure also relates to slowing disease progression of AD. Treatment with an anti-N3pG Aβ antibody of the present disclosure can be initiated in patients with evidence of AD neuropathology and mild cognitive impairment or mild dementia stage disease, optionally in the presence of brain tau load. In some embodiments, the brain tau load is very low, low, intermediate, or high tau. [Background technology]

[0002] A cure for Alzheimer's disease is one of society's most important unmet needs. Accumulation of amyloid-β peptide in the form of cerebral amyloid plaques is an early and essential event in Alzheimer's disease, leading to neurodegeneration and, as a result, the onset of clinical symptoms such as cognitive and functional impairment (Selkoe, "The Origins of Alzheimer's Disease: A is for Amyloid," JAMA 283:1615-7 (2000); Hardy et al., "The Amyloid Hypothesis of Alzheimer's Disease: Progress and Problems on the Road to Therapeutics," Science 297:353-6 (2002); Masters et al., "Alzheimer's Disease," Nat. Rev. Dis. Primers 1:15056 (2015); and Selkoe et al., "The Amyloid Hypothesis of Alzheimer's Disease at 25 Years," EMBO Mol. Med. 8:595-608 (2016)).

[0003] Amyloid beta is formed by proteolytic cleavage of a larger glycoprotein called amyloid precursor protein (APP). APP is an integral membrane protein expressed in many tissues, particularly at neuronal synapses. APP is cleaved by γ-secretase to release Aβ peptides, which comprise a group of peptides ranging in size from 37 to 49 amino acid residues. Aβ monomers aggregate into various types of higher-order structures, including oligomers, prefibrils, and amyloid fibrils. Amyloid oligomers are soluble and can spread throughout the brain, while amyloid fibrils are larger, insoluble, and can further aggregate to form amyloid plaques. Amyloid plaques found in human patients contain a heterogeneous mixture of A® peptides, some of which contain N-terminal truncations and may also contain N-terminal modifications such as N-terminal pyroglutamic acid residues (pGlu).

[0004] The role of amyloid plaques in driving disease progression is supported by studies of rare genetic variants that either increase or decrease Aβ deposition (Fleisher et al., “Associations Between Biomarkers and Age in the Presenilin 1 E280A Autosomal Dominant Alzheimer Disease Kindred: A Cross-sectional Study,” JAMA Neurol 72:316-24 (2015); Jonsson et al., “A Mutation in APP Protects Against Alzheimer's Disease and Age-related Cognitive Decline,” Nature 488:96-9 (2012)). Additionally, the presence of amyloid plaques early in the disease increases the likelihood of progression from mild cognitive impairment (MCI) to AD dementia (Doraiswamy et al., "Amyloid-β Assessed by Florbetapir F18 PET and 18-month Cognitive Decline: A Multicenter Study," Neurology 79:1636-44 (2012)). Interventions or therapies aimed at removing Aβ plaques are hypothesized to slow the clinical progression of AD.

[0005] Some known anti-Aβ antibodies include bapineuzumab, gantenerumab, aducanumab, GSK933776, solanezumab, crenezumab, ponezumab, and lecanemab (BAN2401). Antibodies targeting Aβ have shown promise as treatments for Alzheimer's disease in both preclinical and clinical studies. Despite this promise, many amyloid-targeting antibodies have failed to achieve therapeutic endpoints in multiple clinical trials. The history of anti-amyloid clinical trials spans nearly 20 years, and in most cases, doubt has been cast on the potential of such therapies to effectively treat AD (Aisen et al., “The Future of Anti-amyloid Trials,” The Journal of Prevention of Alzheimer's Disease 7:146-151 (2020); Budd et al., “Clinical Development of Aducanumab, an Anti-Aβ Human Monoclonal Antibody Being Investigated for the Treatment of Early Alzheimer's Disease,” The Journal of Prevention of Alzheimer's Disease 4(4):255-263 (2017); and Klein et al., “Gantenerumab Reduces Amyloid-β Plaques in Patients with Prodromal to Moderate Alzheimer's Disease: A PET Substudy Interim Analysis,” Alzheimer's Research & Therapy 11.1:1-12 (2019)).

[0006] Amyloid plaques found in human patients contain a heterogeneous mixture of Aβ peptides. N3pGlu Aβ (also known as N3pG Aβ, N3pE Aβ, Aβ pE3-42, or Aβ p3-42) is a truncated form of the Aβ peptide found exclusively in amyloid plaques. N3pGlu Aβ lacks the first two amino acid residues at the N-terminus of human Aβ and contains a pyroglutamate-derived glutamate at the third amino acid position of Aβ. N3pGlu Aβ peptides are a minor component of Aβ deposited in the brain, but studies suggest that they possess aggressive aggregation properties and accumulate early in the deposition cascade. Passive immunization through long-term chronic administration of antibodies against plaque-containing Aβ, including N3pGlu Aβ, has been shown to disrupt Aβ aggregates and promote plaque clearance in the brains of various animal models.

[0007] Antibodies against N3pGlu Aβ are known in the art. For example, U.S. Patent No. 8,679,498 (which is incorporated herein by reference in its entirety, including the anti-N3pGlu Aβ antibodies disclosed therein) discloses anti-N3pGlu Aβ antibodies and methods of using these antibodies to treat diseases such as Alzheimer's disease.

[0008] Donanemab (disclosed in U.S. Patent No. 8,679,498) is an antibody directed against the pyroglutamate modification of the third amino acid of the amyloid beta (N3pGlu Aβ) epitope, which is present exclusively in cerebral amyloid plaques. Donanemab's mechanism of action is to target and remove existing amyloid plaques, a key pathological hallmark of AD. A second neuropathological hallmark of AD is the presence of intracellular neurofibrillary tangles containing hyperphosphorylated tau protein. While Aβ drives tau pathology, more complex and synergistic interactions between Aβ and tau may emerge at later stages and promote disease progression (Busche et al., "Synergy Between Amyloid-β and Tau in Alzheimer's Disease," Nature Neuroscience 23:1183-93 (2020)).

[0009] Treatment and prevention strategies for donanemab include, for example, targeting N3pGlu Aβ, specifically in amyloid plaques, in early symptomatic AD patients with cerebral amyloid load. The rationale for this is based on the amyloid hypothesis of AD, which states that Aβ production and deposition are an early and necessary event in the pathogenesis of AD. See, e.g., Selkoe, "The Origins of Alzheimer's Disease: A is for Amyloid," JAMA 283:1615-1617 (2000). Clinical support for this hypothesis comes from the demonstration that parenchymal Aβ levels are elevated before AD symptoms appear and are supported by AD genetic variants that overproduce brain Aβ and genetic variants that prevent Aβ production. See, for example, Jonsson et al., "A Mutation in APP Protects Against Alzheimer's Disease and Age-related Cognitive Decline," Nature 488(7409):96-99 (2012) and Fleisher et al., "Associations Between Biomarkers and Age in the Presenilin 1 E280A Autosomal Dominant Alzheimer's Disease Kindred: A Cross-sectional Study," JAMA Neurol. 72:316-24 (2015).

[0010] However, long-term chronic administration of Aβ antibodies presents significant problems: Aβ antibody administration has resulted in adverse events in humans, such as amyloid-related imaging abnormalities (ARIA), vasogenic edema and crevicular effusion (ARIA-E), microhemorrhages and hemosiderin deposits (ARIA-H), injection site reactions, and the risk of immunogenicity. For example, Piazza and Winblad, “Amyloid-Related Imaging Abnormalities (ARIA) in Immunotherapy Trials for Alzheimer's Disease:Need for Prognostic Biomarkers?” Journal of Alzheimer's Disease, 52:417-420 (2016); Sperling, et al., “Amyloid-related Imaging Abnormalities in Patients with Alzheimer's Disease Treated with Bapineuzumab: A Retrospective Analysis,”The Lancet Neurology 11.3:241-249(2012);Brashear et al.,“Clinical Evaluation of Amyloid-related Imaging Abnormalities in Bapineuzumab Phase III Studies,”J.of Alzheimer's Disease 66.4:1409-1424(2018);Budd et al.,“Clinical Development of Aducanumab,an Anti-Aβ Human Monoclonal Antibody See “Being Investigated for the Treatment of Early Alzheimer’s Disease,” The Journal of Prevention of Alzheimer’s Disease 4.4:255 (2017).

[0011] Although the exact cause of these adverse events remains unclear, it is generally believed that antibody therapy disrupts the blood-brain barrier through interactions with cerebrovascular amyloid, leading to a leaky barrier and the development of edema in patients. Several possible mechanisms of action have been hypothesized, including removal of amyloid from the vascular wall destabilizing the neurovascular unit, localizing inflammation / infiltration in the neurovascular unit, and increasing cerebrovascular amyloid levels due to higher levels of interstitial soluble Aβ, resulting in the removal of parenchymal plaques or altered localization of AQP-4 in the astrocyte end-foot processes of the neurovascular unit.

[0012] Some therapeutic amyloid-targeting antibodies have shown a dose-response-related increase in ARIA-E. See, for example, Brashear et al., "Clinical Evaluation of Amyloid-Related Imaging Abnormalities in Bapineuzumab Phase III Studies," J. of Alzheimer's Disease 66.4:1409-1424 (2018); Budd et al., "Clinical Development of Aducanumab, an Anti-Aβ Human Monoclonal Antibody Being Investigated for the Treatment of Early Alzheimer's Disease," The Journal of Prevention of Alzheimer's Disease 4.4:255 (2017). In some cases, patients with the epsilon 4 allele of apolipoprotein E (referred to herein as APOE4, apoE4, or ApoE-ε4) have a higher incidence of ARIA-E.

[0013] To reduce the adverse event rate of ARIA-E while maintaining plaque clearance, some antibody treatment programs have implemented dose escalation schemes involving multiple dose increases (3–4 steps) over a period of approximately 6 months before reaching an effective dose level. See, for example, Budd et al., “Clinical Development of Aducanumab, an Anti-Aβ Human Monoclonal Antibody Being Investigated for the Treatment of Early Alzheimer's Disease,” The Journal of Prevention of Alzheimer's Disease 4.4:255 (2017) and Klein et al., “Gantenerumab Reduces Amyloid-β Plaques in Patients with Prodromal to Moderate Alzheimer's Disease: a PET Substudy Interim Analysis,” Alzheimer's Research & Therapy 11.1:101 (2019). Such treatment regimens may not completely remove amyloid plaques or may delay their removal.

[0014] Thus, there is a need for improved doses, dosing regimens, or methods that adequately treat subjects without causing or increasing problematic adverse events. Summary of the Invention

[0015] One aspect of the present disclosure provides doses and dosing regimens that avoid problematic adverse events such as ARIA with vasogenic edema that have been observed in patients receiving therapeutic antibodies that bind to deposited amyloid and are dose-limiting in some clinical development programs.

[0016] The antibodies of the present disclosure selectively bind to N3pGlu Aβ, which is primarily found in deposited amyloid plaques. The incidence of N3pGlu Aβ peptide in deposited parenchymal plaques is very low (approximately 1-2%) relative to other Aβ peptide species, with the majority consisting of full-length Aβ. 1-42 Thus, the total number of binding sites for the antibodies of the present disclosure is dramatically reduced relative to other plaque-binding Aβ antibodies. Biochemical analysis of CAA, an amyloid that deposits along CNS blood vessels, demonstrated a similarly low occurrence of N3pGlu peptides (approximately 2%).

[0017] Surprisingly, the antibodies of the present disclosure do not require multiple dose escalations over an extended period of time. In some cases, the antibodies can reach effective dosage levels without causing a high incidence of adverse events. Furthermore, in some cases, the anti-N3pGlu Aβ antibodies and dosing regimens of the present disclosure, as described herein, promote rapid cerebral amyloid clearance while minimizing the incidence and / or severity of ARIA adverse events observed with anti-amyloid antibodies.

[0018] The beneficial effects of the improved doses, dosing regimens, and methods of the present disclosure may be due, for example, to the rapid clearance of parenchymal plaques while the antibodies have low overall binding to vascular amyloid (e.g., due to a low incidence of N3pGlu peptides). In other words, the beneficial effects of the improved doses, dosing regimens, and methods of the present disclosure may be due to a combination of i) their ability to target parenchymal / vascular plaques and achieve rapid reduction of amyloid plaques, and ii) the relative paucity of antibody binding sites found on both parenchymal and vascular amyloid deposits. Clinical studies have demonstrated that treatment of Alzheimer's disease patients using the improved doses, dosing regimens, and methods of the present disclosure results in rapid clearance of deposited amyloid (e.g., amyloid plaques) from the subject's brain. Despite the sparse occurrence of the target epitopes of the antibodies of the present disclosure, the rate of amyloid clearance was significantly faster than published data from other amyloid-targeting therapeutic antibodies at a range of doses (Budd et al., The Journal of Prevention of Alzheimer's Disease 4.4:255 (2017) and Klein et al., Alzheimer's Research & Therapy 11.1:101 (2019)).

[0019] The dosing regimens described herein facilitate rapid clearance of cerebral amyloid by the antibodies of the present disclosure, while minimizing the incidence and / or severity of ARIA adverse events observed with this class of therapeutic antibodies. Furthermore, the dosing regimens disclosed herein provide early, extensive amyloid clearance (e.g., approximately 60% of subjects have an "amyloid-negative" scan by week 52). The dosing schemes described herein facilitate rapid clearance of parenchymal plaques by anti-N3pGlu Aβ antibodies, while resulting in lower overall binding to vascular amyloid (due to lower incidence of N3pGlu peptides).

[0020] As mentioned above, antibodies targeting amyloid plaques, such as those targeting Aβ, have shown promise as treatments for Alzheimer's disease in both preclinical and clinical studies. Despite this promise, amyloid-targeting antibodies have failed to achieve therapeutic endpoints in multiple clinical trials. The history of anti-amyloid clinical trials spans nearly 20 years, and in most cases, the potential for such therapies to effectively treat AD has been questioned (Aisen et al., "The Future of Anti-amyloid Trials," The Journal of Prevention of Alzheimer's Disease 7, 146-151 (2020)). To date, only a handful of AD treatments have been approved. A challenge in treating Alzheimer's disease is that it is still primarily diagnosed and treated based on symptoms, such as psychiatric disorders, rather than on brain pathology. Yet another challenge is the reproducibility crisis faced during clinical trials, which often makes it difficult to obtain reproducible results, even when clinical trials are designed in a similar manner. This is caused by two main factors. First, most trials set enrollment criteria based on symptoms rather than pathology. This results in heterogeneous populations with widely varying levels of underlying pathology, or even worse, patients with different underlying diseases. Consequently, these patients progress to AD at very different rates, and within-group variability, measured by, for example, the standard deviation of the mean, is very large in AD trials. Furthermore, the problem of population heterogeneity is exacerbated by within-subject noise in outcome measurements.

[0021] Determining whether a subject with Aβ plaques will respond to anti-N3pGlu Aβ antibody treatment is extremely difficult. This is in part due to physiological and clinical heterogeneity among subjects with Aβ plaques, and because subjects are still diagnosed primarily based on symptoms. For example, it remains a challenge for clinicians to determine whether a patient with subtle cognitive symptoms, such as memory decline, has prodromal or preclinical Alzheimer's disease and may progress to AD dementia in the near future.

[0022] Placebo cohorts in AD clinical trials vary widely in the trajectories of cognitive and functional decline (Veitch et al., “Understanding Disease Progression and Improving Alzheimer's Disease Clinical Trials: Recent Highlights from the Alzheimer's Disease Neuroimaging Initiative,” Alzheimer's & Dementia 15.1:106-152 (2019)), which is thought to be due to the heterogeneity of study populations (Devi et al., “Heterogeneity of Alzheimer's Disease: Consequence for Drug Trials?” Alzheimer's Research & Therapy 10.1:1-3 (2018)). This exacerbates the challenge of identifying and treating subjects who may benefit from specific treatments. Properly identifying patients who may respond to anti-N3pGlu Aβ antibody treatment is paramount for, for example, timely referral to memory clinics, accurate and early AD diagnosis, initiation of symptomatic treatment, future planning, and initiation of disease-modifying therapies.

[0023] Previously, study cohorts have been selected based on clinical characteristics such as cognitive test score ranges and self-reported memory problems. After years of failure, experts in the field advocate testing anti-amyloid disease-modifying therapies (DMTs) early in the disease progression (Aisen et al. 2020). However, several clinical studies of anti-amyloid DMTs have failed to achieve their endpoints, despite targeting patients with early-stage Alzheimer's disease. For example, the Phase III clinical trial of crenezumab (Cread trial) recruited patients with prodromal to mild AD. The results of this study were largely negative. No differences were found in both primary and secondary endpoints between treatment and placebo groups or within prodromal and mild AD subgroups (NCT03114657, Therapeutics:Crenezumab.Alzforum.AC, Immune SA, Genentech, Hoffmann-La Roche; 2019 [cited 2020Sep7], available at clinicaltrials.gov / alzforum / therapeutics / crenezumab). Similarly, a Phase II / III clinical trial evaluating the efficacy and safety of gantenerumab in patients with prodromal AD (the SCarlet RoAD trial) was halted due to a low likelihood of efficacy in the study's primary and secondary endpoints (Ostrowitzki et al., "A Phase III Randomized Trial of Gantenerumab in Prodromal Alzheimer's Disease," Alzheimer's Research & Therapy 9.1:1-15 (2017)).

[0024] Therefore, there is a need for improved methods to appropriately identify whether a subject will respond to an amyloid-targeted therapy.

[0025] Doody et al., "Phase 3 Trials of Solanezumab for Mild-to-Moderate Alzheimer's Disease," NEJM, 370;4, 311-321 (2014), indicate that "no clear differential treatment effects on efficacy measures were observed between APOE ε4 carriers and non-carriers." It has now been discovered that administering an anti-N3pGlu Aβ antibody to human subjects with one or two APOE4 alleles (e.g., heterozygous or homozygous carriers of APOE4) results in unexpected and surprising benefits compared to non-carriers of one or more of those alleles. Accordingly, some embodiments of the present disclosure include administering a dose of an anti-N3pGlu Aβ antibody to patients with the allele as a means of slowing their cognitive decline. Specifically, it has been discovered that when patients are administered an anti-N3pGlu Aβ antibody, there is a greater benefit in APOE4 carriers than in non-carriers. This means that patients who receive anti-N3pGlu Aβ antibodies who have APOE4 have less cognitive decline than non-carriers, as measured using a variety of clinical measures and a variety of endpoints.

[0026] Across all treatment trials selected for the presence of amyloid pathology, carriers were younger, had higher amyloid loads, and had higher tau pathology at baseline. Clinical decline across all scales in the placebo group did not differ by carrier status. Comparison of carrier status in the placebo group showed no significant longitudinal change in amyloid, however, a trend toward greater tau changes in carriers versus non-carriers. Relative longitudinal changes in amyloid during therapy showed greater reductions in non-carriers than in carriers. One hypothesis to consider is the interaction of APOE with tau. Amyloid deposits are known to concentrate and contain APOE embedded within plaques. More recently, APOE has been shown to be isolated from tau tangles. Animal data further suggest an interaction of APOE with tau. Additionally, rare APOE mutations appeared to protect subjects with autosomal dominant PSEN1 mutations well beyond the typical time of disease onset, despite significant cerebral amyloid load but relatively low tau burden. In some embodiments, the present disclosure demonstrates that APOE also influences tau beyond amyloid interactions, potentially leading to a faster rate of tau alteration in carriers. Furthermore, the impact of treatment may have a significant impact on tau progression, which is more directly related to clinical progression. Tau progression and spread is associated with low-density lipoprotein receptor-related protein 1 (LRP1, also known as alpha-2-macroglobulin receptor, apolipoprotein E receptor, or cluster of differentiation 91). See Rauch et al., "LRP1 is a Master Regulator of Tau Uptake and Spread," Nature 580(7803):381-385 (2020), which is incorporated herein by reference in its entirety. Recent reports suggest that LRP1 promotes tau internalization and degradation via an APOE-mediated mechanism.See Cooper et al., “Regulation of Tau Internalization, Degradation, and Seeding by LRP1 Reveals Multiple Pathways for Tau Catabolism,” Journal of Biological Chemistry 100715 (2021), which is incorporated by reference in its entirety.

[0027] One aspect of the present disclosure is based on the discovery that Alzheimer's patients with low or moderate tau, very low to moderate tau, or no high tau are responsive to treatment with anti-N3pGlu Aβ antibodies, while patients with high tau levels, even if clinically classified as preclinical or early stage AD, may not be effectively treated with anti-N3pGlu Aβ antibodies. Another aspect of the present disclosure is based on the discovery that Alzheimer's patients with one or two alleles of APOE4 are responsive to treatment with anti-N3pGlu Aβ antibodies. Yet another aspect of the present disclosure is based on the discovery that Alzheimer's patients with one or two alleles of APOE4 and low or moderate tau, very low to moderate tau, or no high tau are responsive to treatment with anti-N3pGlu Aβ antibodies.

[0028] Identifying subjects most responsive to treatment with anti-N3pGlu Aβ antibodies solves the over 20-year-old problem of finding clinically effective anti-amyloid therapies and represents a significant advance in the art. Some aspects of the present disclosure are directed to diagnosing and treating patients based on their brain pathology. Selecting patients based on their brain pathology not only provides a more homogenous population for clinical trials, reducing noise and ensuring more reproducible results, but also ensures proper identification of the stage of AD and its progression. Proper identification of the stage of AD allows, for example, timely referral to a memory clinic, accurate and early diagnosis of AD, initiation of symptomatic treatment, future planning, and initiation of disease-modifying treatment. [Brief explanation of the drawings]

[0029] (Not stated in the original text) DETAILED DESCRIPTION OF THE INVENTION

[0030] Some embodiments of the present disclosure provide a two-step dosing regimen for administering an anti-N3pGlu Aβ antibody to a human subject suffering from a disease characterized by Aβ plaques in the brain. In the first step, the human subject receives one or more first doses (or low doses) of about 100 mg to about 700 mg of an anti-N3pGlu Aβ antibody, with each first dose (low dose) administered approximately once every four weeks (i.e., once every four weeks). Approximately four weeks after administering the one or more first doses, in the second step, the human subject receives one or more second doses (or high doses) of greater than 700 mg to about 1400 mg, with each second dose (high dose) administered once every four weeks.

[0031] Some aspects of the present disclosure relate to identifying the stage / progression of AD in a subject based on i) the global or overall tau burden in the brain of a human subject, or ii) the spread of tau in the subject's brain or a portion thereof. In some aspects, an anti-N3pGlu Aβ antibody of the present disclosure can be administered to a subject i) without determining the stage / progression of AD in the subject, or ii) regardless of the stage / progression of AD in the subject.

[0032] In some embodiments, patients can be stratified / identified / selected / treated based on the amount of tau present in the subject's brain (e.g., whole brain or part of the brain). In some embodiments, patients can be stratified / identified / selected / treated based on the amount of tau present in the subject's brain (e.g., whole brain or part of the brain) and the presence of one or two alleles of APOE4.

[0033] In other embodiments, patients are stratified / identified / selected / treated based on the stage of AD progression (e.g., based on the spread of tau in the brain). For example, during some stages, the tau burden in AD patients is isolated to regions of the frontal lobe or temporal lobe, not including the posterior lateral temporal region (PLT). Another stage of AD is where the tau burden in AD patients is limited to the posterior lateral temporal (PLT) or occipital regions. Yet another stage of AD is when the tau burden in AD patients is present in the parietal or precuneus or frontal regions, along with tau burden in the PLT or occipital regions. In some embodiments, patients may be stratified / identified / selected / treated based on the stage of AD progression (e.g., based on the spread of tau in the brain) and the presence of one or two alleles of APOE4.

[0034] Patient stratification based on brain tau load, AD progression in a portion of the brain, and / or the presence of one or two APOE4 alleles can be used to determine, for example, whether a patient will respond to anti-N3pGlu Aβ antibody treatment. Patient population stratification / selection based on brain tau load, AD progression in a portion of the brain, and / or the presence of one or two APOE4 alleles also helps to solve the problems of patient heterogeneity and replicability encountered during the design and conduct of clinical trials.

[0035] Another aspect of the present disclosure provides a human subject that is responsive to the treatment or prevention of a disease characterized by amyloid beta plaques in the brain of the human subject. In some embodiments of this aspect of the present disclosure, the responsive human subject includes a human subject with low to moderate tau burden, very low to moderate tau burden, and / or one or two alleles of APOE4. In some embodiments of this aspect of the present disclosure, the responsive human subject excludes a human subject with high tau burden. In some embodiments of this aspect of the present disclosure, the responsive human subject excludes a human subject with high tau burden and / or one or two alleles of APOE4.

[0036] In some embodiments, anti-N3pGlu Aβ antibodies of the present disclosure are administered to responsive human subjects for the treatment or prevention of diseases characterized by amyloid beta plaques in the brain of the human subject. In some embodiments, anti-N3pGlu Aβ antibodies of the present disclosure are administered to human subjects for the treatment or prevention of diseases characterized by amyloid beta plaques in the brain of the human subject. In some embodiments, anti-N3pGlu Aβ antibodies of the present disclosure are administered to human subjects for the treatment or prevention of diseases characterized by amyloid beta plaques in the brain of the human subject, regardless of brain tau levels.

[0037] In one aspect, the disclosure relates to a method of treating or preventing a disease characterized by Aβ plaques in the brain of a human subject, comprising: i) administering to the human subject one or more first doses of about 100 mg to about 700 mg of an anti-N3pGlu Aβ antibody, wherein each first dose is administered about once every four weeks; and ii) about four weeks after administering the one or more first doses, administering to the human subject one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pGlu Aβ antibody, wherein each second dose is administered about once every four weeks, wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 1 and the HCVR comprises the amino acid sequence of SEQ ID NO: 2. In some embodiments of this aspect of the invention, the anti-N3pGlu Aβ antibody is administered to the human subject regardless of brain tau levels. Some aspects of the present disclosure relate to methods of treating or preventing a disease characterized by Aβ plaques in the brain of a human subject, comprising administering to the subject an anti-N3pGlu Aβ antibody to reduce Aβ plaques in the brain.

[0038] In some embodiments, such treatment results in a reduction or reduction of amyloid deposits, amyloid beta plaques, or Aβ load in the brain of patients with a disease characterized by Aβ plaques. In some embodiments, such treatment results in a reduction or reduction of tau levels in the brain of patients with a disease characterized by Aβ plaques. In some embodiments, such treatment results in a reduction or reduction of plasma tau levels in patients with a disease characterized by Aβ plaques. In some embodiments, the anti-N3pGlu Aβ antibodies of the present disclosure slow the accumulation of tau pathophysiology as measured by brain tau PET and / or plasma p-tau.

[0039] In some embodiments, such treatment results in a decrease or reduction in neurofilament light chain (NfL) levels in the brain of patients with a disease characterized by Aβ plaques. In some embodiments, such treatment results in a decrease or reduction in Aβ levels in the plasma or cerebrospinal fluid (CSF) of patients with a disease characterized by Aβ plaques. 42 / 40 In some embodiments, such treatment results in a decrease or reduction in glial fibrillary acidic protein (GFAP) levels in the blood of patients with a disease characterized by Aβ plaques. In some embodiments, such treatment results in a decrease or reduction in P-tau217 levels in patients with a disease characterized by Aβ plaques.

[0040] Another aspect of the present disclosure relates to an anti-N3pGlu Aβ antibody for use in treating or preventing a disease characterized by Aβ plaques in the brain of a human subject, wherein the anti-N3pGlu Aβ antibody is for administration in one or more first doses of about 100 mg to about 700 mg, where each first dose is administered approximately once every four weeks, followed by one or more second doses of greater than 700 mg to about 1400 mg, four weeks after administration of the one or more first doses, where each second dose is administered approximately once every four weeks, wherein the anti-N3pGlu Aβ antibody comprises an LCVR and an HCVR, where the LCVR comprises the amino acid sequence of SEQ ID NO: 1 and the HCVR comprises the amino acid sequence of SEQ ID NO: 2.

[0041] One aspect of the present disclosure relates to a method of reducing amyloid beta plaques in the brain of a human Alzheimer's disease (AD) subject, comprising administering to the subject three 700 mg first doses of an anti-N3pG Aβ antibody, each first dose administered once every four weeks; and four weeks after administration of the three first doses, administering to the subject one or more 1400 mg second doses of an anti-N3pG Aβ antibody once every four weeks, wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: 1 and the HCVR consists of the amino acid sequence of SEQ ID NO: 2.

[0042] Another aspect of the present disclosure relates to an anti-N3pGlu Aβ antibody for use in treating or preventing a disease characterized by Aβ plaques in the brain of a human subject, wherein one or more first doses of the antibody of about 100 mg to about 700 mg are administered, each first dose being administered about once every four weeks, followed by one or more second doses of greater than 700 mg to about 1400 mg, four weeks after administration of the one or more first doses, each second dose being administered about once every four weeks, wherein the anti-N3pGlu Aβ antibody comprises an LCVR and an HCVR, wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 1 and the HCVR comprises the amino acid sequence of SEQ ID NO: 2.

[0043] Another aspect of the present disclosure relates to use of an anti-N3pGlu Aβ antibody in the manufacture of a medicament for treating or preventing a disease characterized by Aβ plaques in the brain of a human subject, wherein one or more first doses of the antibody of about 100 mg to about 700 mg are administered, each first dose being administered about once every four weeks, followed by one or more second doses of greater than 700 mg to about 1400 mg, four weeks after administration of the one or more first doses, each second dose being administered about once every four weeks, wherein the anti-N3pGlu Aβ antibody comprises an LCVR and an HCVR, wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 1 and the HCVR comprises the amino acid sequence of SEQ ID NO: 2.

[0044] Another aspect of the present disclosure relates to a method of treating or preventing clinical or preclinical Alzheimer's disease, Down's syndrome, or clinical or preclinical CAA in a subject, comprising: i) administering to a human subject one or more first doses of about 100 mg to about 700 mg of an anti-N3pGlu Aβ antibody, wherein each first dose is administered about once every four weeks; and ii) about four weeks after administering the one or more first doses, administering to the human subject one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pGlu Aβ antibody, wherein each second dose is administered about once every four weeks; wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 1 and the HCVR comprises the amino acid sequence of SEQ ID NO: 2.

[0045] Another aspect of the present disclosure is a method of treating or preventing preclinical AD (cognitively intact subjects with evidence of AD pathology), prodromal AD (sometimes referred to as Aβ-related mild cognitive impairment, MCI, or MCI due to AD), mild AD, moderate AD, and severe AD, comprising: i) administering to a human subject one or more first doses of about 100 mg to about 700 mg of an anti-N3pGlu Aβ antibody, wherein each first dose is administered about once every four weeks; and ii) about four weeks after administering the one or more first doses, administering to the human subject one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pGlu Aβ antibody, wherein each second dose is administered about once every four weeks. The method relates to an Aβ antibody comprising a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 1 and the HCVR comprises the amino acid sequence of SEQ ID NO: 2.

[0046] Another aspect of the present disclosure relates to a method of slowing cognitive or functional decline in a patient having a disease characterized by Aβ plaques, comprising: i) administering to a human subject one or more first doses of about 100 mg to about 700 mg of an anti-N3pGlu Aβ antibody, wherein each first dose is administered about once every four weeks; and ii) about four weeks after administering the one or more first doses, administering to the human subject one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pGlu Aβ antibody, wherein each second dose is administered about once every four weeks; wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 1 and the HCVR comprises the amino acid sequence of SEQ ID NO: 2.

[0047] Another aspect of the present disclosure relates to a method of reducing Aβ plaques or Aβ load in a patient having a disease characterized by Aβ plaques, comprising: i) administering to a human subject one or more first doses of about 100 mg to about 700 mg of an anti-N3pGlu Aβ antibody, wherein each first dose is administered about once every four weeks; and ii) about four weeks after administering the one or more first doses, administering to the human subject one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pGlu Aβ antibody, wherein each second dose is administered about once every four weeks; wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 1 and the HCVR comprises the amino acid sequence of SEQ ID NO: 2.

[0048] Another aspect of the present disclosure relates to a method of slowing functional decline in a patient having a disease characterized by Aβ plaques, comprising: i) administering to a human subject one or more first doses of about 100 mg to about 700 mg of an anti-N3pGlu Aβ antibody, wherein each first dose is administered about once every four weeks; and ii) about four weeks after administering the one or more first doses, administering to the human subject one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pGlu Aβ antibody, wherein each second dose is administered about once every four weeks; wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 1 and the HCVR comprises the amino acid sequence of SEQ ID NO: 2.

[0049] Another aspect of the present disclosure relates to a method of preventing memory loss, cognitive decline, or functional decline in a patient having a disease characterized by Aβ plaques, comprising: i) administering to a human subject one or more first doses of about 100 mg to about 700 mg of an anti-N3pGlu Aβ antibody, wherein each first dose is administered about once every four weeks; and ii) about four weeks after administering the one or more first doses, administering to the human subject one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pGlu Aβ antibody, wherein each second dose is administered about once every four weeks; wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 1 and the HCVR comprises the amino acid sequence of SEQ ID NO: 2.

[0050] Another aspect of the present disclosure relates to a method of slowing disease progression in a human Alzheimer's disease subject, comprising administering to the subject an anti-N3pGlu Aβ antibody, slowing disease progression by at least 15% as measured by the integrated Alzheimer's Disease Rating Scale (iADRS), wherein the administering comprises: i) administering to the subject three 700 mg first doses of the anti-N3pGlu Aβ antibody, wherein each first dose is administered once every four weeks; and ii) four weeks after administration of the three first doses, administering one or more 1400 mg second doses of the anti-N3pGlu Aβ antibody once every four weeks, wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: 1 and the HCVR consists of the amino acid sequence of SEQ ID NO: 2.

[0051] Another aspect of the present disclosure relates to a method of slowing disease progression in a human Alzheimer's disease subject, comprising administering to the subject an anti-N3pGlu Aβ antibody, slowing disease progression by at least 20% as measured by Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB), wherein the administering comprises: i) administering to the subject three 700 mg first doses of the anti-N3pGlu Aβ antibody, wherein each first dose is administered once every four weeks; and ii) four weeks after administration of the three first doses, administering one or more 1400 mg second doses of the anti-N3pGlu Aβ antibody once every four weeks, wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: 1 and the HCVR consists of the amino acid sequence of SEQ ID NO: 2.

[0052] Another aspect of the present disclosure relates to methods of i) reducing or preventing brain amyloid beta accumulation, ii) reducing or preventing tau accumulation, iii) preventing or delaying the onset of memory loss, iv) preventing or delaying cognitive decline, v) preventing or delaying functional decline, or vi) preventing or delaying the onset of the symptomatic stage of AD in clinically asymptomatic subjects or cognitively intact subjects with evidence of AD pathology. The method comprises: i) administering to the human subject one or more first doses of about 100 mg to about 700 mg of an anti-N3pGlu Aβ antibody, wherein each first dose is administered about once every four weeks; and ii) about four weeks after administering the one or more first doses, administering to the human subject one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pGlu Aβ antibody, wherein each second dose is administered about once every four weeks; wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 1 and the HCVR comprises the amino acid sequence of SEQ ID NO: 2. In some embodiments, three first doses of about 100 mg to about 700 mg of an anti-N3pGlu Aβ antibody are administered to the patient every four weeks, and about four weeks after the one or more first doses, six doses of greater than 700 mg to about 1400 mg of an anti-N3pGlu Aβ antibody are administered to the patient every four weeks. In some embodiments, three first doses of about 700 mg of an anti-N3pGlu Aβ antibody are administered to the patient every four weeks, and about four weeks after the one or more first doses, six doses of about 1400 mg of an anti-N3pGlu Aβ antibody are administered to the patient every four weeks. In some embodiments, the subject has evidence of AD pathology and is cognitively intact. In some embodiments, the subject has evidence of AD pathology and is clinically asymptomatic.

[0053] Some aspects of the present disclosure relate to a method of treating or preventing a disease characterized by Aβ plaques in the brain of a clinically asymptomatic human subject, comprising: i) administering to the human subject one or more first doses of about 100 mg to about 700 mg of an anti-N3pGlu Aβ antibody, wherein each first dose is administered about once every four weeks; and ii) about four weeks after administering the one or more first doses, administering to the human subject one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pGlu Aβ antibody, wherein each second dose is administered about once every four weeks, wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 1 and the HCVR comprises the amino acid sequence of SEQ ID NO: 2. In some embodiments, three first doses of about 100 mg to about 700 mg of an anti-N3pGlu Aβ antibody are administered to the patient every four weeks, and about four weeks after the one or more first doses, six doses of greater than 700 mg to about 1400 mg of an anti-N3pGlu Aβ antibody are administered to the patient every four weeks. In some embodiments, three first doses of about 700 mg of an anti-N3pGlu Aβ antibody are administered to the patient every four weeks, and about four weeks after the one or more first doses, six doses of about 1400 mg of an anti-N3pGlu Aβ antibody are administered to the patient every four weeks.

[0054] In some embodiments, the clinically asymptomatic subject is known to have an Alzheimer's disease-causing genetic mutation. In the present disclosure, a "clinically asymptomatic subject known to have an Alzheimer's disease-causing genetic mutation" includes patients known to have the PSEN1 E280A Alzheimer's disease-causing genetic mutation (Paisa mutation), an autosomal dominant Alzheimer's disease-causing genetic mutation, or who are at high risk for developing AD due to carrying one or two APOE4 alleles.

[0055] Another aspect of the present disclosure relates to a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject determined to have very low to moderate tau burden, or low to moderate tau burden, comprising: i) administering to the human subject one or more first doses of about 100 mg to about 700 mg of an anti-N3pGlu Aβ antibody, wherein each first dose is administered about once every four weeks; and ii) four weeks after administering the one or more first doses, administering to the human subject one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pGlu Aβ antibody, wherein each second dose is administered about once every four weeks; wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 1 and the HCVR comprises the amino acid sequence of SEQ ID NO: 2.

[0056] Another aspect of the present disclosure is a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject who has one or two alleles of APOE4 and who has been determined to have very low to moderate tau burden or low or moderate tau burden, comprising: i) administering to the human subject one or more first doses of about 100 mg to about 700 mg of an anti-N3pGlu Aβ antibody, wherein each first dose is administered about once every four weeks; and ii) four weeks after administering the one or more first doses, administering to the human subject one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pGlu Aβ antibody, wherein each second dose is administered about once every four weeks. The method relates to an Aβ antibody comprising a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 1 and the HCVR comprises the amino acid sequence of SEQ ID NO: 2.

[0057] Another aspect of the present disclosure is a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject, comprising: determining whether the human subject has a low to moderate tau load or a very low to moderate tau load; and if the human subject has a very low to moderate tau load or a very low to moderate tau load, then i) administering to the human subject one or more first doses of about 100 mg to about 700 mg of an anti-N3pGlu Aβ antibody, wherein each first dose is administered about once every four weeks; and ii) four weeks after administering the one or more first doses, administering to the human subject one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pGlu Aβ antibody, wherein each second dose is administered about once every four weeks. The method relates to an Aβ antibody comprising a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 1 and the HCVR comprises the amino acid sequence of SEQ ID NO: 2.

[0058] Another aspect of the present disclosure is a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject, comprising: determining whether the human subject has a very low to moderate tau load or a low to moderate tau load and one or two alleles of APOE4; and if the human subject has a very low to moderate tau load or a very low to moderate tau load and one or two alleles of APOE4, then i) administering to the human subject one or more first doses of about 100 mg to about 700 mg of an anti-N3pGlu Aβ antibody, wherein each first dose is administered about once every four weeks; and ii) four weeks after administering the one or more first doses, administering to the human subject one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pGlu Aβ antibody, wherein each second dose is administered about once every four weeks. The method relates to an Aβ antibody comprising a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 1 and the HCVR comprises the amino acid sequence of SEQ ID NO: 2.

[0059] Another aspect of the present invention relates to a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject who has been determined to not have high tau burden, comprising: i) administering to the human subject one or more first doses of about 100 mg to about 700 mg of an anti-N3pGlu Aβ antibody, wherein each first dose is administered about once every four weeks; and ii) four weeks after administering the one or more first doses, administering to the human subject one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pGlu Aβ antibody, wherein each second dose is administered about once every four weeks; wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 1 and the HCVR comprises the amino acid sequence of SEQ ID NO: 2.

[0060] Another aspect of the present invention relates to a method of treating or preventing a disease characterized by high tau burden and amyloid beta plaques in the brain of a human subject who has been determined to not have one or two alleles of APOE4, comprising: i) administering to the human subject one or more first doses of about 100 mg to about 700 mg of an anti-N3pGlu Aβ antibody, wherein each first dose is administered about once every four weeks; and ii) four weeks after administering the one or more first doses, administering to the human subject one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pGlu Aβ antibody, wherein each second dose is administered about once every four weeks; wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 1 and the HCVR comprises the amino acid sequence of SEQ ID NO: 2.

[0061] Another aspect of the present invention relates to a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject, comprising determining whether the human subject has high tau burden, and if the human subject does not have high tau burden, then i) administering to the human subject one or more first doses of about 100 mg to about 700 mg of an anti-N3pGlu Aβ antibody, wherein each first dose is administered about once every four weeks; and ii) four weeks after administering the one or more first doses, administering to the human subject one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pGlu Aβ antibody, wherein each second dose is administered about once every four weeks; wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 1 and the HCVR comprises the amino acid sequence of SEQ ID NO: 2.

[0062] Another aspect of the invention is a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject, comprising: determining whether the human subject has a high tau burden and one or two alleles of APOE4; and if the human subject has one or two alleles of APOE4 and does not have a high tau burden, then i) administering to the human subject one or more first doses of about 100 mg to about 700 mg of an anti-N3pGlu Aβ antibody, wherein each first dose is administered about once every four weeks; and ii) four weeks after administering the one or more first doses, administering to the human subject one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pGlu Aβ antibody, wherein each second dose is administered about once every four weeks. The method relates to an Aβ antibody comprising a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 1 and the HCVR comprises the amino acid sequence of SEQ ID NO: 2.

[0063] Another aspect of the present disclosure relates to a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject, the method comprising administering to the human subject an effective amount of an anti-N3pGlu Aβ antibody, wherein the human subject has been determined to have very low to moderate tau burden or low to moderate tau burden.

[0064] Another aspect of the present disclosure relates to a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject, comprising administering to the human subject an effective amount of an anti-N3pGlu Aβ antibody, wherein the human subject has been determined to have very low to moderate tau burden or low to moderate tau burden and one or two alleles of APOE4.

[0065] Another aspect of the present disclosure relates to a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject, comprising determining whether the human subject has a low to moderate tau load or a very low to moderate tau load, and if the human subject has a low to moderate tau load or a very low to moderate tau load, then administering to the human subject an effective amount of an anti-N3pGlu Aβ antibody.

[0066] Another aspect of the present disclosure relates to a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject, comprising determining whether the human subject has one or two alleles of APOE4 and a low to moderate tau burden or a very low to moderate tau burden, and if the human subject has one or two alleles of APOE4 and a low to moderate tau burden or a very low to moderate tau burden, then administering to the human subject an effective amount of an anti-N3pGlu Aβ antibody.

[0067] Another aspect of the present disclosure relates to a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject, comprising administering to the human subject an effective amount of an anti-N3pGlu Aβ antibody, wherein the human subject has been determined to not have a high tau burden.

[0068] Another aspect of the present disclosure relates to a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject, comprising administering to the human subject an effective amount of an anti-N3pGlu Aβ antibody, wherein the human subject has been determined to have one or two alleles of APOE4 and does not have a high tau burden.

[0069] Another aspect of the present disclosure relates to a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject, the method comprising determining whether the human subject has high tau burden, and if the human subject does not have high tau burden, then administering to the human subject an effective amount of an anti-N3pGlu Aβ antibody.

[0070] Another aspect of the present disclosure relates to a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject, comprising determining whether the human subject has one or two alleles of APOE4 and a high tau burden, and if the human subject has one or two alleles of APOE4 and does not have a high tau burden, then administering to the human subject an effective amount of an anti-N3pGlu Aβ antibody.

[0071] In some aspects, anti-N3pGlu Aβ antibodies may be used to reduce, prevent further increases in, or slow the rate of tau accumulation in different parts of the human brain, e.g., different lobes of a human subject's brain. In some embodiments, anti-N3pGlu Aβ antibodies are used to reduce, prevent further increases in, or slow the rate of tau burden / accumulation in the frontal lobe of a human brain. In some embodiments, tau accumulation in the frontal lobe is slowed by at least 30-70% compared to an untreated subject. In some embodiments, tau accumulation in the frontal lobe is slowed by at least 50% compared to an untreated subject. In some embodiments, the subject has a negative tau PET imaging scan in the frontal lobe brain region prior to administration of the anti-N3pGlu Aβ antibody. In some embodiments, the subject has a brain tau level in the frontal lobe region of less than 0.4 SUVr 76 weeks after administration of the anti-N3pGlu Aβ antibody, where the brain tau level is measured by a tau PET imaging scan.

[0072] In some embodiments, anti-N3pGlu Aβ antibodies are used to reduce the rate, prevent further increase, or slow down tau burden / accumulation in the parietal lobe of a human brain. In some embodiments, the subject has an increase in tau levels in the parietal lobe of less than 0.06 SUVr after 76 weeks of administration of the anti-N3pGlu Aβ antibody, where the brain tau levels are measured by a tau PET imaging scan.

[0073] In some embodiments, an anti-N3pGlu Aβ antibody is used to reduce, prevent further increase, or slow the rate of tau burden / accumulation in the occipital lobe of a human brain. In some embodiments, an anti-N3pGlu Aβ antibody is used to reduce, prevent further increase, or slow the rate of tau burden / accumulation in the temporal lobe of a human brain. In some embodiments, an anti-N3pGlu Aβ antibody is used to reduce, prevent further increase, or slow the rate of tau burden / accumulation in the posterolateral temporal lobe. In some embodiments, a human subject is administered i) one or more first doses of an anti-N3pG Aβ antibody of about 100 mg to about 700 mg, each first dose administered about once every four weeks; and ii) about four weeks after administering the one or more first doses, the human subject is administered one or more second doses of an anti-N3pG Aβ antibody of greater than 700 mg to about 1400 mg, each second dose administered about once every four weeks. In some embodiments, the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO:1 and the HCVR comprises the amino acid sequence of SEQ ID NO:2.

[0074] One aspect of the present disclosure relates to a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject who has been determined to have tau burden in the temporal lobe of the brain and / or one or two alleles of APOE4, the method comprising administering an anti-N3pGlu Aβ to the human subject. Another aspect of the present disclosure relates to a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject, the method comprising determining whether the human subject has tau burden in the temporal lobe of the brain and / or one or two alleles of APOE4, and administering an anti-N3pGlu Aβ to the human subject. In some embodiments, the human subject has tau burden in the posterior lateral temporal lobe and / or one or two alleles of APOE4. In some embodiments, the human subject is administered: i) one or more first doses of about 100 mg to about 700 mg of an anti-N3pG Aβ antibody, each first dose administered about once every four weeks; and ii) about four weeks after administering the one or more first doses, the human subject is administered one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pG Aβ antibody, each second dose administered about once every four weeks. In some embodiments, the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 1 and the HCVR comprises the amino acid sequence of SEQ ID NO: 2.

[0075] Another aspect of the present disclosure relates to a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject who has been determined to have tau burden in the occipital lobe of the brain and / or one or two alleles of APOE4, comprising administering an anti-N3pGlu Aβ to the human subject.Another aspect of the present disclosure relates to a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject, comprising determining whether the human subject has tau burden in the occipital lobe of the brain and / or one or two alleles of APOE4, and administering an anti-N3pGlu Aβ to the human subject. In some embodiments, the human subject is administered: i) one or more first doses of about 100 mg to about 700 mg of an anti-N3pG Aβ antibody, each first dose administered about once every four weeks; and ii) about four weeks after administering the one or more first doses, the human subject is administered one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pG Aβ antibody, each second dose administered about once every four weeks. In some embodiments, the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 1 and the HCVR comprises the amino acid sequence of SEQ ID NO: 2.

[0076] Another aspect of the present disclosure relates to a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject who has been determined to have tau burden in the parietal lobe of the brain and / or one or two alleles of APOE4, comprising administering an anti-N3pGlu Aβ to the human subject.Another aspect of the present disclosure relates to a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject, comprising determining whether the human subject has tau burden in the parietal lobe of the brain and / or one or two alleles of APOE4, and administering an anti-N3pGlu Aβ to the human subject. In some embodiments, the human subject is administered: i) one or more first doses of about 100 mg to about 700 mg of an anti-N3pG Aβ antibody, each first dose administered about once every four weeks; and ii) about four weeks after administering the one or more first doses, the human subject is administered one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pG Aβ antibody, each second dose administered about once every four weeks. In some embodiments, the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 1 and the HCVR comprises the amino acid sequence of SEQ ID NO: 2.

[0077] Another aspect of the present disclosure relates to a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject who has been determined to have tau burden in the frontal lobe of the brain and / or one or two alleles of APOE4, comprising administering an anti-N3pGlu Aβ to the human subject.Another aspect of the present disclosure relates to a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject, comprising determining whether the human subject has tau burden in the frontal lobe of the brain and / or one or two alleles of APOE4, and administering an anti-N3pGlu Aβ to the human subject. In some embodiments, the human subject is administered: i) one or more first doses of about 100 mg to about 700 mg of an anti-N3pG Aβ antibody, each first dose administered about once every four weeks; and ii) about four weeks after administering the one or more first doses, the human subject is administered one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pG Aβ antibody, each second dose administered about once every four weeks. In some embodiments, the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 1 and the HCVR comprises the amino acid sequence of SEQ ID NO: 2.

[0078] Another aspect of the present disclosure relates to a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject who has been determined to have tau burden in the posterolateral temporal (PLT) and / or occipital lobes of the brain and / or one or two alleles of APOE4, comprising administering an anti-N3pGlu Aβ to the human subject.Another aspect of the present disclosure relates to a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject, comprising determining whether the human subject has tau burden in the posterolateral temporal (PLT) and / or occipital lobes of the brain and / or one or two alleles of APOE4, and administering an anti-N3pGlu Aβ to the human subject. In some embodiments, the human subject is administered: i) one or more first doses of about 100 mg to about 700 mg of an anti-N3pG Aβ antibody, each first dose administered about once every four weeks; and ii) about four weeks after administering the one or more first doses, the human subject is administered one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pG Aβ antibody, each second dose administered about once every four weeks. In some embodiments, the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 1 and the HCVR comprises the amino acid sequence of SEQ ID NO: 2.

[0079] Another aspect of the present disclosure relates to a method for treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject who has been determined to have i) tau load in the parietal or precuneus regions, or ii) frontal regions, along with tau load in the PLT or occipital regions of the brain, and / or iii) one or two alleles of APOE4, comprising administering an anti-N3pGlu Aβ to the human subject.Another aspect of the present disclosure relates to a method for treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject, comprising determining whether the human subject has i) tau load in the parietal or precuneus regions, or ii) frontal regions, along with tau load in the PLT or occipital regions of the brain, and / or iii) one or two alleles of APOE4, and administering an anti-N3pGlu Aβ to the human subject. In some embodiments, the human subject is administered: i) one or more first doses of about 100 mg to about 700 mg of an anti-N3pG Aβ antibody, each first dose administered about once every four weeks; and ii) about four weeks after administering the one or more first doses, the human subject is administered one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pG Aβ antibody, each second dose administered about once every four weeks. In some embodiments, the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 1 and the HCVR comprises the amino acid sequence of SEQ ID NO: 2.

[0080] Another aspect of the present disclosure relates to a method for treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject who has been determined to have i) tau burden isolated to the frontal lobe, or ii) a region of the temporal lobe that does not include the posterolateral temporal region (PLT) of the brain, and / or iii) one or two alleles of APOE4, comprising administering an anti-N3pGlu Aβ to the human subject.Another aspect of the present disclosure relates to a method for treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject, comprising determining whether the human subject has i) tau burden isolated to the frontal lobe, or ii) a region of the temporal lobe that does not include the posterolateral temporal region (PLT) of the brain, and / or iii) one or two alleles of APOE4, and administering an anti-N3pGlu Aβ to the human subject. In some embodiments, the human subject is administered: i) one or more first doses of about 100 mg to about 700 mg of an anti-N3pG Aβ antibody, each first dose administered about once every four weeks; and ii) about four weeks after administering the one or more first doses, the human subject is administered one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pG Aβ antibody, each second dose administered about once every four weeks. In some embodiments, the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 1 and the HCVR comprises the amino acid sequence of SEQ ID NO: 2.

[0081] In some aspects, the present disclosure relates to methods for selecting a human subject for treatment or prevention of a disease characterized by amyloid beta plaques in the human subject's brain. In some embodiments, the human subject is selected based on the amount of global tau in the human subject's brain. For example, a human subject is selected for treatment or prevention of a disease characterized by amyloid beta plaques in the brain because the patient has very low to moderate tau in the brain and / or one or two alleles of APOE4. In another embodiment, a human subject is selected for treatment or prevention of a disease characterized by amyloid beta plaques in the brain because the patient has low to moderate tau (or intermediate tau) in the brain and / or one or two alleles of APOE4. In another embodiment, a human subject is excluded from treatment or prevention of a disease characterized by amyloid beta plaques in the brain because the patient has high tau in the brain. In some embodiments, the human subject is selected based on the progression of AD in the human subject's brain. For example, a human subject is selected for the treatment or prevention of a disease characterized by amyloid beta plaques in the brain because the patient has a tau load present in the frontal lobe of the brain and / or one or two alleles of APOE4. In another embodiment, a human subject is selected for the treatment or prevention of a disease characterized by amyloid beta plaques in the brain because the patient has a tau load present in the parietal lobe of the brain and / or one or two alleles of APOE4. In another embodiment, a human subject is selected for the treatment or prevention of a disease characterized by amyloid beta plaques in the brain because the patient has a tau load present in the occipital lobe of the brain and / or one or two alleles of APOE4. In another embodiment, a human subject is selected for the treatment or prevention of a disease characterized by amyloid beta plaques in the brain because the patient has a tau load present in the temporal lobe of the brain and / or one or two alleles of APOE4.In some embodiments, a human subject is selected for the treatment or prevention of a disease characterized by amyloid beta plaques in the brain because the patient has tau burden present in the posterolateral temporal (PLT) and / or occipital lobes of the brain and / or one or two alleles of APOE4. In some embodiments, a human subject is selected for the treatment or prevention of a disease characterized by amyloid beta plaques in the brain because the patient has tau burden in the PLT or occipital regions of the brain, as well as i) tau burden in the parietal or precuneus region, or ii) frontal region, and / or iii) one or two alleles of APOE4. In some embodiments, a human subject is selected for the treatment or prevention of a disease characterized by amyloid beta plaques in the brain because the patient has tau burden in i) the frontal lobe, ii) a region of the temporal lobe that does not include the posterolateral temporal region (PLT), and / or iii) one or two alleles of APOE4. In some embodiments, the human subject is administered: i) one or more first doses of about 100 mg to about 700 mg of an anti-N3pG Aβ antibody, each first dose administered about once every four weeks; and ii) about four weeks after administering the one or more first doses, the human subject is administered one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pG Aβ antibody, each second dose administered about once every four weeks. In some embodiments, the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 1 and the HCVR comprises the amino acid sequence of SEQ ID NO: 2.

[0082] In some embodiments, the subject described in various aspects of the present disclosure is determined to have a posterior lateral temporal lobe tau burden and / or one or two alleles of APOE4. In some embodiments, the subject described in various aspects of the present disclosure is determined to have a posterior lateral temporal lobe and occipital lobe tau burden and / or one or two alleles of APOE4. In some embodiments, the subject described in various aspects of the present disclosure is determined to have a posterior lateral temporal lobe, occipital lobe, and parietal lobe tau burden and / or one or two alleles of APOE4. In some embodiments, the subject described in various aspects of the present disclosure is determined to have a lateral temporal lobe, occipital lobe, parietal lobe, and frontal lobe tau burden and / or one or two alleles of APOE4. In some embodiments, the subject described in various aspects of the present disclosure is determined to have a posterior lateral temporal lobe, occipital lobe, parietal lobe, and / or frontal lobe tau burden and / or one or two alleles of APOE4. In some embodiments, a subject described in various aspects of the present disclosure has been determined to have a posterolateral temporal, occipital, parietal, and / or frontal lobe tau burden equivalent to a neurological tau load of greater than 1.46 SUVr based on PET imaging. In some embodiments, an anti-N3pGlu Aβ antibody of the present disclosure limits the increase in frontal lobe tau in the subject over 72 weeks to less than 0.04 SUVr as measured by tau PET imaging.

[0083] In some embodiments, tau burden in a human brain or a portion thereof (e.g., a lobe of the brain or the entire brain) can be used to determine whether administration of an anti-N3pGlu Aβ antibody should be discontinued. For example, a slowing of the rate of tau clearance in the brain, a cessation of reduction in tau levels, prevention of a further increase in tau levels, or a slowing of the rate of tau accumulation can be used as an indicator to determine the duration of administration of an anti-N3pGlu Aβ antibody. In some embodiments, an anti-N3pGlu Aβ antibody is administered to a subject until a slowing of the rate of tau clearance, a cessation of reduction in tau levels, prevention of a further increase in tau levels, or a slowing of the rate of tau accumulation occurs in the temporal, occipital, parietal, or frontal lobe.

[0084] In some embodiments, the amyloid beta burden in a human brain can be used to determine whether administration of an anti-N3pGlu Aβ antibody should be discontinued. For example, a slowing of the rate of Aβ clearance, a cessation of Aβ level reduction, prevention of further increases in Aβ levels, or a slowing of the rate of Aβ accumulation in the brain can be used as an indicator for determining the duration of administration of an anti-N3pGlu Aβ antibody. In some embodiments, administration of an anti-N3pGlu Aβ antibody of the present disclosure is discontinued when Aβ plaques in the subject's brain reach normal levels by 24 weeks or when Aβ plaque levels in the subject's brain stop decreasing. In some embodiments, the level of Aβ plaques in the subject's brain is maintained at a normal level for at least 52 weeks after administration of the anti-N3pGlu Aβ antibody is discontinued. In some embodiments, administration of the anti-N3pGlu Aβ antibody reduces the level of Aβ plaques in the subject's brain to a normal level by 24 weeks. In some embodiments, the level of Aβ plaques in the subject's brain is maintained at a normal level for at least another 52 weeks.

[0085] In some embodiments, the tau burden present in a portion of a human subject's brain can be used to select an optimal treatment regimen or to administer a therapy in combination with an anti-N3pGlu Aβ antibody. For example, the presence of tau burden in the frontal lobe of the brain of an amyloid-positive human subject can be used as an indicator to determine whether the human subject will benefit from administration of an anti-N3pGlu Aβ antibody alone or in combination with an anti-tau antibody. In some embodiments, an anti-N3pGlu Aβ antibody in combination with an anti-tau antibody can be used to reduce, prevent an increase in, or slow the rate of tau accumulation in different portions of the human brain, e.g., different lobes of the human subject's brain. In some embodiments, the tau burden in different portions of the human brain, e.g., different lobes of the human subject's brain, can be used i) to track a patient's response to treatment or ii) when therapy needs to be restarted. In some embodiments, the antibodies, methods, or dosing regimens described in various aspects of the present disclosure cause i) a reduction in Aβ plaques in the human subject's brain and / or ii) a slowing of cognitive or functional decline in the human subject. In some embodiments, the antibodies, methods, or dosing regimens described herein result in a reduction of amyloid plaques.

[0086] Anti-N3pGlu Aβ antibodies described in various aspects of the present disclosure include, ii) can be substituted for, or iii) are used in conjunction with anti-N3pGlu Aβ antibodies such as: an anti-N3pGlu Aβ antibody comprising a light chain complementarity determining region 1 (LCDR1) having the amino acid sequence of SEQ ID NO: 5, a light chain complementarity determining region 2 (LCDR2) having the amino acid sequence of SEQ ID NO: 6, and a light chain complementarity determining region 3 (LCDR3) having the amino acid sequence of SEQ ID NO: 7, or an amino acid sequence having at least 95% identity to light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 5, an amino acid sequence having at least 95% identity to light chain complementarity determining region 2 (LCDR2) of SEQ ID NO: 6, and an amino acid sequence having at least 95% identity to light chain complementarity determining region 3 (LCDR3) of SEQ ID NO: 7; an anti-N3pGlu Aβ antibody comprising a heavy chain complementarity determining region 1 (HCDR1) having the amino acid sequence of SEQ ID NO: 8, a heavy chain complementarity determining region 2 (HCDR2) having the amino acid sequence of SEQ ID NO: 9, and a heavy chain complementarity determining region 3 (HCDR3) having the amino acid sequence of SEQ ID NO: 10, or an amino acid sequence having at least 95% identity to heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 8, an amino acid sequence having at least 95% identity to heavy chain complementarity determining region 2 (HCDR2) of SEQ ID NO: 9, and an amino acid sequence having at least 95% identity to heavy chain complementarity determining region 3 (HCDR3) of SEQ ID NO: 10; a light chain complementarity determining region 1 (LCDR1) having the amino acid sequence of SEQ ID NO: 5, a light chain complementarity determining region 2 (LCDR2) having the amino acid sequence of SEQ ID NO: 6, a light chain complementarity determining region 3 (LCDR3) having the amino acid sequence of SEQ ID NO: 7, a heavy chain complementarity determining region 1 (HCDR1) having the amino acid sequence of SEQ ID NO: 8, a heavy chain complementarity determining region 2 (HCDR2) having the amino acid sequence of SEQ ID NO: 9, and a heavy chain complementarity determining region 3 (HCDR3) having the amino acid sequence of SEQ ID NO: 10, or an amino acid sequence having at least 95% homology to light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 5 an anti-N3pGlu Aβ antibody comprising an amino acid sequence having at least 95% homology with light chain complementarity determining region 2 (LCDR2) of SEQ ID NO: 6, an amino acid sequence having at least 95% homology with light chain complementarity determining region 3 (LCDR3) of SEQ ID NO: 7, an amino acid sequence having at least 95% homology with heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 8, an amino acid sequence having at least 95% homology with heavy chain complementarity determining region 2 (HCDR2) of SEQ ID NO: 9, and an amino acid sequence having at least 95% homology with heavy chain complementarity determining region 3 (HCDR3) of SEQ ID NO: 10; LCVR and HCVR, wherein the LCVR comprises LCDR1, LCDR2 and LCDR3, and the HCVR comprises HCDR1, HCDR2 and HCDR3, selected from the group consisting of LCDR1 which is SEQ ID NO: 5, LCDR2 which is SEQ ID NO: 6, LCDR3 which is SEQ ID NO: 7, HCDR1 which is SEQ ID NO: 8, HCDR2 which is SEQ ID NO: 9, and HCDR3 which is SEQ ID NO: 10; or LCVR and HCVR, wherein the LCVR comprises LCDR1, LCDR2 and LCDR3, and H an anti-N3pGlu Aβ antibody, wherein the CVR comprises an LCVR and HCVR selected from the group consisting of an LCDR1 having at least 95% homology to SEQ ID NO: 5, an LCDR2 having at least 95% homology to SEQ ID NO: 6, an LCDR3 having at least 95% homology to SEQ ID NO: 7, an HCDR1 having at least 95% homology to SEQ ID NO: 8, an HCDR2 having at least 95% homology to SEQ ID NO: 9, and an HCDR3 having at least 95% homology to SEQ ID NO: 10. an N3pGlu Aβ antibody comprising a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 3 or an amino acid sequence having at least 95% homology to SEQ ID NO: 3; an N3pGlu Aβ antibody comprising a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 4 or an amino acid sequence having at least 95% homology to SEQ ID NO: 4; an anti-N3pGlu Aβ antibody comprising an LC and an HC, wherein the LC comprises the amino acid sequence of SEQ ID NO: 3 and the HC comprises the amino acid sequence of SEQ ID NO: 4, or the LC comprises an amino acid sequence having at least 95% identity with SEQ ID NO: 3 and the HC comprises an amino acid sequence having at least 95% identity with SEQ ID NO: 4; An anti-N3pGlu Aβ antibody comprising two light chains and two heavy chains, wherein the LC comprises the amino acid sequence of SEQ ID NO: 3 or an amino acid sequence having at least 95% homology to SEQ ID NO: 3, and the HC comprises the amino acid sequence of SEQ ID NO: 4 or an amino acid sequence having at least 95% homology to SEQ ID NO: 4. an N3pGlu Aβ antibody comprising an LCVR comprising the amino acid sequence of SEQ ID NO: 1, or an amino acid sequence having at least 95% homology to SEQ ID NO: 1; An N3pGlu Aβ antibody comprising an HCVR comprising the amino acid sequence of SEQ ID NO:2, or an amino acid sequence having at least 95% homology to SEQ ID NO:2. An N3pGlu Aβ antibody comprising an LCVR and an HCVR, wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 1 or an amino acid sequence having at least 95% homology to SEQ ID NO: 1, and the HCVR comprises the amino acid sequence of SEQ ID NO: 2 or an amino acid sequence having at least 95% homology to SEQ ID NO: 2.

[0087] In some embodiments, the anti-N3pGlu Aβ antibodies of the present disclosure include a kappa LC and an IgG HC. In certain embodiments, the anti-N3pGlu Aβ antibodies of the present disclosure are of the human IgG1 isotype.

[0088] In some embodiments, a human subject is administered one or more first doses of about 100 mg to about 700 mg of an anti-N3pGlu Aβ antibody described herein. In some embodiments, the one or more first doses are administered to the human subject such that each first dose is administered once every four weeks. In certain embodiments, the first dose is administered to the subject once. In some embodiments, the first dose is administered to the subject twice, with each first dose administered once every four weeks. In some embodiments, the first dose is administered to the subject three times, with each first dose administered once every four weeks.

[0089] In some embodiments, a subject is administered one first dose, two first doses, or three first doses of about 100 mg to about 700 mg, each first dose administered about once every four weeks. In certain embodiments, a human subject is administered three first doses of about 700 mg, each first dose administered about once every four weeks. In some embodiments, a human subject is administered one, two, or three first doses before administering the second dose.

[0090] In some embodiments, three first doses of about 700 mg are administered to a subject every four weeks for a period of 12 weeks, followed by a second dose of about 1400 mg. In some embodiments, one or more first doses of about 700 mg are administered to a subject every four weeks for a period of about three months, followed by a second dose of about 1400 mg.

[0091] In some embodiments, the first dose is about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, or about 700 mg. In some embodiments, the first dose is about 1 mg / kg to about 10 mg / kg of an anti-N3pGlu Aβ antibody. In certain embodiments, the subject is administered up to three first doses of about 1 mg / kg to about 10 mg / kg. In some embodiments, the subject is administered one first dose, two first doses, or three first doses of about 1 mg / kg to about 10 mg / kg. In one specific embodiment, the subject is administered three first doses of about 10 mg / kg, once every four weeks. In some embodiments, the first dose is about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg.

[0092] In certain embodiments, the first dose is administered once every four weeks or once a month. In one particular embodiment, the subject receives three first doses of about 10 mg / kg every four weeks. In some embodiments, the first dose of the anti-N3pGlu Aβ antibody is administered to the subject for about one month, about two months, or about three months.

[0093] In some embodiments, the subject is administered one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pGlu Aβ antibody. In some embodiments, the subject is administered one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pGlu Aβ antibody, each second dose being administered about once every four weeks. In some embodiments, the second dose is administered four weeks after the one or more first doses.

[0094] In certain embodiments, the subject is administered one or more second doses of greater than 700 mg. In some embodiments, the subject is administered one or more second doses of about 1400 mg. In some embodiments, the second dose is greater than 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, or about 1400 mg. In certain embodiments, the second dose is administered once every four weeks. In one particular embodiment, the subject is administered one or more second doses of greater than 700 mg once every four weeks. In one particular embodiment, the subject is administered one or more second doses of about 1400 mg once every four weeks.

[0095] Brain MRI scans may be performed on human subjects to monitor / evaluate the human subject (e.g., for ARIA-E or ARIA-H). In some embodiments, brain MRI scans may be performed on human subjects to diagnose / assess / monitor adverse events caused by administration of an anti-N3pGlu Aβ antibody. In some embodiments, a human subject undergoes brain MRI scans between administration of doses of an anti-N3pGlu Aβ antibody (e.g., once every four weeks). In some embodiments, a baseline brain MRI is obtained before initiating treatment with an anti-N3pGlu Aβ antibody. In some embodiments, a human subject undergoes a brain MRI scan before increasing the dose of an anti-N3pGlu Aβ antibody, for example, to 700 mg to 1400 mg. In some embodiments, a human subject undergoes a brain MRI scan after the first dose of an anti-N3pGlu Aβ antibody. In some embodiments, a human subject undergoes a brain MRI scan after three doses of an anti-N3pGlu Aβ antibody. In some embodiments, a human subject undergoes a brain MRI scan after the first four weeks of treatment. In some embodiments, the human subject undergoes a brain MRI scan after the first 12 weeks of treatment. In some embodiments, the human subject undergoes a brain MRI scan before administering a 1400 mg dose. In some embodiments, the brain MRI scan is performed before initiating administration of one or more 1400 mg second doses. In some embodiments, the human subject undergoes a brain MRI scan before administering a 20 mg / kg dose. In some embodiments, the human subject undergoes a brain MRI scan after the last 700 mg dose. In some embodiments, the human subject undergoes a brain MRI scan after the last 10 mg / kg dose. In some embodiments, the methods of the present disclosure include evaluating the subject's brain MRI scan for amyloid-related imaging abnormalities (ARIA) after administration of the three first doses and before administration of one or more second doses.

[0096] In some embodiments, the disclosure provides a method of treating Alzheimer's disease in a subject in need thereof, comprising: i) administering to the subject three 700 mg first doses of an anti-N3pGlu Aβ antibody, wherein each first dose is administered once every four weeks; ii) evaluating a magnetic resonance imaging (MRI) scan of the subject's brain for amyloid-related imaging abnormalities (ARIA) after administration of the three first doses and prior to administration of one or more second doses, wherein administration of the one or more second doses is temporarily withheld if symptoms consistent with ARIA occur; and iii) four weeks after administration of the three first doses, administering one or more 1400 mg second doses of an anti-N3pGlu Aβ antibody once every four weeks, wherein the anti-N3pGlu Aβ antibody The method relates to an Aβ antibody comprising a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: 1 and the HCVR consists of the amino acid sequence of SEQ ID NO: 2. In some embodiments, after resolution of ARIA symptoms or stabilization of MRI radiographs, administration of one or more second doses is resumed. In some embodiments, the one or more second doses are withheld and a corticosteroid is administered to the subject.

[0097] In some embodiments, the disclosure provides a method of treating Alzheimer's disease in a subject in need thereof, comprising: i) administering to the subject three 700 mg first doses of an anti-N3pGlu Aβ antibody, wherein each first dose is administered once every four weeks; ii) evaluating a magnetic resonance imaging (MRI) scan of the subject's brain for amyloid-related imaging abnormalities (ARIA) after administration of the three first doses and prior to administration of one or more second doses, wherein administration of the one or more second doses is discontinued if symptoms consistent with severe or symptomatic ARIA occur; and iii) four weeks after administration of the three first doses, administering one or more 1400 mg second doses of an anti-N3pGlu Aβ antibody once every four weeks, wherein the anti-N3pGlu Aβ antibody The method relates to an Aβ antibody comprising a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: 1 and the HCVR consists of the amino acid sequence of SEQ ID NO: 2. In some embodiments, administration of the one or more second doses is discontinued and a corticosteroid is administered to the subject.

[0098] In some embodiments, the present disclosure relates to a method of treating Alzheimer's disease in a subject in need thereof until symptoms consistent with ARIA-E occur, comprising: i) administering to the subject three 700 mg first doses of an anti-N3pGlu Aβ antibody, each first dose administered once every four weeks; and ii) four weeks after administration of the three first doses, administering one or more 1400 mg second doses of an anti-N3pGlu Aβ antibody once every four weeks, wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: 1 and the HCVR consists of the amino acid sequence of SEQ ID NO: 2. In some embodiments, symptoms of ARIA are detected by MRI or are present in the subject.

[0099] In some embodiments, the disclosure relates to a method for treating a patient with donanemab, wherein the patient has Alzheimer's disease, the method comprising: a) administering (or having been administered) 700 mg of donanemab every four weeks for the first three doses; b) determining whether the patient has symptoms of ARIA-E i) by performing or having performed an MRI before dose escalation, or ii) if clinical symptoms consistent with ARIA-E occur; c) if the patient has moderate symptoms of ARIA-E, temporarily discontinuing treatment with donanemab; and d) if the patient does not have symptomatic ARIA-E, administering donanemab to the patient in an amount of 1400 mg every four weeks until cerebral amyloid is cleared, negative, or <24.1 CL.

[0100] In some embodiments, the disclosure relates to a method for treating a patient with donanemab, wherein the patient has Alzheimer's disease, the method comprising: a) administering (or having been administered) 700 mg of donanemab every four weeks for the first three doses; and b) determining whether the patient has symptoms of ARIA-E i) by performing or having performed an MRI before dose escalation or ii) if clinical symptoms consistent with ARIA-E occur; and if the patient does not have symptomatic ARIA-E, administering donanemab to the patient in an amount of 1400 mg every four weeks until cerebral amyloid is cleared, becomes negative, or is <24.1 CL.

[0101] In some embodiments, the disclosure provides an improved method for treating a patient with donanemab for Alzheimer's disease, the improvement comprising: a) administering or having administered 700 mg of donanemab every four weeks for the first three doses; b) determining whether the patient has symptoms of ARIA-E by i) performing or having performed an MRI before dose escalation or ii) if clinical symptoms consistent with ARIA-E occur; c) temporarily discontinuing treatment with donanemab if the patient has moderate symptoms of ARIA-E; and d) if the patient does not have symptomatic ARIA-E, administering donanemab orally to the patient in an amount of 1400 mg every four weeks until cerebral amyloid is cleared, becomes negative, or is <24.1 CL.

[0102] In some embodiments, the disclosure provides an improved method for treating a patient with donanemab for a patient suffering from Alzheimer's disease, the improvement comprising: a) administering or having administered 700 mg of donanemab every four weeks for the first three doses; and b) determining whether the patient has symptoms of ARIA-E by i) performing or having an MRI performed before dose escalation or ii) if clinical symptoms consistent with ARIA-E occur; and if the patient does not have symptomatic ARIA-E, administering donanemab orally to the patient in an amount of 1400 mg every four weeks until cerebral amyloid is cleared, becomes negative, or is <24.1 CL.

[0103] In some embodiments, the disclosure relates to a method for treating a patient with donanemab, wherein the patient has Alzheimer's disease, the method comprising: a) administering or having been administered 700 mg of donanemab every four weeks for the first three doses; b) discontinuing treatment if the patient has moderate ARIA-E symptoms; and c) upon resolution of ARIA-E, continuing treatment by administering donanemab to the patient in an amount of 1400 mg every four weeks until cerebral amyloid is cleared, becomes negative, or is <24.1 CL, or ARIA-E symptoms recur. In some embodiments, the symptoms or ARIA-E are confirmed or determined by an MRI scan.

[0104] In some embodiments, the disclosure relates to a method for treating a patient with donanemab, wherein the patient has Alzheimer's disease, the method comprising: a) administering or having been administered 700 mg of donanemab every four weeks for the first three doses; and b) administering donanemab to the patient in an amount of 1400 mg every four weeks until cerebral amyloid is cleared, negative, or <24.1 CL, unless the patient has symptomatic ARIA-E. In some embodiments, the symptoms or ARIA-E are confirmed or determined by an MRI scan.

[0105] In some embodiments, a brain MRI of the patient is obtained before increasing the dose (e.g., from 700 mg to 1400 mg) or if symptoms consistent with ARIA-E occur. In some embodiments, treatment with an anti-N3pGlu Aβ antibody is withheld or discontinued due to or upon the occurrence of severe or symptomatic ARIA-E. In some embodiments, treatment with an anti-N3pGlu Aβ antibody may be temporarily interrupted if a patient experiences mild or moderate asymptomatic ARIA-E. In some embodiments, the dose of the anti-N3pGlu Aβ antibody may be temporarily reduced from 1400 mg to 700 mg if a patient experiences mild or moderate asymptomatic ARIA-E. In some embodiments, supportive care including corticosteroids may be administered to the patient upon the occurrence of ARIA-E. In some embodiments, treatment with an anti-N3pGlu Aβ antibody may be resumed after resolution of symptoms or stabilization of abnormal brain MRI radiographs.

[0106] If symptoms of ARIA-H occur, they are often indicative of ARIA-E and are managed similarly to ARIA-E. In some embodiments, a brain MRI of the patient is obtained before increasing the dose or if symptoms consistent with ARIA-H occur. In some embodiments, treatment with an anti-N3pGlu Aβ antibody is withheld or discontinued due to or upon the occurrence of ARIA-H. In some embodiments, treatment with an anti-N3pGlu Aβ antibody may be temporarily interrupted if a patient develops ARIA-H, e.g., if ARIA-H symptoms are mild or moderate. In some embodiments, if a patient develops mild or moderate asymptomatic ARIA-H, the dose of the anti-N3pGlu Aβ antibody may be temporarily reduced to 1400 mg to 700 mg. In some embodiments, if ARIA-H occurs, supportive care including corticosteroids may be administered to the patient. In some embodiments, treatment with an anti-N3pGlu Aβ antibody may be temporarily discontinued until symptoms of ARIA-E or ARIA-H improve.

[0107] In some embodiments, the subject is administered one or more second doses of greater than 10 mg / kg to about 20 mg / kg of an anti-N3pGlu Aβ antibody. In some embodiments, the second dose is greater than 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, or about 20 mg / kg. In one embodiment, the subject is administered one or more second doses of greater than 10 mg / kg. In one embodiment, the subject is administered one or more second doses of about 20 mg / kg. In certain embodiments, the first dose is administered monthly. In one embodiment, the subject is administered one or more second doses of greater than 10 mg / kg, each second dose being administered once every four weeks or once a month. In one embodiment, the subject receives one or more second doses of about 20 mg / kg, with each second dose administered once every four weeks or once a month.

[0108] In some embodiments, a first dose of an anti-N3pGlu Aβ antibody is administered to a subject once, followed by one or more second doses, where the second dose is administered four weeks after the one or more first doses and once every four weeks thereafter. In some embodiments, a first dose of an anti-N3pGlu Aβ antibody is administered to a subject twice (once every four weeks), followed by one or more second doses four weeks after the first dose and once every four weeks thereafter. In some embodiments, a first dose of an anti-N3pGlu Aβ antibody is administered to a subject three times (once every four weeks), followed by one or more second doses four weeks after the first dose and once every four weeks thereafter.

[0109] In some embodiments, the subject is treated with one or more first doses, one or more second doses of about 1400 mg, followed by one or more second doses of greater than 700 mg to about 1300 mg. In one particular embodiment, the subject is treated with one or more first doses of about 700 mg, one or more second doses of about 1400 mg, followed by one or more doses of about 700 mg.

[0110] In some embodiments, an anti-N3pGlu Aβ antibody slows disease progression in patients with early symptomatic Alzheimer's disease and intermediate brain tau burden. In some embodiments, the patient is administered 700 mg of an anti-N3pG Aβ antibody every four weeks for the first three doses, followed by 1400 mg of an anti-N3pG Aβ antibody every four weeks until brain amyloid plaques reach the normal range. In some embodiments, the patient undergoes an MRI before increasing the dose of the anti-N3pG Aβ antibody from 700 mg to 1400 mg.

[0111] In some embodiments, anti-N3pGlu Aβ antibodies slow disease progression in patients with early symptomatic Alzheimer's disease (i.e., patients with mild cognitive impairment or mild dementia due to AD). In some embodiments, anti-N3pGlu Aβ antibodies show clinical benefit in patients who are amyloid-positive and have intermediate brain tau burden. In some embodiments, patients receive 700 mg of anti-N3pGlu Aβ antibody every four weeks for the first three doses, followed by 1400 mg of anti-N3pGlu Aβ antibody every four weeks until brain amyloid plaques are cleared. In some embodiments, patients undergo brain MRI before increasing the dose of anti-N3pGlu Aβ antibody from 700 mg to 1400 mg. In some embodiments, a baseline brain MRI is obtained before initiating treatment.

[0112] In some embodiments, anti-N3pGlu Aβ antibodies slow disease progression in patients with early symptomatic Alzheimer's disease (mild cognitive impairment or mild dementia due to AD) with biomarker evidence consistent with AD neuropathology. In some embodiments, patients receive 700 mg of anti-N3pGlu Aβ antibody every four weeks for the first three doses, followed by 1400 mg of anti-N3pGlu Aβ antibody every four weeks until cerebral amyloid plaques are cleared. In some embodiments, a brain MRI is performed on the patient before increasing the dose of anti-N3pGlu Aβ antibody from 700 mg to 1400 mg. In some embodiments, a baseline brain MRI is obtained before initiating treatment. In some embodiments, if a dose / infusion of anti-N3pGlu Aβ antibody is missed, administration of the anti-N3pGlu Aβ antibody is resumed on the same dosing schedule as needed.

[0113] In some embodiments, the dosing regimen of the present disclosure includes one or more first doses of about 100 mg to about 700 mg and one or more second doses of greater than 700 mg to about 1400 mg, followed by one or more additional doses (also referred to herein as the third dose). In some embodiments, the third dose is administered to a subject to reduce Aβ deposition in the subject's brain, prevent further Aβ deposition in the subject's brain, prevent further cognitive decline, prevent memory loss, or prevent functional decline. The third dose can be about 100 mg to about 1400 mg. In some embodiments, different or the same antibodies are used for the first, second, and third doses. In some embodiments, a different Aβ-targeting antibody is administered in the third dose. For example, some embodiments of the present disclosure include: i) administering to a human subject one or more first doses of about 100 mg to about 700 mg of an anti-N3pG Aβ antibody, wherein each first dose is administered about once every four weeks; ii) about four weeks after administering the one or more first doses, administering to the human subject one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pG Aβ antibody, wherein each second dose is administered about once every four weeks; and iii) subsequently administering one or more third doses of about 100 mg to about 1400 mg of an anti-N3pGlu Aβ antibody, wherein the anti-N3pGlu Aβ antibody comprises an LCVR and an HCVR, wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 1 and the HCVR comprises the amino acid sequence of SEQ ID NO: 2. In some embodiments, one or more third doses of an anti-N3pGlu Aβ antibody of the present disclosure may be administered to a subject every 2 or 4 weeks, monthly, yearly, every 2 years, every 3 years, every 4 years, every 5 years, or every 10 years. In some embodiments, the third dose is given every 2 weeks. In some embodiments, the third dose is given every 4 weeks. In some embodiments, the third dose is given annually. In one embodiment, the third dose is given every 2 years. In another embodiment, the third dose is given every 3 years. In another embodiment, the third dose of antibody is given every 5 years. In another embodiment, the third dose of antibody is given every 10 years.In another embodiment, the third dose of the antibody is given every 2 to 5 years, hi another embodiment, the third dose of the antibody is given every 5 to 10 years.

[0114] In some embodiments, the anti-N3pGlu Aβ antibody is administered to the subject for a period sufficient to treat or prevent the disease. In some embodiments, the anti-N3pGlu Aβ antibody (comprising a first dose of antibody and a second dose of antibody) is administered to the subject for a period of up to about 72 weeks, optionally once every four weeks or once a month. In some embodiments, the anti-N3pGlu Aβ antibody (comprising a first dose of antibody and a second dose of antibody) is administered to the subject for a period of up to about 98 weeks, optionally once every four weeks or once a month. In some embodiments, the anti-N3pGlu Aβ antibody (comprising a first dose of antibody and a second dose of antibody) is administered to the subject for a period of up to about 124 weeks, optionally once every four weeks or once a month. In some embodiments, the anti-N3pGlu Aβ antibody (comprising a first dose of antibody and a second dose of antibody) is administered to the human subject until a normal level of amyloid is achieved in the subject. In some embodiments, the antibody is administered to the subject until cerebral amyloid plaques reach normal range or are eliminated. In some embodiments, a second dose of an antibody of the present disclosure is administered to the subject until cerebral amyloid plaques reach normal range or are eliminated. In some embodiments, the antibody is administered to the subject until the reduction in cerebral amyloid plaque levels stops. In some embodiments, a second dose of an antibody of the present disclosure is administered to the subject until the reduction in cerebral amyloid plaque levels stops. In some embodiments, the antibody is administered to the subject until the subject is amyloid negative. In some embodiments, a second dose of an antibody of the present disclosure is administered to the subject until the subject is amyloid negative. In some embodiments, a subject is considered amyloid negative if the amyloid plaque level in the subject's brain is less than 24.1 CL. In some embodiments, the level of cerebral amyloid plaques in the subject can be measured by amyloid PET imaging scan.

[0115] In some embodiments, the dose of the anti-N3pGlu Aβ antibody is 700 mg every 4 weeks for the first three doses, followed by 1400 mg every 4 weeks for up to 72 weeks or until cerebral amyloid plaques reach normal range or are cleared. In some embodiments, the dose of the anti-N3pGlu Aβ antibody is 700 mg every 4 weeks for the first three doses, followed by 1400 mg every 4 weeks until cerebral amyloid plaques stop reducing.

[0116] In some embodiments, the anti-N3pGlu Aβ antibody (comprising a first dose of antibody and a second dose of antibody) is administered to the subject, optionally once every four weeks or once a month, for a period of up to about 18 months. In some embodiments, the anti-N3pGlu Aβ antibody (comprising a first dose of antibody and a second dose of antibody) is administered to the subject, optionally once every four weeks or once a month, for a period of up to about 24 months. In some embodiments, the anti-N3pGlu Aβ antibody (comprising a first dose of antibody and a second dose of antibody) is administered to the subject, optionally once every four weeks or once a month, for a period of up to about 30 months.

[0117] In one embodiment, a subject receives a first dose of 700 mg three times every four weeks, followed by a second dose of 1400 mg once every four weeks for a period of up to 72 weeks. In some embodiments, an anti-N3pGlu Aβ antibody (e.g., comprising a first dose of antibody and a second dose of antibody) is administered to a subject for a period of about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks, about 56 weeks, about 60 weeks, about 64 weeks, about 68 weeks, about 72 weeks, or about 76 weeks. In some embodiments, the anti-N3pGlu Aβ antibody (e.g., comprising a first dose of antibody and a second dose of antibody) is administered to the subject for a period of about 76 weeks, about 80 weeks, about 84 weeks, about 88 weeks, about 92 weeks, about 96 weeks, about 100 weeks, about 104 weeks, about 108 weeks, about 112 weeks, about 116 weeks, or about 120 weeks.

[0118] In certain embodiments, the anti-N3pGlu Aβ antibody is administered to the subject for a period of about 24 weeks. In certain embodiments, the antibody is administered to the subject for a period of about 28 weeks. In certain embodiments, the antibody is administered to the subject for a period of about 52 weeks. In certain embodiments, the antibody is administered to the subject for a period of about 72 weeks. In some embodiments, the antibody of the present disclosure is administered to the subject for a period of 72 weeks or less.

[0119] In some embodiments, the anti-N3pGlu Aβ antibody (e.g., comprising a first dose of antibody and a second dose of antibody) is administered to the subject for a period of about 1 month to about 18 months. In some embodiments, the anti-N3pGlu Aβ antibody is administered to the subject for a period of about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, or about 18 months. In some embodiments, the anti-N3pGlu Aβ antibody is administered to the subject for a period of about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 24 months, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, or about 30 months.

[0120] In some embodiments, the antibody is administered to the subject until cerebral amyloid plaques reach normal range, hi some embodiments, the antibody is administered to the subject until cerebral amyloid plaques are cleared.

[0121] In certain embodiments, the antibody is administered to the subject for a period of about 3 months. In certain embodiments, the antibody is administered to the subject for a period of about 6 months. In certain embodiments, the antibody is administered to the subject for a period of about 12 months. In certain embodiments, the antibody is administered to the subject for a period of about 18 months.

[0122] In some embodiments, a human subject is administered an anti-N3pGlu Aβ antibody for a period sufficient to treat or prevent a disease characterized by amyloid beta plaques in the human subject's brain. In some embodiments, the human subject is administered an anti-N3pGlu Aβ antibody (e.g., comprising a first dose and / or a second dose) for a period sufficient to bring amyloid plaques in the subject's brain into the normal range (or until the brain amyloid plaques are cleared). The normal range of amyloid plaques is defined as two consecutive PET scans at least six months apart demonstrating an amyloid plaque level of 25 centiloids or less, or a single PET scan demonstrating an amyloid plaque level of less than 11 centiloids. In the present disclosure, the term "normal range" of amyloid plaques in the brain is used interchangeably with "cleared" brain amyloid plaques.

[0123] In some embodiments, an antibody of the present disclosure is administered to a subject until the amyloid plaque level in the subject is about 25 centiloids or less. In some embodiments, the amyloid plaque is measured by PET imaging. In other embodiments, an antibody of the present disclosure is administered to a subject until the amyloid plaque level in the subject is about 25 centiloids or less in two consecutive PET imaging scans. In some embodiments, the two consecutive PET imaging scans are at least six months apart. In some embodiments, an antibody of the present disclosure is administered to a subject until the amyloid plaque level in the subject is about 11 centiloids or less, as measured by a single PET imaging.

[0124] In certain embodiments, a subject is administered three 700 mg first doses of an antibody of the present disclosure, each first dose administered once every four weeks, and then one or more 1400 mg second doses of the antibody, each second dose administered once every four weeks, until the patient has an amyloid plaque level of about 25 centiloids or less.

[0125] In other embodiments, a subject is administered three 700 mg first doses of an antibody of the present disclosure, each first dose administered once every four weeks, followed by a 1400 mg second dose of the antibody, each second dose administered once every four weeks, until the patient has amyloid plaque levels of about 25 centiloids or less on two consecutive PET imaging scans, or 11 centiloids or less on one PET imaging scan. In some embodiments, the two consecutive PET imaging scans are at least six months apart.

[0126] In some embodiments, the subject is not administered an anti-N3pGlu Aβ antibody dose after the patient's amyloid plaque levels are about 25 centiloids or less in two consecutive PET imaging scans, or about 11 centiloids or less in one PET imaging scan, in some embodiments, the two consecutive PET imaging scans are at least 6 months apart.

[0127] In some embodiments, a subject may be administered one or more 700 mg doses of an anti-N3pGlu Aβ antibody after the patient has amyloid plaque levels of about 25 centiloids or less on two consecutive PET imaging scans, or about 11 centiloids or less on one PET imaging scan.

[0128] In some embodiments, an antibody of the disclosure is administered to a subject until amyloid plaques in the subject's brain are reduced by about 25 to about 150 centiloids. See, e.g., Klunk et al., "The Centiloid Project: Standardizing Quantitative Amyloid Plaque Estimation by PET," Alzheimer's & Dementia 11.1:1-15 (2015) and Navitsky et al., "Standardization of Amyloid Quantitation with Florbetapir Standardized Uptake Value Ratios to the Centiloid Scale," Alzheimer's & Dementia 14.12:1565-1571 (2018), which are incorporated by reference in their entireties.

[0129] In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ deposits in the subject's brain are reduced by about 50 to about 150 centiloids. In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ deposits in the subject's brain are reduced by about 25, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 140, or about 150 centiloids. In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ plaques in the subject's brain are reduced by about 50 centiloids. In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ plaques in the subject's brain are reduced by about 60 centiloids. In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ plaques in the subject's brain are reduced by about 70 centiloids. In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ plaques in the subject's brain are reduced by about 80 centiloids. In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ plaques in the brain of the subject are reduced by about 84 centiloids. In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ plaques in the brain of the subject are reduced by about 90 centiloids. In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ plaques in the brain of the subject are reduced by about 100 centiloids. In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ plaques in the brain of the subject are reduced by about 110 centiloids. In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ plaques in the brain of the subject are reduced by about 120 centiloids. In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ plaques in the brain of the subject are reduced by about 130 centiloids. In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ plaques in the brain of the subject are reduced by about 140 centiloids. In some embodiments, an antibody of the disclosure is administered to a subject until there is about a 150 centiroid reduction in Aβ plaques in the subject's brain.

[0130] In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ deposits in the subject's brain are reduced by an average of about 25 to about 100 centiloids. In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ deposits in the subject's brain are reduced by an average of about 50 to about 100 centiloids. In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ deposits in the subject's brain are reduced by an average of about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 84, about 90, or about 100 centiloids. In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ plaques in the subject's brain are reduced by an average of about 50 centiloids. In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ plaques in the subject's brain are reduced by an average of about 60 centiloids. In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ plaques in the subject's brain are reduced by an average of about 70 centiloids. In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ plaques in the subject's brain are reduced by an average of about 80 centiloids. In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ plaques in the subject's brain are reduced by an average of about 84 centiloids. In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ plaques in the subject's brain are reduced by an average of about 90 centiloids. In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ plaques in the subject's brain are reduced by an average of about 100 centiloids.

[0131] In some embodiments, a second dose of an antibody of the present disclosure is administered to a subject until Aβ deposits in the subject's brain are reduced by about 25 to about 150 centiloids. In some embodiments, a second dose of an antibody of the present disclosure is administered to a subject until Aβ deposits in the subject's brain are reduced by about 50 to about 150 centiloids. In some embodiments, a second dose of an antibody of the present disclosure is administered to a subject until Aβ deposits in the subject's brain are reduced by about 25, about 30, about 40, about 50, about 60, about 70, about 80, about 84, about 90, about 100, about 110, about 120, about 130, about 140, or about 150 centiloids. In some embodiments, a second dose of an antibody of the present disclosure is administered to a subject until Aβ plaques in the subject's brain are reduced by about 50 centiloids. In some embodiments, a second dose of an antibody of the present disclosure is administered to a subject until Aβ plaques in the brain of the subject are reduced by about 60 centiloids. In some embodiments, a second dose of an antibody of the present disclosure is administered to a subject until Aβ plaques in the brain of the subject are reduced by about 70 centiloids. In some embodiments, a second dose of an antibody of the present disclosure is administered to a subject until Aβ plaques in the brain of the subject are reduced by about 80 centiloids. In some embodiments, a second dose of an antibody of the present disclosure is administered to a subject until Aβ plaques in the brain of the subject are reduced by about 84 centiloids. In some embodiments, a second dose of an antibody of the present disclosure is administered to a subject until Aβ plaques in the brain of the subject are reduced by about 90 centiloids. In some embodiments, a second dose of an antibody of the present disclosure is administered to a subject until Aβ plaques in the brain of the subject are reduced by about 100 centiloids. In some embodiments, a second dose of an antibody of the present disclosure is administered to a subject until Aβ plaques in the subject's brain are reduced by about 110 centiloids. In some embodiments, a second dose of an antibody of the present disclosure is administered to a subject until Aβ plaques in the subject's brain are reduced by about 120 centiloids. In some embodiments, a second dose of an antibody of the present disclosure is administered to a subject until Aβ plaques in the subject's brain are reduced by about 130 centiloids. In some embodiments, a second dose of an antibody of the present disclosure is administered to a subject until Aβ plaques in the subject's brain are reduced by about 140 centiloids.In some embodiments, a second dose of an antibody of the disclosure is administered to the subject until there is about a 150 centiroid reduction in Aβ plaques in the subject's brain.

[0132] In some embodiments, a second dose of an antibody of the present disclosure is administered to a subject until Aβ deposits in the subject's brain are reduced by an average of about 25 to about 100 centiloids. In some embodiments, a second dose of an antibody of the present disclosure is administered to a subject until Aβ deposits in the subject's brain are reduced by an average of about 50 to about 100 centiloids. In some embodiments, a second dose of an antibody of the present disclosure is administered to a subject until Aβ deposits in the subject's brain are reduced by an average of about 25, about 30, about 40, about 50, about 60, about 70, about 80, about 84, about 90, or about 100 centiloids. In some embodiments, a second dose of an antibody of the present disclosure is administered to a subject until Aβ plaques in the subject's brain are reduced by an average of about 50 centiloids. In some embodiments, a second dose of an antibody of the present disclosure is administered to a subject until Aβ plaques in the subject's brain are reduced by an average of about 60 centiloids. In some embodiments, a second dose of an antibody of the present disclosure is administered to a subject until Aβ plaques in the subject's brain are reduced by an average of about 70 centiloids. In some embodiments, a second dose of an antibody of the present disclosure is administered to a subject until Aβ plaques in the subject's brain are reduced by an average of about 80 centiloids. In some embodiments, a second dose of an antibody of the present disclosure is administered to a subject until Aβ plaques in the subject's brain are reduced by an average of about 84 centiloids. In some embodiments, a second dose of an antibody of the present disclosure is administered to a subject until Aβ plaques in the subject's brain are reduced by an average of about 90 centiloids. In some embodiments, a second dose of an antibody of the present disclosure is administered to a subject until Aβ plaques in the subject's brain are reduced by an average of about 100 centiloids.

[0133] In some embodiments, the antibodies, methods, dosing regimens, and / or uses of the present disclosure result in a reduction of Aβ plaques in the brain of a human subject. In certain embodiments, Aβ plaques are reduced by about 20-100% after treatment. In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ plaques in the brain of the subject are reduced by about 20-100%. In some embodiments, an antibody of the present disclosure is administered to a human subject until Aβ plaques in the brain of the subject are reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 75%, or about 100%. In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ plaques in the brain of the subject are reduced by about 20%. In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ plaques in the brain of the subject are reduced by about 25%. In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ plaques in the brain of the subject are reduced by about 30%. In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ plaques in the brain of the subject are reduced by about 35%. In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ plaques in the brain of the subject are reduced by about 40%. In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ plaques in the brain of the subject are reduced by about 50%. In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ plaques in the brain of the subject are reduced by about 75%. In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ plaques in the brain of the subject are reduced by about 100%.

[0134] In some embodiments, the first and / or second dose of an antibody of the present disclosure is administered to a subject until Aβ plaques in the subject's brain are reduced by about 20-100%. In certain embodiments, the second dose of an antibody of the present disclosure is administered to a subject until Aβ plaques in the subject's brain are reduced by about 20-100%. In some embodiments, the second dose of an antibody of the present disclosure is administered to a subject until Aβ plaques in the subject's brain are reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 75%, or about 100%. In some embodiments, the second dose is administered to a subject until Aβ plaques in the subject's brain are reduced by about 20%. In some embodiments, the second dose is administered to a subject until Aβ plaques in the subject's brain are reduced by about 25%. In some embodiments, the second dose is administered to a subject until Aβ plaques in the subject's brain are reduced by about 30%. In some embodiments, the second dose is administered to the subject until Aβ plaques in the subject's brain are reduced by about 35%. In some embodiments, the second dose is administered to the subject until Aβ plaques in the subject's brain are reduced by about 40%. In some embodiments, the second dose is administered to the subject until Aβ plaques in the subject's brain are reduced by about 50%. In some embodiments, the second dose is administered to the subject until Aβ plaques in the subject's brain are reduced by about 75%. In some embodiments, the second dose is administered to the subject until Aβ plaques in the subject's brain are reduced by about 100%.

[0135] In some embodiments, the percentage reduction in Aβ plaques in the subject's brain is measured at about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks, about 56 weeks, about 60 weeks, about 64 weeks, about 68 weeks, or about 72 weeks. In some embodiments, Aβ plaque levels in the subject are reduced by at least 60% within 24 weeks of administration (including both the first and second doses) of an anti-N3pGlu Aβ antibody of the invention.

[0136] In some embodiments, centiloid reduction of Aβ plaques in the subject's brain is measured at about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks, about 56 weeks, about 60 weeks, about 64 weeks, about 68 weeks, or about 72 weeks.

[0137] In some embodiments, the mean centiloid reduction of Aβ plaques in the subject's brain is measured at about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks, about 56 weeks, about 60 weeks, about 64 weeks, about 68 weeks, or about 72 weeks.

[0138] In some embodiments, the present disclosure provides about a 15 to about 45 percent slowing of decline from baseline in a cognitive-composite functional endpoint. In some embodiments, the present disclosure provides about a 15 to about 45 percent slowing of decline from baseline in a cognitive-composite functional endpoint over a period of about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks, about 56 weeks, about 60 weeks, about 64 weeks, about 68 weeks, about 72 weeks, or 76 weeks.

[0139] In some embodiments, the present disclosure results in about a 15 to about 45 percent slowing of decline in a cognitive-functional composite endpoint from baseline over a 76-week period. In some embodiments, the slowing of decline in a cognitive-functional composite endpoint from baseline is provided by a mixed model repeated measures (MMRM) model or a Bayesian disease progression model (DPM). In some embodiments, an antibody of the present disclosure is administered to a subject until about a 15 to about 45 percent slowing of decline in a cognitive-functional composite endpoint from baseline is reached. In some embodiments, a first dose or a second dose of the present disclosure is administered to a subject until about a 15 to about 45 percent slowing of decline in a cognitive-functional composite endpoint from baseline is reached.

[0140] In some embodiments, administration of an anti-N3pGlu Aβ antibody of the present disclosure to a subject slows disease progression by about 15% to about 45% compared to untreated subjects, where disease progression is measured by DPM. In some embodiments, administration of an anti-N3pGlu Aβ antibody of the present disclosure to a subject slows disease progression by about 15% compared to untreated subjects, where disease progression is measured by DPM. In some embodiments, administration of an anti-N3pGlu Aβ antibody of the present disclosure to a subject slows disease progression by about 20% compared to untreated subjects, where disease progression is measured by DPM. In some embodiments, administration of an anti-N3pGlu Aβ antibody of the present disclosure to a subject slows disease progression by about 25% compared to untreated subjects, where disease progression is measured by DPM. In some embodiments, administration of an anti-N3pGlu Aβ antibody of the present disclosure to a subject slows disease progression by at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, or at least 45% compared to an untreated subject, where disease progression is measured by DPM.

[0141] In some embodiments, administration of an anti-N3pGlu Aβ antibody of the present disclosure to a subject slows disease progression by about 15% to about 45% compared to untreated subjects, where disease progression is measured by MMRM. In some embodiments, administration of an anti-N3pGlu Aβ antibody of the present disclosure to a subject slows disease progression by about 15% compared to untreated subjects, where disease progression is measured by MMRM. In some embodiments, administration of an anti-N3pGlu Aβ antibody of the present disclosure to a subject slows disease progression by about 20% compared to untreated subjects, where disease progression is measured by MMRM. In some embodiments, administration of an anti-N3pGlu Aβ antibody of the present disclosure to a subject slows disease progression by about 25% compared to untreated subjects, where disease progression is measured by MMRM. In some embodiments, administration of an anti-N3pGlu Aβ antibody of the present disclosure to a subject slows disease progression by at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, or at least 45% compared to an untreated subject, where disease progression is measured by MMRM.

[0142] In some embodiments, the disclosure provides a slowing of decline on the integrated Alzheimer's Disease Rating Scale (iADRS) or disease progression by about 15 to about 60 percent from baseline or compared to untreated subjects. In some embodiments, the disclosure provides a slowing of decline on the integrated Alzheimer's Disease Rating Scale or disease progression by about 15 to about 60 percent from baseline or compared to untreated subjects over a period of about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks, about 56 weeks, about 60 weeks, about 64 weeks, about 68 weeks, about 72 weeks, or 76 weeks. In some embodiments, the slowing of decline measured by the iADRS is provided by a mixed model repeated measures (MMRM) model or a Bayesian disease progression model (DPM).

[0143] In some embodiments, the present disclosure results in a slowing of decline in the Unified Alzheimer's Disease Rating Scale or disease progression by about 20 percent, about 25 percent, about 30 percent, about 32 percent, about 35 percent, about 40 percent, about 45 percent, about 50%, about 55%, or about 60% from baseline or compared to untreated subjects.

[0144] In some embodiments, the disclosure results in about a 15 to about 60 percent slowing of decline on the Unified Alzheimer's Disease Rating Scale over a 76-week period, either from baseline or compared to untreated subjects. In certain embodiments, the disclosure results in about a 32 percent slowing of decline on the Unified Alzheimer's Disease Rating Scale over a 76-week period, either from baseline or compared to untreated subjects. In some embodiments, an antibody of the disclosure is administered to a subject until about a 15 to about 60 percent slowing of decline on the Unified Alzheimer's Disease Rating Scale is reached, either from baseline or compared to untreated subjects. In some embodiments, a first or second dose of the disclosure is administered to a subject until about a 15 to about 60 percent slowing of decline on the Unified Alzheimer's Disease Rating Scale is reached, either from baseline or compared to untreated subjects.

[0145] In some embodiments, the disclosure results in a slowing of decline on the Integrated Alzheimer's Disease Rating Scale (iADRS) or disease progression by about 3 to about 6 from baseline or compared to untreated subjects. In some embodiments, the disclosure results in a slowing of decline on the Integrated Alzheimer's Disease Rating Scale or disease progression by about 3 to about 6 from baseline or compared to untreated subjects over a period of about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks, about 56 weeks, about 60 weeks, about 64 weeks, about 68 weeks, about 72 weeks, or 76 weeks.

[0146] In some embodiments, the disclosure results in a slowing of decline or disease progression on the Unified Alzheimer's Disease Rating Scale by about 3, about 4, about 5, or about 6 points from baseline or compared to untreated subjects. In some embodiments, the disclosure results in a slowing of decline or disease progression on the Unified Alzheimer's Disease Rating Scale by 3 to about 6 points from baseline or compared to untreated subjects over a 76-week period.

[0147] In some embodiments, the slowing of disease progression as measured by the iADRS is provided by a mixed model repeated measures (MMRM) model or a Bayesian disease progression model (DPM).

[0148] In some embodiments, a subject's composite cognitive endpoint comprising iADRS is measured at about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks, about 56 weeks, about 60 weeks, about 64 weeks, about 68 weeks, or about 72 weeks.

[0149] In some embodiments, the disclosure results in about a 20 to about 40 percent slowing of the decline in Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) or disease progression from baseline or compared to untreated subjects. In some embodiments, the disclosure results in about a 20 to about 40 percent slowing of the decline in CDR-SB or disease progression from baseline or compared to untreated subjects over a period of about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks, about 56 weeks, about 60 weeks, about 64 weeks, about 68 weeks, about 72 weeks, or 76 weeks.

[0150] In some embodiments, the present disclosure results in a slowing of the decline in CDR-SB or disease progression by about 20 percent, about 25 percent, about 30 percent, about 35 percent, or about 40 percent from baseline or compared to untreated subjects.

[0151] In some embodiments, the disclosure results in about a 20 to about 40 percent slowing of the decline in CDR-SB from baseline or compared to untreated subjects over a 76-week period. In some embodiments, an antibody of the disclosure is administered to a subject until about a 20 to about 40 percent slowing of the decline in CDR-SB from baseline or compared to untreated subjects is reached. In some embodiments, a first or second dose of the disclosure is administered to a subject until about a 20 to about 40 percent slowing of the decline in CDR-SB from baseline or compared to untreated subjects is reached. In some embodiments, the slowing of disease progression as measured by CDR-SB is provided by a mixed model repeated measures (MMRM) model or a Bayesian disease progression model (DPM).

[0152] In some embodiments, the antibodies, methods, dosing regimens, and / or uses of the disclosure do not result in a reduction in hippocampal volume in a subject. In some embodiments, administration of the antibody does not result in a reduction in hippocampal volume in a subject.

[0153] In some embodiments, the antibodies, methods, dosing regimens, and / or uses of the present disclosure result in a reduction or reduction of tau levels in the brain of a human subject. In some embodiments, the antibodies, methods, dosing regimens, and / or uses of the present disclosure result in a reduction or reduction of plasma tau levels in patients with a disease characterized by Aβ plaques. In some embodiments, the antibodies, methods, dosing regimens, and / or uses of the present disclosure result in a reduction or reduction of P-tau217 levels in patients with a disease characterized by Aβ plaques. In some embodiments, the antibodies, methods, dosing regimens, and / or uses of the present disclosure result in a rapid and sustained reduction of P-tau217 levels in patients with a disease characterized by Aβ plaques. In some embodiments, P-tau217 levels are reduced by about 5% to about 40% from baseline. In some embodiments, P-tau217 levels are reduced by about 10% to about 30% from baseline. In some embodiments, P-tau217 levels are reduced by about 20% to about 30% from baseline. In some embodiments, P-tau217 levels are reduced by about 25% to about 30% from baseline. In some embodiments, P-tau217 levels are reduced by 5%, 10%, 15%, 20%, 24%, 25%, 29%, 30%, 35%, or 40% from baseline. In some embodiments, P-tau217 levels are reduced by about 5% to about 40% from baseline after treatment with an anti-N3pG antibody. In some embodiments, P-tau217 levels are reduced by about 10% to about 30% from baseline after treatment with an anti-N3pG antibody. In some embodiments, P-tau217 levels are reduced by about 20% to about 30% from baseline after treatment with an anti-N3pG antibody. In some embodiments, P-tau217 levels are reduced by about 25% to about 30% from baseline after treatment with an anti-N3pG antibody. In some embodiments, P-tau217 levels are reduced by 5%, 10%, 15%, 20%, 24%, 25%, 29%, 30%, 35%, or 40% from baseline after treatment with an anti-N3pG antibody. In some embodiments, P-tau217 levels are reduced by about 5% to about 40% from baseline at one or more time points during or after treatment with an anti-N3pG antibody of the disclosure.

[0154] In some embodiments, the antibodies, methods, dosing regimens, and / or uses of the present disclosure result in a decrease or reduction in neurofilament light chain (NfL) levels in the brain of patients with a disease characterized by Aβ plaques. In some embodiments, NfL levels are reduced by about 1% to about 20% compared to placebo. In some embodiments, NfL levels are reduced by about 5% to about 15% compared to placebo. In some embodiments, NfL levels are reduced by about 10% to about 15% compared to placebo. In some embodiments, NfL levels are reduced by 2%, 3%, 4%, 5%, 10%, 15%, or 20% compared to placebo. In some embodiments, NfL levels are reduced by about 1% to about 20% compared to placebo after treatment with an anti-N3pG antibody. In some embodiments, NfL levels are reduced by about 5% to about 15% after treatment with an anti-N3pG antibody compared to placebo. In some embodiments, NfL levels are reduced by about 10% to about 15% after treatment with an anti-N3pG antibody compared to placebo. In some embodiments, NfL levels are reduced by 2%, 3%, 4%, 5%, 10%, 15%, or 20% after treatment with an anti-N3pG antibody compared to placebo. In some embodiments, NfL levels are reduced by 2%, 3%, 4%, 5%, 10%, 15%, or 20% after treatment with an anti-N3pG antibody compared to placebo. In some embodiments, NfL levels are reduced by about 1% to about 20% compared to placebo at one or more time points during or after treatment with an anti-N3pG antibody of the disclosure.

[0155] In some embodiments, the antibodies, methods, dosing regimens, and / or uses of the present disclosure result in an increase in the Aβ42 / 40 ratio in the plasma or cerebrospinal fluid (CSF) of patients with a disease characterized by Aβ plaques. 42 / 40 In some embodiments, the plasma Aβ ratio is increased by about 1% to about 10% compared to baseline. 42 / 40 In some embodiments, the ratio of Aβ in plasma increases by about 1% to about 5% compared to baseline. 42 / 40In some embodiments, the ratio of Aβ in plasma is increased by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% compared to baseline. 42 / 40 The ratio increases by about 1% to about 10% compared to baseline after treatment with an anti-N3pG antibody. 42 / 40 The ratio increases by about 1% to about 5% compared to baseline after treatment with an anti-N3pG antibody. 42 / 40 The ratio increases by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% compared to baseline after treatment with an anti-N3pG antibody. In some embodiments, the plasma Aβ42 / 40 ratio increases by about 1% to about 10% compared to baseline at one or more time points during or after treatment with an anti-N3pG antibody of the disclosure.

[0156] In some embodiments, the antibodies, methods, dosing regimens, and / or uses of the present disclosure result in a reduction or decrease in glial fibrillary acidic protein (GFAP) in the blood of patients with a disease characterized by Aβ plaques. In some embodiments, GFAP levels are reduced by about 5% to about 40% from baseline. In some embodiments, GFAP levels are reduced by about 10% to about 30% from baseline. In some embodiments, GFAP levels are reduced by about 10% to about 20% from baseline. In some embodiments, GFAP levels are reduced by about 10% to about 15% from baseline. In some embodiments, GFAP levels are reduced by 5%, 10%, 12%, 15%, 20%, 24%, 25%, 29%, 30%, 35%, or 40% from baseline. In some embodiments, GFAP levels are reduced by about 5% to about 40% from baseline after treatment with an anti-N3pG antibody. In some embodiments, GFAP levels are reduced by about 10% to about 30% from baseline after treatment with an anti-N3pG antibody. In some embodiments, GFAP levels are reduced by about 10% to about 20% from baseline after treatment with an anti-N3pG antibody. In some embodiments, GFAP levels are reduced by about 10% to about 15% from baseline after treatment with an anti-N3pG antibody. In some embodiments, GFAP levels are reduced by 5%, 10%, 12%, 15%, 20%, 24%, 25%, 29%, 30%, 35%, or 40% from baseline after treatment with an anti-N3pG antibody. In some embodiments, GFAP levels are reduced by about 5% to about 40% from baseline at one or more time points during or after treatment with an anti-N3pG antibody of the disclosure. In some embodiments, GFAP levels are reduced by about 5% to about 30% from baseline at one or more time points during or after treatment with an anti-N3pG antibody of the disclosure. In some embodiments, GFAP levels are reduced by about 5% to about 20% from baseline at one or more time points during or after treatment with an anti-N3pG antibody of the disclosure, hi some embodiments, GFAP levels are reduced by about 5% to about 15% from baseline at one or more time points during or after treatment with an anti-N3pG antibody of the disclosure.In some embodiments, GFAP levels are reduced by 5%, 10%, 14%, 15%, 20%, 25%, 30%, 35%, or 40% from baseline at one or more time points during or after treatment with an anti-N3pG antibody of the disclosure.

[0157] In some embodiments, the antibody of the present disclosure may be administered simultaneously, separately, or sequentially in combination with an effective amount of a symptomatic treatment agent for treating Alzheimer's disease. The symptomatic treatment agent may be selected from a cholinesterase inhibitor (ChEI) and / or an N-methyl-D-aspartate (NMDA) partial antagonist. In a preferred embodiment, the agent is a ChEI. In another preferred embodiment, the agent is an NMDA antagonist, or a combination agent comprising a ChEI and an NMDA antagonist.

[0158] In some embodiments, the dosing regimen or method described herein comprises administering solanezumab or an antibody comprising a solanezumab portion to a human patient. In some embodiments, the anti-N3pGlu Aβ antibody is administered simultaneously, separately, or sequentially in combination with an effective amount of an antibody having a light chain of SEQ ID NO: 15. In some embodiments, the anti-N3pGlu Aβ antibody is administered simultaneously, separately, or sequentially in combination with an effective amount of an antibody having a heavy chain of SEQ ID NO: 16. In some embodiments, the anti-N3pGlu Aβ antibody is administered simultaneously, separately, or sequentially in combination with effective amounts of an antibody having two heavy chains of SEQ ID NO: 16 and two light chains of SEQ ID NO: 15. In some embodiments, the anti-N3pGlu Aβ antibody of the present disclosure may be administered simultaneously, separately, or sequentially in combination with an effective amount of solanezumab.

[0159] Additional information about solanezumab, including its CDR sequences, LCVR, HCVR sequences, and methods of making and using it, can be found in the following patent documents, which are incorporated herein by reference in their entireties: ●U.S. Patent No. 7,195,761 ●US Patent Application Publication No. 2006 / 0039906 ●U.S. Patent No. 7,195,761 ●U.S. Patent No. 8,591,894 ●U.S. Patent No. 7,771,722 ●US Patent Application Publication No. 2007 / 0190046.

[0160] Information about using solanezumab in combination with other antibodies can be found in U.S. Patent Application Publication No. 2019 / 03824, which is incorporated herein by reference in its entirety.

[0161] In some embodiments, solanezumab or an antibody comprising a solanezumab portion is administered to a human subject to maintain amyloid beta levels within the normal range. In embodiments, solanezumab or an antibody comprising a solanezumab portion is administered to a human subject to prevent an increase in amyloid plaque levels. In embodiments, solanezumab or an antibody comprising a solanezumab portion is administered to a human subject to reduce the rate of increase in amyloid plaque levels.

[0162] In some embodiments, a human subject may receive a dose or dosing regimen of an anti-N3pGlu Aβ antibody described herein in combination with a dose or dosing regimen of solanezumab or an antibody containing a solanezumab moiety. In some embodiments, the solanezumab dose is 400 mg every four weeks, 800 mg every four weeks, 1200 mg every four weeks, or 1600 mg every four weeks. In some embodiments, the solanezumab dosing regimen includes an initial dose of 400 mg and either maintaining the patient at 400 mg, or gradually increasing to 800 mg every four weeks, or gradually increasing to 1200 mg every four weeks, or gradually increasing to 1600 mg over time. Other embodiments may include giving an initial dose of 1600 mg, and then maintaining that dose or gradually increasing to 400 mg, 800 mg, or 1200 mg. One of ordinary skill in the art would understand how to titrate the dose up or down, or how to maintain a patient on a particular dose (and the associated timing of any dosing changes).

[0163] In some embodiments, administration of solanezumab causes a reduction in available soluble Aβ in the brain, which can be measured at about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks, about 56 weeks, about 60 weeks, about 64 weeks, about 68 weeks, about 72 weeks, or about 80 weeks.

[0164] In some embodiments, administration of solanezumab results in a 5% decrease in soluble Aβ levels. In other embodiments, administration of solanezumab results in a 10% decrease in soluble Aβ levels. In other embodiments, administration of solanezumab results in a 15% decrease in soluble Aβ levels. In other embodiments, administration of solanezumab results in a 20% decrease in soluble Aβ levels. In other embodiments, administration of solanezumab results in a 25% decrease in soluble Aβ levels. In other embodiments, administration of solanezumab results in a 30% decrease in soluble Aβ levels. In other embodiments, administration of solanezumab results in a 35% decrease in soluble Aβ levels. In other embodiments, administration of solanezumab results in a 40% decrease in soluble Aβ levels. In other embodiments, administration of solanezumab results in a 45% decrease in soluble Aβ levels. In other embodiments, administration of solanezumab results in a 50% decrease in soluble Aβ levels. In other embodiments, administration of solanezumab results in a greater than 50% decrease in soluble Aβ levels. One of ordinary skill in the art would understand how to measure soluble Aβ levels. See Siemers et al., "Safety and Changes in Plasma and Cerebrospinal Fluid Amyloid β After a Single Administration of an Amyloid β Monoclonal Antibody in Subjects with Alzheimer's Disease," Clinical Neuropharmacology 33.2 (2010):67-73 and Farlow et al., "Safety and Biomarker Effects of Solanezumab in Patients with Alzheimer's Disease," Alzheimer's & Dementia 8.4 (2012):261-271, each of which is incorporated herein by reference in its entirety.

[0165] Those skilled in the art will appreciate that modifications to the dose of solanezumab or another antibody may be based on a variety of factors, including PET scans, clinical observations, the patient's performance in various "tests," and the like.

[0166] In some embodiments, the disease characterized by Aβ deposition in the brain of the subject is selected from preclinical Alzheimer's disease, clinical AD, prodromal AD, mild AD, moderate AD, severe AD, Down's syndrome, clinical cerebral amyloid angiopathy, or preclinical cerebral amyloid angiopathy. In some embodiments, the subject is an early symptomatic AD patient. In some embodiments, the subject has prodromal AD and mild dementia due to AD.

[0167] The present disclosure includes the use of biomarkers for diseases characterized by Aβ plaques in the brain of human subjects, including Alzheimer's disease. Such biomarkers include, for example, amyloid deposits, amyloid plaques, Aβ in CSF, Aβ in plasma, brain tau deposits, tau in plasma, or tau in cerebrospinal fluid, and their use in screening, diagnosis, treatment, or prevention. Non-limiting potential uses of such biomarkers include: 1) identifying subjects destined to develop the disease or who are in the "preclinical" stage of the disease; 2) reducing disease heterogeneity in clinical trials or epidemiological studies; 3) reflecting the natural history of the disease, including stages of induction, latency, and detection; and 4) targeting subjects for clinical trials or disease treatment / prevention.

[0168] In some embodiments, biomarkers can be used to assess whether a subject can be treated using an antibody, dosing regimen, or method described herein. In some embodiments, biomarkers can be used to assess whether a disease (as described herein) can be prevented in a subject using an antibody, dosing regimen, or method described herein. In some embodiments, biomarkers can be used to assess whether a subject will respond to treatment or prevention of a disease (as described herein) using an antibody, dosing regimen, or method described herein. In some embodiments, biomarkers can be used to stratify or classify subjects into groups and identify which groups of subjects will respond to treatment / prevention of a disease (as described herein) using an antibody, dosing regimen, or method described herein. In some embodiments, biomarkers can be used to assess a subject's condition and / or the duration of administration of an antibody or dose thereof to a subject, as described herein.

[0169] In some embodiments, the subject has a genetic mutation that causes autosomal dominant Alzheimer's disease or has one or two APOE4 alleles and therefore is at high risk for developing AD. In certain embodiments, the subject has one or two APOE4 alleles, i.e., the patient is heterozygous or homozygous.

[0170] In some embodiments, the subject has a baseline MMSE (Mini-Mental State Examination) score of 20-28 prior to administration of the anti-N3pGlu Aβ antibody.

[0171] In some embodiments, the subject has a low to moderate tau burden or has been determined to have a low to moderate tau burden. 18A subject has low to moderate tau burden if the tau burden, as measured by F (using Flortaucipir), is ≧1.10 standardized uptake value ratio (SUVr) to ≦1.46 SUVr. In some embodiments, the subject has low to moderate tau burden or has been determined to have low to moderate tau burden and carries one or two APOE4 alleles.

[0172] In some embodiments, the subject has a very low tau burden or has been determined to have a very low tau burden. 18 A subject has very low tau burden if their tau burden, as measured by F(using flortaucipir), is less than 1.10 SUVr. In some embodiments, the subject has, or has been determined to have, very low tau burden and carries one or two APOE4 alleles.

[0173] In some embodiments, the subject has been determined to have a very low to moderate tau burden, or a very low to moderate tau burden. 18 A subject has very low to moderate tau burden if their tau burden, as measured by Fflourtaucipir (using Fflourtaucipir), is ≦1.46 SUVr. In some embodiments, the subject has very low to moderate tau burden, or has been determined to have very low to moderate tau burden, and carries one or two APOE4 alleles.

[0174] In some embodiments, the subject does not have high tau burden or has been determined not to have high tau burden. In some embodiments, the subject is assessed by PET brain imaging (e.g., 18A human subject has high tau burden if their tau burden, as measured by Fflourtaucipir (using Fflourtaucipir), is greater than 1.10 SUVr. In some embodiments, a subject with high tau is not administered an antibody of the present disclosure. In some embodiments, the subject does not have, or has been determined not to have, high tau burden and carries one or two APOE4 alleles.

[0175] In some embodiments, an anti-N3pGlu Aβ antibody, dosing regimen, or method described herein is effective in a human subject with very low to moderate tau. In some embodiments, an anti-N3pGlu Aβ antibody, dosing regimen, or method described herein is effective in a human subject with low to moderate tau. In some embodiments, an antibody of the present disclosure is most effective in a human subject with tau levels i) about 1.14 SUVr or less, or ii) about 1.14 SUVr to about 1.27 SUVr. In some embodiments, an anti-N3pGlu Aβ antibody, dosing regimen, or method described herein is effective in a human subject regardless of tau levels.

[0176] In some embodiments, an anti-N3pGlu Aβ antibody, dosing regimen, or method described herein is effective in a human subject with very low to moderate tau and one or two APOE4 alleles. In some embodiments, an anti-N3pGlu Aβ antibody, dosing regimen, or method described herein is effective in a human subject with low to moderate tau and one or two APOE4 alleles. In some embodiments, an antibody of the present disclosure is most effective in a human subject with one or two APOE4 alleles and a tau level of i) about 1.14 SUVr or less, or ii) about 1.14 SUVr to about 1.27 SUVr.

[0177] In some embodiments, the methods of the present disclosure are such that the level of Aβ plaques in the subject's brain is maintained at normal levels for at least 52 weeks after administration of the second dose is completed.

[0178] Tau levels in a human subject can be determined by techniques and methods familiar to a diagnosing physician or one skilled in the art. In some embodiments, a human subject suffering from a disease characterized by amyloid beta plaques is determined to have very low to moderate tau, low to moderate tau, or no high tau using techniques and methods familiar to a diagnosing physician or one skilled in the art. In some embodiments, such methods can also be used to pre-screen, screen, diagnose, or evaluate increases or reductions in brain tau burden and / or to evaluate progress achieved in treating or preventing a disease described herein. In some embodiments, the methods can also be used to stratify subjects into groups and / or identify which groups of subjects will respond to a disease treatment / prevention (as described herein) using the antibodies, dosing regimens, or methods described herein. In some embodiments, the methods or techniques used to determine / detect tau levels in a human subject can be used to pre-screen or screen subjects using the antibodies, dosing regimens, or methods described herein to determine which subjects will respond to a disease treatment / prevention (as described herein).

[0179] In some embodiments, tau levels in a human subject may be determined using, for example, techniques or methods that detect or quantify i) brain tau deposits, ii) tau in plasma, or iii) tau in cerebrospinal fluid. In some embodiments, brain tau load, tau in plasma, or tau in cerebrospinal fluid may be used to stratify subjects into groups and / or identify which groups of subjects will respond to disease treatment / prevention (as described herein) using the antibodies, dosing regimens, or methods described herein.

[0180] Tau levels in the brain of a human subject can be determined using methods such as tau imaging with radiolabeled PET compounds (Leuzy et al., "Diagnostic Performance of RO948 F18 Tau Positron Emission Tomography in the Differentiation of Alzheimer Disease from Other Neurodegenerative Disorders," JAMA Neurology 77.8:955-965 (2020); Ossenkoppele et al., "Discriminative Accuracy of F18-flortaucipir Positron Emission Tomography for Alzheimer Disease vs. Other Neurodegenerative Disorders," JAMA 320, 1151-1162, doi:10.1001 / jama.2018.12917 (2018)), which are incorporated herein by reference in their entireties.

[0181] In some embodiments, the PET ligand biomarker F18-Flortaucipir may be used for purposes of the present disclosure. For example, PET tau images may be quantitatively evaluated to estimate SUVr (standardized uptake value ratio) by published methods (Pontecorvo et al., "A Multicentre Longitudinal Study of Flortaucipir"). 18F) in Normal Aging, Mild Cognitive Impairment and Alzheimer's Disease Dementia,” Brain 142:1723-35 (2019); Devous et al., “Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F18,” Journal of Nuclear Medicine 59:937-43 (2018); Southekal et al., “Flortaucipir F18 Quantitation Using Parametric Estimation of Reference Signal Intensity,” J. Nucl. Med. 59:944-51 (2018), which are incorporated by reference in their entireties), and / or visually assess the patient, e.g., to determine whether the patient has an AD pattern (Fleisher et al., “Positron Emission Tomography Imaging With F18-flortaucipir and Postmortem Assessment of Alzheimer's Disease Neuropathology” Changes,” JAMA Neurology 77:829-39 (2020), which is incorporated herein by reference in its entirety). Lower SUVr values ​​indicate lower tau burden, while higher SUVr values ​​indicate higher tau burden. In one embodiment, quantitative assessment from flortaucipir scans is achieved by an automated image processing pipeline described below (Southekal et al., “Flortaucipir F18 Quantitation Using Parametric Estimation of Reference Signal Intensity,” J. Nucl. Med. 59:944-951 (2018), which is incorporated herein by reference in its entirety).In some embodiments, counts within specific target regions of interest within the brain (e.g., multiblock centroid discriminant analysis or MUBADA, see Devous et al., "Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F18," J. Nucl. Med. 59:937-943 (2018)), which is incorporated herein by reference in its entirety, are compared to a reference region, e.g., the whole cerebellum (wholeCere), cerebellar GM (cereCrus), atlas-based white matter (atlasWM), or subject-specific WM (ssWM, e.g., using parametric estimation of reference signal intensity (PERSI)); see Southekal et al., "Flortaucipir F18 Quantitation Using Parametric Estimation of Reference Signal Intensity," J. Nucl. Med. 59:944-951 (2018), which is incorporated herein by reference in its entirety). The preferred method for determining tau burden is quantitative analysis reported as the standardized uptake value ratio (SUVr), which represents counts within a specific target region of interest in the brain when compared to a reference region (e.g., using PERSI) (e.g., MUBADA, 2014).

[0182] In some embodiments, phosphorylated tau (P-tau, phosphorylated at either threonine 181 or 217) may be used to measure tau load for purposes of the present disclosure (Barthelemy et al., "Cerebrospinal Fluid Phospho-tau T217 Outperforms T181 as a Biomarker for the Differential Diagnosis of Alzheimer's Disease and PET Amyloid-Positive Patient Identification," Alzheimer's Res. Ther. 12, 26, doi:10.1186 / s13195-020-00596-4 (2020); Mattsson et al., "Aβ Deposition is Associated with Increases in Soluble and Phosphorylated Tau that Precede a Positive Tau PET in Alzheimer's Disease," Science Advances 6, eaaz2387 (2020), which are incorporated herein by reference in their entireties. In certain embodiments, an antibody against human tau phosphorylated at threonine residue 217 may be used to measure tau load / burden in a subject for purposes of the present disclosure (see International Patent Application Publication No. WO2020 / 242963, which is incorporated by reference in its entirety). The present disclosure, in some embodiments, includes measuring tau load / burden in a subject using the anti-tau antibodies disclosed in WO2020 / 242963. The anti-tau antibodies disclosed in WO2020 / 242963 are directed against isoforms of human tau expressed in the CNS (e.g., they recognize isoforms expressed in the CNS, but not isoforms of human tau expressed only outside the CNS).Such antibodies against isoforms of human tau expressed in the CNS may be used in methods to identify / select patients as one or more of the following: (i) having a disease disclosed herein, (ii) at risk for a disease disclosed herein, (iii) in need of treatment for a disease disclosed herein, or (iv) in need of neurological imaging.

[0183] In some embodiments, a subject is positive for amyloid plaques if amyloid is detected in the brain by methods such as amyloid imaging with a radiolabeled PET compound or by using a diagnostic agent that detects Aβ or a biomarker of Aβ. Exemplary methods that can be used in the present disclosure to measure brain amyloid load / burden include, for example, florbetapir (Carpenter, et al., "The Use of the Exploratory IND in the Evaluation and Development of 18 F-PET Radiopharmaceuticals for Amyloid Imaging in the Brain: A Review of One Company's Experience,” The Quarterly Journal of Nuclear Medicine and Molecular Imaging 53.4:387 (2009), which is incorporated herein by reference in its entirety), florbetaben (Syed et al., “[ 18 [F]Florbetaben: A Review in β-Amyloid PET Imaging in Cognitive Impairment,” CNS Drugs 29, 605-613 (2015), which is incorporated herein by reference in its entirety), and flutemetamol (Heurling et al., “Imaging β-amyloid Using [ 18[F]Flutemetamol Positron Emission Tomography: From Dosimetry to Clinical Diagnosis,” European Journal of Nuclear Medicine and Molecular Imaging 43.2:362-373 (2016), which is incorporated herein by reference in its entirety.

[0184] F18-florbetapir can provide qualitative and quantitative measurements of brain plaque load in patients, including those with prodromal AD or mild AD dementia. For example, the absence of a significant F18-florbetapir signal upon visual reading indicates sparse to no amyloid plaques in patients clinically exhibiting cognitive impairment. Thus, F18-florbetapir also provides confirmation of amyloid pathology (see, e.g., Clark, et al., "Use of Florbetapir-PET for Imaging β-amyloid Pathology," JAMA 305.3:275-283 (2011), which is incorporated herein by reference in its entirety). F18-florbetapir PET also provides a quantitative assessment of fibrillar amyloid plaques in the brain and, in some embodiments, can be used to assess the reduction of amyloid plaques from the brain by the antibodies of the present disclosure. The F18-Florbetapir method can also be automated (see, e.g., Joshi, et al., "A Semiautomated Method for Quantification of F18 Florbetapir PET Images," J. Nuclear Medicine 56.11:1736-1741 (2015), which is incorporated herein by reference in its entirety).

[0185] Amyloid imaging with radiolabeled PET compounds can be used to determine whether Aβ deposits are reduced or increased in the brain of a human patient (e.g., to calculate the percentage reduction in Aβ deposits after treatment or to assess the progression of AD). One skilled in the art can correlate the standardized uptake value ratio (SUVr) values ​​obtained from amyloid imaging (using radiolabeled PET compounds) to calculate the % reduction in Aβ deposits in the patient's brain before and after treatment. SUVr values ​​can be converted to standardized centiloid units, where 100 is the mean for AD and 0 is the mean for young controls, allowing for comparisons between amyloid PET tracers and calculation of reductions according to centiloid units (Klunk et al., "The Centiloid Project: Standardizing Quantitative Amyloid Plaque Estimation by PET," Alzheimer's & Dementia 11.1:1-15 (2015) and Navitsky et al., "Standardization of Amyloid Quantitation with Florbetapir Standardized Uptake Value Ratios to the Centiloid Scale," Alzheimer's & Dementia 14.12:1565-1571 (2018), which are incorporated herein by reference in their entireties). In some embodiments, change in cerebral amyloid plaque deposition from baseline is measured by F18-florbetapir PET scan.

[0186] Cerebrospinal fluid or plasma-based assays of β-amyloid may also be used to measure amyloid load / burden for the purposes of this disclosure. For example, Aβ42 can be used to measure brain amyloid (Palmqvist, S. et al., "Accuracy of Brain Amyloid Detection in Clinical Practice Using Cerebrospinal Fluid Beta-amyloid 42: a Cross-validation Study Against Amyloid Positron Emission Tomography. JAMA Neurol 71, 1282-1289 (2014), incorporated herein by reference in its entirety). In some embodiments, the ratio of Aβ42 / Aβ40 or Aβ42 / Aβ38 can be used as amyloid beta biomarkers (Janelidze et al., "CSF Abeta42 / Abeta40 and Abeta42 / Abeta38 Ratios: Better Diagnostic Markers of Alzheimer Disease," Ann Clin Transl Neurol 3, 154-165 (2016), incorporated herein by reference in its entirety).

[0187] In some embodiments, deposited cerebral amyloid plaques or Aβ in CSF or plasma can be used to stratify subjects into groups and identify which groups of subjects will respond to disease treatment / prevention (as described herein) using the antibodies, dosing regimens, or methods described herein.

[0188] As used herein, the terms "anti-N3pGlu Aβ antibody," "anti-N3pG antibody," or "anti-N3pE antibody" are used interchangeably and refer to an antibody that preferentially binds to N3pGlu Aβ over Aβ1-40 or Aβ1-42. Those skilled in the art will understand and appreciate that "anti-N3pGlu Aβ antibodies," as well as several specific antibodies, including "hE8L," "B12L," and "R17L," are identified and disclosed (along with methods of making and using) in U.S. Patent No. 8,679,498 B2, which is incorporated herein by reference in its entirety. See, for example, Table 1 in U.S. Patent No. 8,679,498 B2. Each of the antibodies disclosed in U.S. Patent No. 8,679,498 B2, including the "hE8L," "B12L," and "R17L" antibodies, can be used as the anti-N3pGlu Aβ antibody of the present disclosure or in place of the anti-N3pGlu Aβ antibodies described in various aspects of the present disclosure. Other representative species of anti-N3pGlu Aβ antibodies include, but are not limited to, U.S. Pat. No. 8,961,972, U.S. Pat. No. 10,647,759, U.S. Pat. No. 9,944,696, WO2010 / 009987A2, WO2011 / 151076A2, WO2012 / 136552A1 and equivalents thereof, e.g., antibodies disclosed under 35 U.S.C. § 112(f).

[0189] Those skilled in the art will understand and appreciate that "anti-N3pGlu Aβ antibodies," and several specific antibodies, are identified and disclosed (along with methods of making and using such antibodies) in U.S. Patent No. 8,961,972 (hereby incorporated by reference in its entirety), U.S. Patent No. 10,647,759 (hereby incorporated by reference in its entirety), and U.S. Patent No. 9,944,696 (hereby incorporated by reference in its entirety). Any of the anti-N3pGlu Aβ antibodies disclosed in U.S. Patent Nos. 8,961,972, 9,944,696, and 10,647,759 can be used as the anti-N3pGlu Aβ antibody of the present disclosure or in place of the anti-N3pGlu Aβ antibodies described in various aspects of the present disclosure.

[0190] Those skilled in the art will understand and appreciate that several specific antibodies, including "anti-N3pGlu Aβ antibodies," as well as "Antibody VI," "Antibody VII," "Antibody VIII," and "Antibody IX," are identified and disclosed (along with methods of making and using such antibodies) in WO 2010 / 009987 A2, which is incorporated herein by reference in its entirety. Each of these four antibodies (e.g., "Antibody VI," "Antibody VII," "Antibody VIII," and "Antibody IX") can be used as the anti-N3pGlu Aβ antibody of the present disclosure or in place of the anti-N3pGlu Aβ antibodies described in various aspects of the present disclosure.

[0191] Those skilled in the art will understand and appreciate that several specific antibodies, including "anti-N3pGlu Aβ antibodies," and "Antibody X" and "Antibody XI," are identified and disclosed (along with methods of making and using such antibodies) in WO2011 / 151076A2, which is incorporated herein by reference in its entirety. Each of these two antibodies (e.g., "Antibody X" and "Antibody XI") can be used as the anti-N3pGlu Aβ antibody of the present disclosure or in place of the anti-N3pGlu Aβ antibodies described in various aspects of the present disclosure.

[0192] Those skilled in the art will understand and appreciate that several specific antibodies, including "anti-N3pGlu Aβ antibodies," as well as "Antibody XII" and "Antibody XIII," are identified and disclosed (along with methods for making and using such antibodies) in WO2012 / 136552A1, which is incorporated herein by reference in its entirety. Each of these two antibodies (e.g., "Antibody XII" and "Antibody XIII") can be used as the anti-N3pGlu Aβ antibody of the present disclosure or in place of the anti-N3pGlu Aβ antibodies described in various aspects of the present disclosure.

[0193] As used herein, an "antibody" is an immunoglobulin molecule comprising two HCs and two LCs interconnected by disulfide bonds. The amino-terminal portions of each LC and HC comprise variable regions involved in antigen recognition via the complementarity-determining regions (CDRs) contained therein. The CDRs are interspersed with more conserved regions called framework regions. The assignment of amino acids to the CDR domains within the LCVR and HCVR regions of the antibodies of the present invention is based on the Kabat numbering convention (Kabat, et al., Ann. NY Acad. Sci. 190:382-93 (1971); Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, USDapartment of Health and Human Services, NIH Publication No. 91-3242 (1991)) and the North numbering convention (North et al., A New Clustering of Antibody CDR Loop Conformations, Journal of Molecular Biology, 406:228-256 (2011)). The CDRs of the antibodies of the present disclosure were determined according to the above methods.

[0194] The antibodies of the present disclosure are monoclonal antibodies ("mAbs"). Monoclonal antibodies can be produced, for example, by hybridoma technology, recombinant technology, phage display technology, synthetic technology, such as CDR grafting, or a combination of such techniques or other techniques known in the art. The monoclonal antibodies of the present disclosure are human or humanized. Humanized antibodies can be engineered to contain one or more human framework regions (or substantially human framework regions) surrounding CDRs derived from a non-human antibody. Human framework germline sequences can be obtained from ImmunoGeneTics (INGT) via its website, http: / / imgt.cines.fr, or from The Immunoglobulin Facts Book by Marie-Paule Lefranc and Gerard Lefranc, Academic 25 Press, 2001, ISBN 01244135. Techniques for generating human or humanized antibodies are well known in the art. In another embodiment of the present disclosure, the antibody or nucleic acid encoding it is provided in isolated form. As used herein, the term "isolated" refers to a protein, peptide, or nucleic acid that is free or substantially free of any other macromolecular species found in a cellular environment. "Substantially free," as used herein, means that the protein, peptide, or nucleic acid of interest contains more than 80% (on a molar basis), preferably more than 90%, and more preferably more than 95% of the macromolecular species present.

[0195] The anti-N3pGlu Aβ antibodies of the present disclosure are administered as pharmaceutical compositions. Pharmaceutical compositions comprising the antibodies of the present disclosure can be administered to subjects at risk of or exhibiting a disease or disorder described herein via a parenteral route (e.g., subcutaneously, intravenously, intraperitoneally, intramuscularly). Subcutaneous and intravenous routes are preferred. In some embodiments, the anti-N3pGlu Aβ antibodies are administered by intravenous infusion.

[0196] Terms such as "treatment," "treating," or "treat" include inhibiting, slowing, or halting the progression or severity of an existing symptom, condition, disease, or disorder in a subject. The term "subject" refers to a human.

[0197] The term "prevention" refers to the prophylactic administration of an antibody of the present disclosure to an asymptomatic subject or a subject with preclinical Alzheimer's disease to prevent the onset or progression of the disease.

[0198] The terms "disease characterized by Aβ deposition" or "disease characterized by Aβ plaques" are used interchangeably and refer to diseases pathologically characterized by Aβ plaques in the brain or cerebral vasculature. This includes diseases such as Alzheimer's disease, Down's syndrome, and cerebral amyloid angiopathy. The clinical diagnosis, staging, or progression of Alzheimer's disease can be readily determined by an attending diagnostician or medical professional, such as one skilled in the art, by using known techniques and observing the results. This generally involves brain plaque imaging, psychiatric or cognitive assessments (e.g., Clinical Dementia Rating-Summary of Boxes (CDR-SB), Mini-Mental State Examination (MMSE), or Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog)), or functional assessments (e.g., Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL)). Cognitive and functional assessments can be used to determine changes in a patient's cognition (e.g., cognitive decline) and function (e.g., functional decline). As used herein, "clinical Alzheimer's disease" refers to a diagnosed stage of Alzheimer's disease. This includes conditions diagnosed as prodromal Alzheimer's disease, mild Alzheimer's disease, moderate Alzheimer's disease, and severe Alzheimer's disease. The term "preclinical Alzheimer's disease" refers to a stage preceding clinical Alzheimer's disease, characterized by measurable changes in biomarkers (e.g., amyloid PET, CSF Preclinical Alzheimer's disease also includes presymptomatic autosomal dominant carriers, patients who carry one or two APOE4 alleles and are therefore at high risk for developing AD.

[0199] A reduction or slowing of cognitive decline can be measured by a cognitive assessment such as the Clinical Dementia Rating-Summary of Boxes, Mini-Mental State Examination, or Alzheimer's Disease Assessment Scale-Cognition. A reduction or slowing of functional decline can be measured by a functional assessment such as the ADCS-ADL.

[0200] As used herein, "mg / kg" refers to the amount of an antibody or drug administered to a subject in milligrams based on the subject's body weight in kilograms. The dose is given at one time. For example, a 10 mg / kg dose of an antibody to a subject weighing 70 kg is a single 700 mg dose of the antibody administered in a single dose. Similarly, a 20 mg / kg dose of an antibody to a subject weighing 70 kg is a 1400 mg dose of the antibody administered in a single dose.

[0201] In some embodiments, each dose of anti-N3pGlu Aβ antibody is administered intravenously to a subject over at least 30 minutes at a concentration of about 4 mg / mL to about 10 mg / mL. In some embodiments, a 700 mg dose of anti-N3pGlu Aβ antibody is reconstituted to form 40 mL of reconstituted solution, which is further diluted to reach an antibody concentration of about 4 mg / mL to about 10 mg / mL, and the diluted solution is administered intravenously to a subject over a 30 minute period. In some embodiments, a 1400 mg dose of anti-N3pGlu Aβ antibody is reconstituted to form 80 mL of reconstituted solution, which is further diluted to reach an antibody concentration of about 4 mg / mL to about 10 mg / mL, and the diluted solution is administered intravenously to a subject over a 30 minute period.

[0202] As used herein, 18Using F-flortaucipir-based quantitative analysis, a human subject has a "very low tau" burden if the tau burden is less than 1.10 SUVr (<1.10 SUVr), where quantitative analysis refers to the calculation of SUVr, which represents counts within a specific target region of interest in the brain when compared to a reference region (multiblock centroid discriminant analysis or MUBADA, see Devous et al., "Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F18," J. Nucl. Med. 59:937-943 (2018)) (parametric estimation of reference signal intensity or PERSI, see Southekal et al., "Flortaucipir F18 Quantitation Using Parametric Estimation of Reference Signal Intensity," J. Nucl. Med. 59:944-951 (2018)).

[0203] As used herein, 18 Using F-flortaucipir-based quantitative analysis, a human subject has a "very low to moderate tau" load if the tau load is 1.46 SUVr or less (i.e., ≦1.46 SUVr), where quantitative analysis refers to the calculation of SUVr, which represents counts within a specific target region of interest in the brain when compared to a reference region (see MUBADA, Devous et al., "Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F18," J. Nucl. Med. 59:937-943 (2018)) (see PERSI, Southekal et al., "Flortaucipir F18 Quantitation Using Parametric Estimation of Reference Signal Intensity," J. Nucl. Med. 59:944-951 (2018)).

[0204] As used herein,18 Using F-flortaucipir-based quantitative analysis, a human subject has a "low to moderate tau" burden if the tau burden is greater than or equal to 1.10 SUVr and less than or equal to 1.46 SUVr (i.e., ≥1.10 SUVr to ≤1.46 SUVr). Quantitative analysis refers to the calculation of SUVr, which represents counts within a specific target region of interest in the brain compared to a reference region (see MUBADA, Devous et al., "Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F18," J. Nucl. Med. 59:937-943 (2018)). (PERSI, see Southekal et al., "Flortaucipir F18 Quantitation Using Parametric Estimation of Reference Signal Intensity," J. Nucl. Med. 59:944-951 (2018)). "Low to moderate tau" load is also referred to as "intermediate" tau load.

[0205] As used herein, 18 Using F-flortaucipir-based quantitative analysis, a human subject has a "high tau" burden if the tau burden is greater than 1.46 SUVr (i.e., >1.46 SUVr), and quantitative analysis refers to the calculation of SUVr, which represents counts within a specific target region of interest in the brain when compared to a reference region (see MUBADA, Devous et al., "Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F18," J. Nucl. Med. 59:937-943 (2018)) (see PERSI, Southekal et al., "Flortaucipir F 18 Quantitation Using Parametric Estimation of Reference Signal Intensity," J. Nucl. Med. 59:944-951 (2018)).

[0206] As used herein, early symptomatic Alzheimer's disease encompasses the mild cognitive impairment stage of AD (also known as prodromal AD) and the mild dementia stage of AD. The National Institute on Aging and Alzheimer's Association (NIA-AA) has developed a framework to help define Alzheimer's disease (see Jack et al., "NIA-AA Research Framework: Toward a Biological Definition of Alzheimer's Disease," Alzheimer's & Dementia: The Journal of the Alzheimer's Association 14(4)535-562 (2018), which is incorporated herein by reference in its entirety).

[0207] As used herein, mild cognitive impairment is defined as cognitive performance below the expected range for that individual based on all available information. This may be based on clinical judgment and / or performance on cognitive testing. Cognitive performance is typically within the impaired / abnormal range based on population norms, but this is not required as long as performance is below the range expected for that individual. In addition to evidence of cognitive impairment, there must also be evidence of a decline in cognitive performance from baseline. This may be reported by the individual or an observer, or observed by changes in longitudinal cognitive testing / behavioral assessments, or a combination of these. At this stage, the individual independently performs activities of daily living, but cognitive difficulties may result in detectable but mild functional impact on more complex activities of daily living, either by self-report or corroboration by a research partner. As used herein, mild dementia is defined as substantial, progressive cognitive and / or neurobehavioral impairment affecting several domains. This may be documented by individual report, observer (e.g., research partner) report, or changes in longitudinal cognitive testing. This stage involves a clear functional impact on daily living, primarily affecting instrumental activities, and the individual is no longer fully independent and requires occasional assistance with activities of daily living. If AD has worsened to the point where a) there is impairment in basic activities and a significant functional impact on daily living, and b) the individual is no longer independent and requires frequent assistance with activities of daily living, the individual is considered to not have mild AD dementia.

[0208] As used herein, the term "about" means up to ±10%.

[0209] The terms "subject" and "patient" are used interchangeably in this disclosure.

[0210] The terms "first dose" and "low dose" may be used interchangeably in this disclosure. The terms "second dose" and "high dose" may be used interchangeably in this disclosure.

[0211] The phrases "slowing decline" and "slowing disease progression" are used interchangeably in this disclosure.

[0212] As used herein, "method of treatment" is equally applicable to the use of a composition to treat a disease or disorder described herein and / or the use of a composition in and / or for use in the manufacture of a medicament to treat a disease or disorder described herein.

[0213] The following examples further illustrate the present disclosure, however, it should be understood that the following examples are given by way of illustration rather than limitation, and that various modifications may be made by those skilled in the art. [Example]

[0214] Example 1: Expression and purification of engineered N3pGlu Aβ antibodies Antibodies against N3pGlu Aβ are known in the art. For example, U.S. Patent Nos. 8,679,498 and 8,961,972 (incorporated herein by reference in their entireties) disclose anti-N3pGlu Aβ antibodies, methods for making the antibodies, antibody formulations, and methods for using the antibodies to treat diseases such as Alzheimer's disease.

[0215] An exemplary method for expressing and purifying an anti-N3pGlu Aβ antibody of the present disclosure is as follows: Suitable host cells, such as HEK293EBNA or CHO, can be either transiently or stably transfected with an expression system for antibody secretion using an optimal, predetermined heavy chain to light chain (HC:LC) vector ratio, or a single vector system encoding both HC and LC. The clarified medium into which the antibody is secreted is purified using any of a number of commonly used techniques. For example, the medium can be conveniently applied to a Protein A or G Sepharose FF column equilibrated with a compatible buffer, such as phosphate-buffered saline (pH 7.4). The column is washed to remove nonspecifically bound components. The bound antibody is eluted, for example, by a pH gradient (e.g., from 0.1 M sodium phosphate buffer (pH 6.8) to 0.1 M sodium citrate buffer (pH 2.5)). The antibody fractions are detected, for example, by SDS-PAGE, and pooled. Depending on the intended use, further purification is optional. The antibody may be concentrated and / or sterile filtered using common techniques. Soluble aggregates and multimers may be effectively removed by common techniques, including size exclusion, hydrophobic interaction, ion exchange, or hydroxyapatite chromatography. The purity of the antibody after these chromatography steps may be greater than 99%. The product may be immediately frozen at -70°C or lyophilized. The amino acid sequences of some of the anti-N3pGlu Aβ antibodies of the present disclosure are provided in the Sequence Listing.

[0216] Example 2: Evaluation of the safety, tolerability, and efficacy of anti-N3pGlu Aβ antibodies The multicenter, randomized, double-blind, placebo-controlled, Phase 2 clinical study (NCT03367403, clinicaltrials.gov) (also known as TRAILBLZER-ALZ or AACG) was designed to evaluate the safety and efficacy of an N3pGlu Aβ antibody (also referred to herein as donanemab) in AD subjects with early symptomatic AD (i.e., subjects with mild cognitive impairment or mild dementia due to AD). The study evaluated, among other things, whether removal of existing amyloid plaques over up to 72 weeks of treatment could slow disease progression as determined by clinical measures and biomarkers of disease pathology and neurodegeneration.

[0217] This study was a 133-week study, including a screening period of up to 9 weeks, a treatment period of up to 72 weeks with a final assessment 4 weeks later at week 76, and 48 weeks of immunogenicity and safety follow-up (see Figure 1). Figure 1 shows the study design of the clinical protocol.

[0218] Treatment Groups and Duration: Approximately 1,497 patients were screened and approximately 266 were randomized. Patients received treatment for up to 72 weeks. Donanemab: Intravenous donanemab (700 mg Q4WK for the first 3 doses, then 1400 mg Q4WK) for up to 72 weeks, or ●Placebo: Intravenous placebo Q4WK for up to 72 weeks.

[0219] Primary and secondary endpoints: The primary endpoints of this study were: • Cognitive and functional change as measured by change in integrated Alzheimer's Disease Rating Scale (iADRS) score from baseline to 18 months.

[0220] The secondary endpoints of this study were: Cognitive change from baseline to 18 months as measured by: ADAS-Cog 13Change in score, change in Clinical Dementia Rating Scale-Sum of Boxes score (CDR-SB), change in Mini-Mental State Examination score (MMSE), and change in Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living Scale (ADCS-iADL) score. Change in cerebral amyloid plaque deposition from baseline to 18 months as measured by F18-florbetapir PET scan. Change in brain tau deposition from baseline to 18 months as measured by F18-flortaucipir PET scan. • Change in volumetric MRI measurements from baseline to 18 months.

[0221] Safety Endpoints: The safety endpoints of this study were: Standard safety assessments: spontaneously reported adverse events (AEs), clinical tests, vital signs and weight measurements, 12-lead electrocardiogram (ECG), physical and neurological examinations. ●MRI (Amyloid-related imaging abnormalities [ARIA] and emergency radiological findings) Columbia-Suicide Severity Rating Scale (C-SSRS)

[0222] Statistical Analysis: All efficacy analyses followed the intention-to-treat (ITT) principle unless otherwise specified. An ITT analysis is the analysis of data by group to which subjects were assigned by random assignment, even if they did not receive the assigned treatment, did not receive the correct treatment, or otherwise did not follow the protocol. Pairwise tests of treatment effects were performed at a two-sided alpha (α) level of 0.05 unless otherwise noted. Two-sided confidence intervals (CI) are presented at the 95% confidence level.

[0223] Efficacy: The primary objective of this study was to test the hypothesis that intravenous infusion of donanemab slows cognitive and / or functional decline associated with AD, as measured by the composite iADRS scale, compared with placebo, in patients with early symptomatic AD. Changes from baseline score on the iADRS at each scheduled post-baseline visit during the treatment period were analyzed using a MMRM model, which included the following terms: baseline score, pooled investigator, treatment, visit, treatment-by-visit interaction, baseline-by-visit interaction, concomitant use of acetylcholinesterase inhibitors (AChEIs) and / or memantine at baseline (yes / no), and age at baseline. The primary time point for treatment comparisons was the end of the double-blind treatment period (week 76). Treatment group contrasts in least-squares mean progression and their associated p-values ​​and 95% CIs were calculated for the donanemab vs. placebo treatment comparison. In addition, we calculated the Bayesian posterior probability of the active treatment group being superior to placebo by at least the margin of interest (slowing progression of placebo by 25%).

[0224] ADAS-Cog 13 Changes from baseline at each scheduled post-baseline visit during the treatment period in secondary efficacy outcomes, including ADCS-iADL, CDR-SB, and MMSE, will be analyzed using the same MMRM model described in the primary analysis.

[0225] Safety: Safety will be assessed by summarizing and analyzing adverse events (AEs), clinical laboratory parameters, vital signs, MRI scans, ECGs, and immunogenicity during the double-blind treatment period.

[0226] Pharmacokinetics / Pharmacodynamics: The pharmacokinetic or pharmacodynamic (PK / PD) relationships between plasma donanemab concentrations and SUVr, cognitive function endpoints, ARIA incidence, or other markers of PD activity were investigated graphically. The relationships between the presence of antibodies to donanemab and PK, PD, safety, and / or efficacy may be evaluated graphically. If warranted, additional analyses may be considered to evaluate potential interactions between anti-drug antibodies, PD, and other endpoints (PET scan, ARIA-E, etc.). Additional modeling may be performed based on the results of graphical analysis.

[0227] Dosing and Dose Justification: Donanemab (700 mg or 1400 mg) will be administered every 4 weeks as an IV infusion of approximately 140 mL over a minimum of 30 minutes. The 700 mg and 1400 mg donanemab doses, administered intravenously once every 4 weeks, will be selected based on current preclinical pharmacology and toxicology data, and clinical PK, PD, and safety data. Prior and ongoing exposures will include 0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, 3 mg / kg, 10 mg / kg, 20 mg / kg, and 40 mg / kg doses in single and / or multiple dose dosing schedules. Data from Study AACC (NCT01837641, clinicaltrials.gov) suggest that the PK of donanemab is linear when doses are 10 mg / kg or higher. At doses of 10 mg / kg or higher, the mean half-life is approximately 9–11 days, and plasma PK accumulation is predicted to be minimal at 700 mg and 1400 mg IV dosing every 4 weeks. A high level of F18-florbetapir PET signal reduction was observed with a single 20 mg / kg dose, comparable to that seen with a 10 mg / kg 2-weekly dosing schedule over 3 months. Based on this and the reduced patient burden and comparable safety profile of a 4-weekly dosing schedule compared with a 2-weekly dosing schedule, a 1400 mg 4-weekly dosing schedule was selected as the highest dose regimen for robust amyloid plaque reduction. The lowest rate of ARIA-E was observed with a monthly 10 mg / kg dosing schedule. Therefore, a titration schedule (first three doses at 700 mg every 4 weeks, followed by 1400 mg every 4 weeks) is proposed to reduce the incidence of ARIA while enabling patients to achieve high PD efficacy. In addition, dose reduction rules have been established for the ARIA-E accident.

[0228] Inclusion Criteria: Patients, both males and females, aged 60 to 85 years (inclusive) at the time of informed consent were eligible to enroll in the study. Patients may demonstrate gradual and progressive changes in memory function as reported by the patient or study partner (informant) for at least 6 months. In some cases, patients may have an MMSE score of 20 to 28 (inclusive) at Visit 1 or an acceptable previous F18-flortaucipir PET scan within the 6 months prior to Visit 1, meeting the central reading criteria. Patients may also meet the F18-flortaucipir scan (central reading) criteria and / or the F18-florbetapir scan (central reading) criteria.

[0229] Exclusion criteria: Patients will be excluded from study enrollment if they meet any of the following criteria: Modified Hachinski Ischemia Scale (MHIS, Hachinski et al. al. 1975) score ≥ 4; lacking sufficient premorbid literacy, sufficient vision, or sufficient hearing, in the opinion of the investigator, to complete the required psychometric testing; significant neurological disease affecting the central nervous system (CNS) other than AD that may affect cognition or ability to complete the study, including, but not limited to, other dementias, serious infection of the brain, Parkinson's disease, multiple concussions, or epilepsy or recurrent seizures (excluding childhood febrile seizures); current serious or unstable illness, including cardiovascular, liver, kidney, gastrointestinal, respiratory, endocrine, neurological (other than Alzheimer's disease), psychiatric, immune, or hematologic disorders, and other conditions that, in the opinion of the investigator, may interfere with the analysis of this study; or life expectancy less than 24 months; excluding nonmetastatic basal cell and / or squamous cell carcinoma of the skin, cervical carcinoma in situ, non-advanced prostate cancer, or other cancers with a low risk of recurrence or metastasis. , a history of cancer within the past 5 years; a current primary psychiatric diagnosis other than AD if, in the investigator's judgment, the psychiatric disorder or symptom may confound interpretation of drug effect, affect cognitive assessment, or affect the patient's ability to complete the study; a history of schizophrenia or other chronic psychosis; a history of long QT syndrome; clinically determined by the investigator to be at significant risk for suicide as assessed by medical history, examination, or C-SSRS; a history of alcohol or drug use disorder (excluding smoking disorder) within 2 years prior to the screening visit; a history of clinically significant multiple or severe drug allergies or severe post-treatment hypersensitivity reactions (including, but not limited to, erythema multiforme major, linear immunoglobulin A dermatosis, toxic epidermal necrolysis, and / or exfoliative dermatitis); or known positive serology for human immunodeficiency virus (HIV) antibodies. Local laws and regulations may apply regarding whether testing is required.At screening, any clinically significant abnormality in the physical or neurological examination, vital signs, ECG, or laboratory test results that, as determined by the investigator, may be harmful to the patient, may interfere with the study, or shows evidence of another etiology of dementia; a screening MRI showing evidence of significant abnormalities suggesting another potential etiology of progressive dementia or clinically significant findings that may affect the patient's ability to safely participate in the study; claustrophobia or contraindicated metal (ferromagnetic) implants / cardiac pacemakers. Contraindications to MRI, such as the presence of a manufacturer; central-read MRI showing ARIA-E, more than four cerebral microbleeds, more than one superficial siderosis, any macroscopic hemorrhage, or the presence of severe white matter disease; mean (three ECGs) corrected QT (QTcF) interval measurement at screening >450 msec (men) or >470 msec (women) (determined by the clinical trial site); patients with a history of hepatitis B should undergo HBsAg testing at screening, and a positive HBsAg result will exclude them; patients with a history of hepatitis C should undergo HCV RNA PCR testing at screening, and a positive HCV RNA PCR result will exclude them; calculated creatinine clearance <30 mL / min (Cockcroft-Gault formula, Cockcroft and Gault 1976); alanine transaminase (ALT) ≥ 2 × upper limit of normal (ULN) for the laboratory in question, aspartate aminotransferase (AST) ≥ 2 × ULN, total bilirubin level (TBL) ≥ 1.5 × ULN, or alkaline phosphatase (ALP) ≥ 1.5 × ULN at screening; treatment with stable doses of AChEI and / or memantine for less than 2 months prior to randomization; changes in concomitant medications that may affect cognition, which must have been stable for at least 1 month prior to screening and for at least 1 year between screening and randomization (this does not apply to medications that are discontinued due to exclusion or limited duration of use, such as antibiotics); current use of medications known to significantly prolong the QT interval; treatment with passive anti-amyloid immunotherapy with a half-life < 5 before randomization; active immunization against Aβ in another study;Known allergy to donanemab, related compounds, or any component of the formulation; or history of significant atopy; allergy to monoclonal antibodies, diphenhydramine, epinephrine, or methylprednisolone; sensitivity to F18-flobetapir or F18-flortaucipir; contraindication to MRI; contraindication to PET; current or planned exposure to ionizing radiation that, when combined with the planned administration of the investigational PET ligand, could result in cumulative exposure exceeding local recommended exposure limits;

[0230] Dose Modification for ARIA-E: Dose modifications of donanemab will be adjusted for the occurrence of ARIA-E in the following cases as shown in Table A. If a dose reduction is necessary, the dose of donanemab will be reduced to the next lower dose (1400 mg to 700 mg, or 700 mg to placebo). [Table 1]

[0231] All cases of ARIA-E require unscheduled MRI scans every 4 to 6 weeks until the ARIA-E resolves.

[0232] Discontinuation of Study Treatment: Reasons that may lead to permanent discontinuation of study treatment: subject decision (e.g., request to discontinue study drug by subject or subject's designee or legal guardian), or discontinuation due to a hepatic event or abnormal liver test. Subjects who are discontinued from study drug due to a hepatic event or abnormal liver test will require collection of additional hepatic safety data via CRF / electronic data entry.

[0233] Discontinuation of study drug for liver test abnormalities will be considered if the subject meets any of the following conditions: alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8 × upper limit of normal (ULN); ALT or AST >5 × ULN for more than 2 weeks; ALT or AST >3 × ULN and total bilirubin level (TBL) >2 × ULN or international normalized ratio (INR) >1.5; ALT or AST >3 × ULN with the occurrence of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and / or eosinophilia (>5%); alkaline phosphatase (ALP) >3 × ULN; ALP >2.5 × ULN and TBL >2 × ULN; or ALP >2.5 × ULN with the occurrence of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and / or eosinophilia (>5%).

[0234] In addition, subjects will be discontinued from the investigational product under the following circumstances: Treatment with donanemab is permanently discontinued in patients with: recurrence of ARIA-E after a previous dose reduction or temporary discontinuation of donanemab, Any increase in ARIA-H accompanied by clinically significant symptoms, >4 new microbleeds, >1 new superficial siderosis or significant worsening of existing superficial siderosis, or macrobleeds regardless of symptoms, or ARIA-E events reported as serious adverse events (SAEs), regardless of symptom severity or MRI findings. Donanemab treatment will also be permanently discontinued in patients with: prolonged acute infusion reaction (i.e., unresponsive to medications such as antihistamines, nonsteroidal anti-inflammatory drugs, and / or narcotics, and / or short-term interruption of the infusion), or Adverse events or clinically significant laboratory values, electrocardiogram results, physical examination findings, MRI findings (such as symptomatic ischemic stroke),

[0235] Suspension of donanemab study treatment due to ARIA-E A temporary interruption of donanemab treatment is permitted if the ARIA-E meets the interruption criteria listed in Table A. In the case of an ARIA-E where the protocol indicates continued dosing or a dose reduction rather than a temporary interruption, administration of donanemab may be temporarily discontinued.

[0236] For example, if medication is temporarily discontinued due to ARIA-E and symptoms and radiological findings completely resolve within 16 weeks after temporary drug discontinuation, donanemab may be resumed after the first episode of ARIA-E. If symptoms and radiological findings of ARIA-E do not completely resolve within 16 weeks, patients will be permanently discontinued from donanemab treatment.

[0237] The study drug may be restarted at either 700 mg or placebo in a double-blind fashion, depending on the original study arm to which the patient was randomly assigned. An unscheduled safety MRI scan is required 4 to 6 weeks after dose restart.

[0238] Efficacy Assessment: Cognitive and functional testing will be conducted using the eCOA tablet. Audio recordings of assessor questions and patient and study partner responses will also be collected via the eCOA tablet during cognitive and functional testing to centrally monitor assessor scale administration. Cognitive and functional testing for each patient should be conducted at approximately the same time each day to reduce potential variability. Note that the ADAS-Cog and MMSE should be administered by a different assessor than the ADCS-ADL and CDR. These two assessors should continue administering the same scales for the same patients throughout the study. If possible, each assessment should be conducted for a specific patient by the same assessor at each visit. The principal investigator (PI) is responsible for selecting the assessor to administer the instruments on-site, provided that the assessor meets all training requirements.

[0239] If administered, cognitive and functional testing should be performed first before potentially stressful medical procedures (e.g., blood draws). Note that some procedures (MRI, F18-flortaucipir PET tau imaging, F18-florbetapir PET amyloid imaging) may be performed on other days within the visit window.

[0240] Primary efficacy endpoint: The integrated Alzheimer's Disease Rating Scale (iADRS, Wessels et al., "A Combined Measure of Cognition and Function for Clinical Trials: The Integrated Alzheimer's Disease Rating Scale (iADRS)," J Prev Alzheimer's Dis. 2(4):227-241 (2015), which is incorporated herein by reference in its entirety). The iADRS represents a composite developed using both a theory-driven approach (incorporating measures of both cognition and function) and a data-mining approach (identifying the most sensitive combination of scales through analysis of data from the Alzheimer's Disease Neuroimaging Initiative). The iADRS is a composite of two well-established, treatment-sensitive, and widely accepted measures of Alzheimer's disease: the ADAS-Cognitive Assessment Score (ADAS-Cognitive Assessment Score). 13 The iADRS is a simple linear combination of the ADCS-Cog and ADCS-iADL scores, which measure the core domains of AD. All items from these two scales were included without additional item weighting, allowing for face validity and ease of interpretation of the composite relative to its components. The iADRS score is a linear combination of the ADAS-Cog and ADCS-iADL scores. 13 and ADCS-iADL, and is the primary efficacy measure. 13 and ADCS-ADL are the actual scales administered to patients.

[0241] Secondary efficacy assessment: ADAS-Cog 13Immediately following the assessment, additional clinical outcome measures should be administered in the same order at every visit. To minimize missing data, the assessor should include each measure verbally with the patient or study partner (as specified in the instructions) and record responses appropriately. The same study partner should be used as the informant at all visits.

[0242] Alzheimer's Disease Assessment Scale-Cognitive Subscale: ADAS-Cog 13 The ADAS-Cog is a rater-administered instrument designed to assess the severity of characteristic cognitive and non-cognitive behavioral impairments in individuals with AD (Rosen et al., "A New Rating Scale for Alzheimer's Disease," Am J Psychiatry. 141(11):1356-1364 (1984), which is incorporated herein by reference in its entirety). 13 The ADAS-Cognitive subscale should be administered by the same assessor at each visit to reduce potential variability. 13 The ADAS-Cog consists of 13 items that assess the areas of cognitive function most typically impaired in AD: orientation, verbal memory, language, praxis, delayed free recall, digit elimination, and maze completion (Mohs et al., “Development of Cognitive Instruments for Use in Clinical Trials of Antidementia Drugs: Additions to the Alzheimer's Disease Assessment Scale that Broaden its Scope,” The Alzheimer's Disease Cooperative Study. Alzheimer Dis Assoc Disord. 11(Suppl 2):S13-S21 (1997), which is incorporated herein by reference in its entirety). 13は It is included as a secondary outcome because it is able to better discriminate between mildly affected patients than the ADAS-Cog11. 13The scale ranges from 0 to 85, with higher scores indicating greater disease severity.

[0243] Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory: The ADCS-ADL is a 23-item inventory designed as an assessor-administered questionnaire that must be completed by the patient's research partner (Galasko et al., "An Inventory to Assess Activities of Daily Living for Clinical Trials in Alzheimer's Disease," The Alzheimer's Disease Cooperative Study. Alzheimer Dis Assoc Disord. 1997;11(Suppl 2):S33-S39; Galasko et al., "Galantamine Maintains Ability to Perform Activities of Daily Living in Patients with Alzheimer's Disease," J Am Geriat Soc. 52(7):1070-1076 (2004), which are incorporated herein by reference in their entireties). The ADCS-ADL should be administered by the same assessor at each visit to reduce potential variability. The ADCS-ADL subset (items 7–23) of items related to instrumental activities of daily living (ADCS-iADL) is used as a secondary efficacy measure. The focus in the early symptomatic AD population is on instrumental activities of daily living (iADL), rather than basic activities of daily living (bADL), which are thought to be affected in more severe stages of the disease. iADL scores range from 0 to 56, with lower scores indicating greater disease severity. For each specific item, the research partner first asks whether the patient has attempted an ADL within the past 4 weeks. If the patient has attempted an ADL, the research partner is asked to rate the patient's level of ability based on a series of ability descriptions. Scores for each item and a total score for the tool are calculated. The total ADCS-ADL score ranges from 0 to 78, with higher scores indicating greater levels of disability. A separate bADL score (0–22) is also calculated.

[0244] Clinical Dementia Rating Scale: The CDR is a semi-structured interview administered to the patient and research partner (informant) to provide an index of global functioning (Berg et al., "Mild Senior Dementia of the Alzheimer's Type 4. Evaluation of Intervention," Ann Neurol. 31(3):242-249 (1992), which is incorporated herein by reference in its entirety). The CDR should be administered by the same assessor at each visit to reduce potential variability. Informants are asked questions about the patient's memory, orientation, judgment and problem-solving, community affairs, home and hobbies, and personal care. The patient's memory, orientation, judgment, and problem-solving abilities are assessed. Higher scores indicate greater disease severity. Assigning severity scores to each of the six domains results in a total score known as the sum of the boxes, hence the abbreviation CDR-SB. The CDR-SB ranges from 0 to 18, with higher scores indicating greater impairment.

[0245] The Mini-Mental State Examination (MMSE) is a brief instrument used to assess a patient's cognitive function (Folstein et al., "Mini-Mental State." A Practical Method for Grading the Cognitive State of Patients for the Clinician," J Psychiatr Res. 12(13):189-198 (1975), which is incorporated herein by reference in its entirety). The MMSE should be administered by the same assessor at each visit to reduce potential variability. The instrument is divided into two sections. The first section measures orientation, memory, and attention. The maximum score for the first section is 21. The second section tests the patient's ability to name objects, follow oral and written instructions, write sentences, and copy pictures. The maximum score for the second section is 9. Total MMSE scores range from 0 to 30, with lower scores indicating greater levels of impairment.

[0246] Biomarker Efficacy Measures (Double-Blind Period) F18-Florbetapir PET Scan: Changes in amyloid burden (assessed by F18-Florbetapir PET signal) will be compared in donanemab- and placebo-treated patients for patients who underwent F18-Florbetapir PET scans at baseline, Week 52 [Visit 15], and Week 76 [Visit 21], or the early discontinuation visit (ED).

[0247] F18-flortaucipir PET scans: Changes in tau burden (assessed by F18-flortaucipir PET signal) will be compared in donanemab- and placebo-treated patients for patients who underwent both baseline and endpoint (Visit 21 [Week 76] or ED) F18-flortaucipir scans.

[0248] Volumetric MRI: Brain magnetic resonance imaging may be performed during Visits 2-14. The effects of donanemab treatment and placebo treatment on volumetric MRI will be evaluated and compared to assess brain volume loss that occurs in patients with AD.

[0249] Amyloid Plaque Clearance: Amyloid plaque clearance (assessed by F18-florbetapir PET signal) will be compared in donanemab-treated and placebo-treated patients for patients who underwent F18-florbetapir PET scans at baseline, Visit 8 (Week 24), Visit 15 (Week 52), and Endpoint Visit 21 (Week 76), or ED.

[0250] Accumulation of Tau Deposits: The extent of tau versus helical filament (PHF) plaque accumulation (assessed by F18-flortaucipir PET signal) will be compared in donanemab- and placebo-treated patients for patients who underwent baseline and endpoint Visit 21 (Week 76) or ED F18-flortaucipir PET scans.

[0251] Biomarkers: Biomarker studies are conducted to address questions related to pharmacokinetics, target engagement, PD, mechanism of action, patient response variability (including safety), and clinical outcomes. Sample collection is integrated into clinical studies to investigate these questions through the measurement of biomolecules, including deoxyribonucleic acid (DNA), ribonucleic acid (RNA), proteins, lipids, and other cellular elements. Serum, plasma, and whole blood RNA samples for biomarker studies will be collected during Visits 2–14, if local regulations permit.

[0252] Example 3: Safety, Tolerability, and Efficacy Study Results This example provides results from the safety, adverse events, and efficacy of donanemab in participants with early symptomatic AD. Enrollment was based on positron emission tomography (PET) scans of florbetapir and flortaucipir, which show tau and amyloid plaque pathology, respectively. Participants received either placebo or donanemab (700 mg for doses 1-3, then 1,400 mg thereafter) intravenously every 4 weeks for up to 72 weeks. The primary outcome measure was the change from baseline in the Integrated AD Rating Scale (iADRS, range 0-144; lower scores indicate greater cognitive deficits and greater impairment in activities of daily living) at 76 weeks. Secondary outcome measures included the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB, range 0-18; higher scores indicate greater functional impairment), the AD Assessment Scale-Cognitive (ADAS-Cognitive), and the Clinical Dementia Rating Scale-Cognitive (ADAS-Cognitive). 13 , range 0-85, higher values ​​indicate greater disease severity), Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-iADL, range 0-59, lower values ​​indicate greater disability), Mini-Mental State Examination (MMSE, range 0-30, lower values ​​indicate greater disability), amyloid and tau burden assessed by florbetapir and F18-flortaucipir PET, respectively, and volumetric magnetic resonance imaging MRI (vMRI).

[0253] Patient Population and Study Design: This study (TRAILBLAZER-ALZ) is a multicenter, randomized, double-blind, placebo-controlled study evaluating the safety, adverse events, and efficacy of donanemab in participants aged 60 to 85 years with early symptomatic AD (a combination of prodromal AD, symptomatic pre-dementia stage of AD with overt MCI [MCI-AD], and mild AD dementia [symptoms severe enough to meet diagnostic criteria for dementia and AD]) (Dubois et al., "Research Criteria for the Diagnosis of Alzheimer's Disease: Revising the NINCDS-ADRDA Criteria," The Lancet Neurology 6:734-46 (2007), which is incorporated herein by reference in its entirety). Screening procedures included the Mini-Mental State Examination (MMSE, range 0–30, with lower scores indicating greater functional impairment; Folstein et al., “Mini-mental state. A Practical Method for Grading the Cognitive State of Patients for the Clinician,” J. Psychiatr. Res. 12:189–98 (1975), which is incorporated herein by reference in its entirety), F18-flortaucipir PET scan, magnetic resonance imaging (MRI), and F18-florbetapir PET scan. The flortaucipir and F18-florbetapir PET scans were performed by a centralized PET imaging laboratory to assess patient eligibility. All eligible patients were required to have evidence of pathological tau on the PET scan, with quantitative tau levels below a specified upper threshold. The latter criterion addressed concerns about the limited efficacy of anti-amyloid treatment in advanced disease, as indicated by the presence of widespread tau pathology. Published methods (Pontecorvo et al., "A Multicenter Longitudinal Study of Flortaucipirvir") were used to quantitatively assess tau imaging and determine whether patients had AD patterns. 18F) in Normal Aging, Mild Cognitive Impairment and Alzheimer's Disease Dementia,” Brain 142:1723-35 (2019); Devous et al., “Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F18,” Journal of Nuclear Medicine 59:937-43 (2018); Southekal et al., “Flortaucipir F18 Quantitation Using Parametric Estimation of Reference Signal Intensity,” J. Nucl. Med. 59:944-51 (2018), which are incorporated by reference in their entireties), and visually assessed (Fleisher et al., “Positron Emission Tomography Imaging With F18-flortaucipir and Postmortem Assessment of Alzheimer's Disease Neuropathologic Changes,” JAMA Neurology 77:829-39 (2020), which is incorporated herein by reference in its entirety), SUVr (standardized uptake value ratio) was estimated.

[0254] Images with an SUVr > 1.46 were excluded as having high tau. For images not excluded as having high tau, images with an SUVr value < 1.10 or images visually interpreted as having a negative AD pattern were excluded as having inappropriate tau levels, unless the image was visually interpreted as having a progressive AD pattern but had an SUVr value < 1.10, in which case it was still included. With the exception of MRI, each patient was required to meet all other Visit 1 eligibility criteria before the screening F18 florbetapir PET scan.

[0255] Participants who met the inclusion criteria were randomized 1:1 to receive either intravenous (IV) donanemab (700 mg for the first three doses, then 1400 mg) or IV placebo every four weeks for up to 72 weeks. Randomization of participants was stratified by study site to allow for comparability of site factors between groups. There was no stratification by inclusion criteria. Participants treated with donanemab had their dose tapered to 700 mg if their amyloid clearance in centimeters (CL) measured by florbetapir scan (weeks 24 and 52) was ≥11 and <25, or switched to placebo if either measurement was <11, or if two consecutive scans were ≥11 and <25. If amyloid-related imaging abnormalities-edema / exudates (ARIA-E, signal hyperintensity on MRI on fluid-attenuated inversion recovery imaging sequences due to parenchymal fluid accumulation or crevicular fluid exudation, Sperling et al., "Amyloid-related Imaging Abnormalities in Amyloid-Modifying Therapeutic Trials: Recommendations from the Alzheimer's Association Research Roundtable Workgroup," Alzheimer's & Dementia 7:367-85 (2011), which is incorporated herein by reference in its entirety) occurred during the first three dose escalations of 700 mg, the dose was not increased. The final endpoint measurement and safety assessment was performed at week 76, 4 weeks after the last infusion.

[0256] Clinical and Biomarker Outcome Measures: The primary outcome measure was the change in iADRS (range 0-144, lower scores indicate greater cognitive impairment and impairment in daily activities) from baseline to week 76 compared with placebo. The iADRS is a multi-component scale that measures cognitive impairment (ADAS-Cognitive) and its individual components. 13, range 0-85, with higher scores indicating greater disease severity; Mohs et al., "Development of Cognitive Instruments for Use in Clinical Trials of Antidementia Drugs: Additions to the Alzheimer's Disease Assessment Scale that Broaden its Scope. The Alzheimer's Disease Cooperative Study," Alzheimer Dis Assoc Disord 11 Suppl 2:S13-21 (1997), which are incorporated herein by reference in their entireties) and AD Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL, range 0-59, with lower scores indicating greater functional impairment; Galasko et al., "An Inventory to Assess Activities of Daily Living for Clinical Trials in Alzheimer's Disease," Alzheimer Disease and Associated Disorders 11:S33-S9 (1997) and Galasko et al., "Galantamine Maintains Ability to Perform Activities of Daily Living in Patients with Alzheimer's Disease,” Journal of the American Geriatrics Society 52:1070-6 (2004), which are incorporated herein by reference in their entireties.

[0257] The iADRS was developed using theoretical constructs intended to measure core disease processes, and clinical trial data were used to identify items / scales that best fit the implementation of those constructs. 13All items from the total score and the ADCS-iADL score are included without item weighting, providing face validity and ease of interpretation of both the composite and its components. The iADRS is capable of measuring not only an overall measure of AD impairment (total score) but also the individual subscores (cognitive and functional). Validation of the iADRS has been established, and the statistical properties of the composite performance have been described.

[0258] Secondary outcome measure methodology: Clinical Dementia Rating Scale Sum of Boxes (CDR-SB, range 0-18, higher scores indicate greater impairment; Morris, "The Clinical Dementia Rating (CDR)," Current Version and Scoring Rules 43:2412-a (1993), which is incorporated herein by reference in its entirety), ADAS-Cognitive Assessment Score (ADAS-Cognitive Assessment Score), and Cognitive Assessment Score (ADAS-Cognitive Assessment Score). 13 Amyloid and tau burden assessed by ADCS-iADL, MMSE, F18-florbetapir and F18-flortaucipir PET, and volumetric MRI, respectively, are detailed in the clinical protocol. Assessment of overall tau load includes tau analysis, which describes the spatiotemporal distribution of tau. IQ This was performed using an algorithm (Whittington et al., “TauIQ-A Canonical Image Based Algorithm to Quantify Tau PET Scans,” J. of Nuclear Medicine (2021), which is incorporated herein by reference in its entirety).

[0259] Sample Size Determination and Statistical Analysis: Enrolling 250 participants randomized 1:1 to two treatment groups, with 200 participants expected to complete treatment, was determined to provide approximately 84% power to demonstrate a posterior probability of 0.6 or greater for the active treatment group to slow iADRS progression by at least 25% compared to placebo. Power calculation assumptions were 18-month mean progression levels of approximately 12 and 6 points (50% slowing) in the placebo and donanemab groups, respectively, with a common standard deviation of 17. Efficacy analyses were conducted on a modified intention-to-treat basis, with participants receiving baseline and at least one post-baseline iADRS measurement (unless otherwise specified). Unless otherwise noted, all pairwise tests of treatment effect were performed at a two-sided alpha level of 0.05.

[0260] Baseline characteristics were summarized by treatment group and overall, with descriptive statistics for continuous and categorical measures. The primary outcome was analyzed using mixed-model repeated measures (MMRM) analysis, with the change from baseline in iADRS score at each scheduled post-baseline time point used as the dependent variable. The fixed-effects model included the following terms: baseline score, investigator, treatment, visit, treatment-by-visit interaction, baseline-by-visit interaction, concomitant use of acetylcholinesterase inhibitors (AChEIs) and / or memantine at baseline (yes / no), and age at baseline. Visit was considered a categorical variable. Secondary efficacy outcomes were assessed using MMRM analysis. Bretz's graphical approach (Bretz, et al., "A Graphical Approach to Sequentially Rejective Multiple Test Procedures," Statistics in Medicine, 28(4):586-604 (2009), which is incorporated herein by reference in its entirety) was used to provide control for type I error rates for the study of the primary and key secondary hypotheses at an alpha level of 0.05. Assuming the primary analysis was significant, the MMRM analysis described for the primary analysis was significant for CDR-SB, ADAS-Cog, and 13, ADCS-iADL, and MMSE scores, and significance was determined based on hypothesis multiplicity graphs. Long-term clinical outcomes are provided with point estimates and error bars. For post-baseline categorical data, Fisher's exact test was used to compare treatment groups. For post-baseline continuous data collected at endpoint, analysis of covariance (ANCOVA) with independent factors of treatment and age was used. Each primary site investigator was responsible for selecting assessors who met the training requirements to administer the instruments at the site. Assessors were blinded to treatment assignment.

[0261] A Bayesian disease progression model (DPM) was used to assess the rate of decline in the iADRS between the donanemab and placebo groups over the 76-week study. This model assumes a proportional treatment effect relative to placebo and includes a diffuse prior distribution. A similar model has been used previously, except that the current model does not enforce a monotonic prior for the parameter representing placebo decline. This analysis generated a posterior probability distribution for the disease progression rate (DPR), defined as the proportional decline in the donanemab group relative to placebo. A DPR < 1 favors donanemab. The 95% confidence intervals and posterior mean disease progression rates are displayed. The posterior probability of the active treatment group slowing disease progression by at least 25% relative to placebo was prespecified and calculated from the DPM. The DPM model was used to assess the CDR-SB, ADAS-Cog, and variance scores. 13 The rate of decline in ADCS-iADL, and MMSE was assessed. The DPM model was not included as part of the pre-specified multiplicity testing strategy for secondary endpoints.

[0262] Safety parameters (AEs, laboratory analytes, vital signs, electrocardiogram, MRI) were summarized using descriptive statistics for continuous variables and frequencies with percentages for categorical variables during the treatment period.

[0263] To handle missing data in the MMRM model, a repeated-measures likelihood-based mixed-effects model was used. Model parameters were simultaneously estimated using restricted likelihood estimation incorporating all observed data. Estimates have been shown to be unbiased when missing data are missing at random and when there is negligible nonrandom missing data. In repeated-measures analyses, only data from visits where data collection was scheduled are used. If a participant discontinued the study early, efficacy or safety data measurements may be taken at visits where variables were not scheduled to be collected. This data was used in all other analyses.

[0264] Population and Baseline Characteristics: Baseline population demographics for the placebo and donanemab monotherapy groups were: mean age 75.4 and 75.0 years, 51.6% and 51.9% women, 96.0% and 93.1% white, and 74.2% and 72.5% APOE4 carriers, respectively (Table B). [Table 2-1] [Table 2-2]

[0265] At the start of the study, the study consisted of three arms, including one receiving the combination of donanemab and a BACE1 inhibitor. This arm was discontinued early, and 15 participants were randomly assigned to it. In the modified intention-to-treat population, of the 1,955 screened participants, 126 were randomized to placebo and 131 to donanemab. The mean baseline iADRS scores were 105.9 for placebo and 106.2 for donanemab, respectively; the MMSE scores were 23.7 and 23.6, respectively; the CDR-SB scores were 3.4 and 3.6; the overall tau loads on F18-flortaucipir PET were 0.46 and 0.47, respectively; and the amyloid PET scores were 101.1 and 107.6 (Table B).

[0266] Primary Outcome: Donanemab demonstrated significantly slower decline in a composite measure of cognition and daily functioning compared with placebo in patients with early symptomatic Alzheimer's disease. Donanemab met the primary endpoint of change from baseline to week 76 on the Integrated Alzheimer's Disease Rating Scale (iADRS), slowing the decline by 32% versus placebo (Figure 2A-C), which was statistically significant. The iADRS is a composite of two commonly used measures of Alzheimer's disease: the cognitive scale ADAS-Cognitive Assessment Scale (ADAS-Cognitive Assessment Scale). 13 The clinical composite tool combines the iADRS and the functional scale ADCS-iADL. At 76 weeks, the change from baseline in iADRS was -10.06 in the placebo group and -6.86 in donanemab-treated patients (treatment difference: 3.20, 95% confidence interval [CI]: 0.12, 6.27, p = 0.04) (Figure 2A-C and Table D). Figures 2A-C show clinical outcomes for the primary iADRS, secondary CDR-SB, ADAS-Cog13, ADCS-iADL, and MMSE. Figure 2A shows the results of the LS mean change from baseline to week 76 in the primary outcome, iADRS score, analyzed with the MMRM. Figure 2B shows the percent slowing estimates from the MMRM model at the 18-month endpoint and the Bayesian DPM model across the entire 18-month study. 95% confidence intervals are shown. Figure 2C shows the secondary outcomes analyzed in MMRM: (i) CDR-SB, (ii) ADAS-Cog 13 The results show the LS mean change from baseline to week 76 in (iii) ADCS-iADL, and (iv) MMSE scores. In Figure 2A-C, Δ = difference, W = week, iADRS = Integrated Alzheimer's Disease Rating Scale, ADAS-Cog 13 = Alzheimer's Disease Rating Scale-Cognitive Subscale, ADCS-iADL = Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living Scale, CDR-SB = Clinical Dementia Rating Scale Sum of Boxes, MMSE = Mini-Mental State Examination, MMRM = Mixed Model for Repeated Measures, DPM = Disease Progression Model, LS = Least Squares, CI = Confidence Interval, n = Number of Participants, SE = Standard Error.

[0267] Figure 2D shows clinical results for primary iADRS and secondary CDR-SB outcomes using a Bayesian model of disease progression from TRAILBLZER-ALZ (AACG study, Example 2). In Figure 2D, iADRS = Integrated Alzheimer's Disease Rating Scale, CDR-SB = Clinical Dementia Rating-Sum of Boxes, and ++ indicates at least a 0% posterior probability of >99% slowing.

[0268] Figure 2E shows a frequentist analysis of the clinical results of Example 2 for the iADRS primary efficacy outcome and the CDR-SB secondary outcome using a natural cubic spline with two degrees of freedom (NCS2), a natural cubic spline with three degrees of freedom (NCS3), and a quadratic mixed model (QMM) from TRAILBLZER-ALZ (AACG Study, Example 2). (*=p<0.05 vs. placebo, **=p<0.01 vs. placebo) (AACG Study, Example 2). The natural cubic spline (NCS) model provides a type of smoothing function for the data and can appropriately estimate longitudinal trajectories under various shapes (linear, quadratic, etc.) for each treatment group. The degrees of freedom of the model can be specified in advance to establish the level of data smoothing. Quadratic mixed models have many similar characteristics to MMRMs, but additional assumptions are made on the estimation of longitudinal means so that the longitudinal trajectories for each treatment group are smoothed over the scheduled or observed visit times, allowing for linear or quadratic shapes. In Figure 2E, iADRS = Integrated Alzheimer's Disease Rating Scale, CDR-SB = Clinical Dementia Rating-Sum of Boxes, ++ indicates at least 0% posterior probability of >99% slowing, NCS2 = natural cubic spline with 2 degrees of freedom, NCS3 = natural cubic spline with 3 degrees of freedom, QMM = quadratic mixed model. [Table 3] [Table 4-1] [Table 4-2]

[0269] Percent slowing of disease progression relative to placebo estimates from the MMRM model at the 18-month endpoint and the Bayesian DPM over the entire 18-month period showed a slowing of iADRS decline with both methods (Figure 2B). The posterior probability of at least a 25% slowing of disease progression relative to placebo on the iADRS was calculated to be 0.78 from the Bayesian DPM.

[0270] Secondary Outcomes: Donanemab also demonstrated consistent improvements compared with placebo in all prespecified secondary endpoints measuring cognition and function, although no secondary endpoints reached nominal statistical significance. In the donanemab group, the difference from baseline in CDR-SB at week 76 compared with placebo was -0.36 (95% CI: -0.83 to 0.12) for CDR-SB and -0.36 (95% CI: -0.83 to 0.12) for ADAS-Cog. 13 The mean scores for ADCS-iADL were −1.86 (95% CI: −3.63 to −0.09), for ADCS-iADL were 1.21 (95% CI: −0.77 to 3.20), and for MMSE were 0.64 (95% CI: −0.40 to 1.67) (Figure 2C and Table E). [Table 5-1] [Table 5-2]

[0271] By targeting the biomarker N3pGlu Aβ, donanemab treatment has been shown to rapidly result in high levels of amyloid plaque clearance, as measured by amyloid imaging. For PET amyloid, donanemab-treated participants demonstrated a reduction of 85 CL amyloid plaques at 76 weeks compared to placebo (placebo = 0.93, donanemab = -84.13) (Figure 3A). A distinct reduction of 68 CL was evident by week 24 in the donanemab group compared to placebo (placebo = -1.82, donanemab = -69.64, a 65% reduction from baseline in the donanemab group). The percentage of participants in the donanemab group who were "amyloid negative" (defined as amyloid plaque count <24.1) was 40.0%, 59.8%, and 67.8% at weeks 24, 52, and 76, respectively (Figure 3A). Approximately 27% and 55% of donanemab participants administered the drug at weeks 28 and 56, respectively, achieved amyloid slowing sufficient to result in a reduction relative to placebo infusion. In this study, patients stopped receiving donanemab and switched to placebo if amyloid plaque levels fell below 25 centimeters on two consecutive measurements or below 11 centimeters on any single measurement.

[0272] Assessment of overall tau load, as assessed by F18-florbetapir PET, revealed no differences between groups from baseline to week 76 (Figure 3B). Hippocampal volumetric changes, as assessed by vMRI, also showed no differences between groups (Figure 3C(iii)). Participants treated with donanemab at 52 demonstrated a greater decrease in total brain volume and a greater increase in ventricular volume compared with placebo (Figure 3C(i) and (ii)). Figures 3A-C show secondary biomarker outcomes. Figure 3A shows the results from baseline to week 76 in cerebral amyloid plaque deposition measured by F18-florbetapir PET scans for the secondary outcome, centiloid (CL). Figure 3B shows overall tau load measured by F18-florbetapir PET scans. "Amyloid-negative" / <24.1 CL = average CL level in otherwise healthy individuals of similar age. Figure 3C shows vMRI of (i) the whole brain, (ii) the ventricles, and (iii) the hippocampus. In Figure 3, Δ = difference, W = week, LS = least squares, CI = confidence interval, CL = centiroid, n = number of participants, SE = standard error.

[0273] Adverse Events: There was no difference in the incidence of death or serious adverse events (SAEs) between the donanemab and placebo groups. During the double-blind period in the safety population, a total of 113 of 125 placebo participants (90.4%) and 119 of 131 donanemab participants (90.8%) experienced at least one treatment-emergent adverse event (TEAE). The incidence of ARIA-E was significantly higher in the donanemab group (27%) compared with placebo (0.8%). Symptomatic ARIA-E was reported in 6.1% of donanemab participants overall (22% of participants with ARIA-E) compared with 0.8% in the placebo group. Most ARIA-E cases occurred within the first 12 weeks of treatment. Severe symptomatic ARIA-E requiring hospitalization occurred in two donanemab-treated participants (1.5%). Both participants experienced symptoms of confusion, and one reported difficulty expressing himself, all of which resolved completely. ARIA-E resolved completely in both cases, with a mean resolution time of 18 weeks. The incidence of superficial siderosis of the central nervous system (a type of ARIA with hemorrhage (ARIA-H)), nausea, and infusion-related reactions (IRRs) were all significantly higher in the donanemab group compared with the placebo group. Treatment discontinuation due to ARIA-E occurred in seven participants (5.3%) in the donanemab group. Two participants (1.5%) discontinued the study due to ARIA-E. No major cerebral hemorrhages were observed in either group. IRRs were reported in 7.6% of participants in the donanemab group and 0% in the placebo group. Three participants (2.3%) treated with donanemab experienced serious IRRs or hypersensitivity reactions. The incidence of treatment-emergent anti-drug antibodies (TE-ADAs) in participants treated with donanemab was approximately 90%.

[0274] These results demonstrate that amyloid clearance in the donanemab group was accompanied by a slowing of disease progression compared with placebo in an amyloid plaque-specific intervention for patients with early symptomatic Alzheimer's disease. The treatment difference of 3.20 on the iADRS scale at 76 weeks should be interpreted not only in light of the score range across the disease spectrum (0-144), but also, importantly, in light of the dynamic range of the iADRS within the participant population (26 points) and the decline in the placebo group (-10.06).

[0275] The results presented here are unexpected and surprising in several aspects: the donanemab dosing regimen cleared a large amount of amyloid early in the trial, with nearly 60% of participants having "amyloid-negative" scans by week 52. This was the first study to screen all participants with F18-flortaucipir PET scans, likely narrowing the extent of underlying pathology and thereby reducing the variance in clinical decline.

[0276] Tau PET screening of patients excluded subjects with high tau, who may have disease that is less responsive to or more resistant to anti-amyloid treatment.

[0277] Using a relatively new disease progression model as proposed by the European Alzheimer's Disease Prevention Project, we compared the iADRS, ADAS-Cog 13Analyses of treatment differences in ADCS-iADL, CDR-SB, and MMSE scores were conducted. Given the greater sensitivity for detecting treatment effects (Solomon et al., "European Prevention of Alzheimer's Dementia Longitudinal Cohort Study (EPAD LCS): Study Protocol," BMJ Open 8:e021017 (2018), which is incorporated herein by reference in its entirety), this model allows for significantly improved statistical power (Wang et al., "A Novel Cognitive Disease Progression Model for Clinical Trials in Autosomal-Dominant Alzheimer's Disease," Statistics in Medicine 37:3047-55 (2018), which is incorporated herein by reference in its entirety), this study revealed estimates of disease slowing similar to single-point estimates of the MMRM model.

[0278] The observed lack of treatment effect on overall tau load may be due to the significant lag between tau changes by PET and amyloid changes, and the 18-month time frame is too short to detect imaging changes. Modeling in autosomal dominant subjects suggests a 10-20 year lag between the first detectable PET amyloid changes and the first detectable tau PET changes (Barthelemy et al., “A Soluble Phosphorylated Tau Signature Links Tau, Amyloid, and the Evolution of Stages of Dominantly Inherited Alzheimer's Disease,” Nat. Med. 26:398-407 (2020), which are incorporated herein by reference in their entirety). The lack of effect on overall tau may raise questions about whether targeting amyloid-β reduction will impact biological disease progression. However, additional prespecified analyses of brain regions suggest reduced tau accumulation in various brain regions (e.g., frontal, parietal, occipital, and temporal lobe regions) in the donanemab group compared with placebo (Figure 4).

[0279] Robust reductions in tau accumulation or prevention of further increases are seen, for example, in the frontal lobe of the brain. The occipital lobe has some of the highest baseline signal, and therefore may have a ceiling effect on the ability to demonstrate a decrease in increasing tau load. Figure 4 shows a regional SUVr analysis of tau accumulation in the cerebellar gray reference. Using the cerebellar reference region, frontal lobe tau load, measured by F18 flortaucipitin, correlates with changes in the iADRS and CDR-SB over the following 76 weeks in symptomatic early AD subjects. Figure 5 shows that lower frontal tau load is associated with less patient decline. Higher frontal lobe tau load is associated with more rapid patient decline. In other words, patients with lower frontal lobe tau load experience slower decline (as measured by iADRS or CDR-SB) compared with patients with higher frontal lobe tau load.

[0280] This measure reflects global changes in tau load, and further investigation may reveal subregions that are more susceptible to change. Optimal methods for region selection and analysis to quantify tau changes and therapy response are still in their infancy.

[0281] In contrast to recent BACE inhibitor studies that showed significant volumetric changes, there were no significant changes in hippocampal volume (Wessels et al., “Efficacy and Safety of Lanabecestat for Treatment of Early and Mild Alzheimer Disease: The AMARANTH and DAYBREAK-ALZ Randomized Clinical Trials,” JAMA Neurology 77:199-209 (2020), which is incorporated herein by reference in its entirety). The observation that donanemab treatment resulted in greater reductions in total brain volume and greater increases in ventricular volume compared with placebo may be interpreted in the context of protein clearance rather than atrophy. In natural history studies of AD, global volumetric MRI changes are typically attributed to atrophy, but it remains unclear whether they represent true atrophy in the context of rapid structural clearance of protein aggregates, as seen in this and other anti-amyloid therapy studies. (Sur et al., “BACE Inhibition Causes Rapid, Regional, and Non-progressive Volume Reduction in Alzheimer's Disease Brain,” Brain 143:3816-26 (2020), which is incorporated herein by reference in its entirety.)

[0282] ARIA-E and ARIA-H are associated with amyloid plaque removal therapy. Sperling et al., “Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: Recommendations from the Alzheimer's Association Research Roundtable Workgroup,” Alzheimer's & Dementia 7:367-85 (2011); Sevigny et al., “The Antibody Aducanumab Reduces Aβ Plaques in Alzheimer's Disease,” Nature 537:50-6 (2016); Ostrowitzki et al., “Mechanism of Amyloid Removal in Patients With Alzheimer's Disease Treated With Gantenerumab,” Archives of Neurology 69:198-207 (2012); Salloway et al., “Two Phase 3 Trials of Bapineuzumab in Mild-to-Moderate Alzheimer's Disease,” New England Journal of Medicine 370:322-33 (2014); Salloway et al., "A Phase 2 Multiple Ascending Dose Trial of Bapineuzumab in Mild to Moderate Alzheimer's Disease," Neurology 73:2061-70 (2009) and Sperling et al., "Amyloid-related Imaging Abnormalities in Patients with Alzheimer's Disease Treated with Bapineuzumab: A Retrospective Analysis," Lancet Neurol. 11:241-9 (2012), each of which is incorporated by reference in its entirety.

[0283] In a phase 1b study, the incidence of ARIA-E in participants treated with donanemab was 26.1%, with two participants reporting symptomatic ARIA-E (4.3%). In this study, a similar incidence of ARIA-E (27%) was seen in the donanemab group, with 6.1% reporting symptomatic ARIA-E. As seen in other trials of plaque-targeting antibodies, the incidence of ARIA-E was more common in APOE4 carriers (Sevigny et al., “The Antibody Aducanumab Reduces Aβ Plaques in Alzheimer's Disease,” Nature 2016;537:50-6; Ostrowitzki et al., “Mechanism of Amyloid Removal in Patients With Alzheimer's Disease Treated With Gantenerumab,” Archives of Neurology 69:198-207; Salloway et al., “Two Phase 3 Trials of Bapineuzumab in Mild-to-Moderate Alzheimer's Disease,” NEJM 2014;370:322-33 (2014) and Sperling et al., “Amyloid-Related Imaging Abnormalities in Patients with Alzheimer's Disease Treated with Bapineuzumab: A Retrospective Analysis,” Lancet Neurol. 11:241-9 (2012), which are incorporated herein by reference in their entireties. The incidence of treatment-emergent anti-drug antibodies (TE-ADAs) in participants treated with donanemab (approximately 90%) was similar to findings in Phase 1 (>85%).

[0284] These results show that in participants with early symptomatic AD, treatment with donanemab resulted in the clearance of amyloid plaques and slowed cognitive and functional decline as measured by the iADRS scale.

[0285] Example 4: Efficacy Associated with Baseline Tau PET Patient Stratification The anti-N3pGlu Aβ antibody, donanemab, has been found to be most effective in subjects with the lowest baseline flortaucipir levels. This antibody may be less effective in subjects with high tau (>1.46 SUVr). In other words, subjects with high tau (>1.46 SUVr) may be less responsive to Aβ therapy, particularly therapy based on anti-N3pGlu antibodies, including donanemab.

[0286] Tau levels (e.g., for stratification of human subjects with Alzheimer's disease) are determined based on an initial visual assessment of the flortaucipir scan, followed by quantitative analysis. Visual assessment relies on a three-level readout (tAD-, tAD+, tAD++) based on the presence of tracer uptake in specific regions of the neocortex. Quantitative analysis refers to the calculation of SUVr (multiblock centroid discriminant analysis or MUBADA), which represents counts within specific target regions of interest in the brain compared to a reference region (parametric estimate of reference signal intensity or PERSI). Lower SUVr values ​​indicate lower tau burden, while higher SUVr values ​​indicate higher tau burden.

[0287] As shown in Table F, scans in the low to moderate tau group (e.g., with an SUVr of ≥1.10 to ≤1.46) are eligible for administration of anti-N3pGlu Aβ antibodies in the AACG study.

[0288] Visual Assessment: The method for visual assessment of human subjects is described by Fleisher et al., “Positron Emission Tomography Imaging With 18[F]flortaucipir and Postmortem Assessment of Alzheimer Disease Neuropathologic Changes,” JAMA Neurol. 77(7):829-839 (2020), which is incorporated herein by reference in its entirety. Briefly, a flortaucipir scan is negative (tAD-) if there is no increase in neocortical tracer activity in any region of the brain, or if the activity is isolated to regions of the frontal lobe or temporal lobe that do not include the posterolateral temporal (PLT) region. Positive scans are classified into two categories based on the region of increased neocortical tracer activity. A flortaucipir scan in which neocortical tracer activity is limited to the posterolateral temporal (PLT) or occipital regions is classified as tAD+.

[0289] Finally, if the flortaucipir scan shows increased tracer activity in the parietal or precuneus regions, or if activity in the frontal regions is present along with activity in the PLT or occipital regions, it is classified as tAD++. Quantitative analysis is performed on all tAD+ and tAD++ scans.

[0290] Quantitative Analysis: Quantitative analysis is performed through an automated image processing pipeline. A previously developed neocortical target volume of interest (VOI) (see MUBADA, Devous et al., "Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F18," J. Nucl. Med. 2018;59:937-943 (2018)), which is incorporated herein by reference in its entirety) is applied to each scan, and derived counts are normalized to a patient-specific reference region (PERSI). Other target and reference regions are also extracted through the pipeline. PERSI reference regions are a subject-specific, data-driven technique that identifies voxels with nonspecific flortaucipir uptake within atlas-defined white matter regions (see, e.g., Southekal et al., "Flortaucipir F18 Quantitation Using Parametric Estimation of Reference Signal Intensity," J. Nucl. Med. 59:944-951 (2018) which is incorporated herein by reference in its entirety). MUBADA target regions were developed using statistical methods that maximize separation of diagnostic groups based on imaging features (see, Devous et al., "Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F18," J. Nucl. Med. 59:937-943 (2018) which is incorporated herein by reference in its entirety). When applied to F18 flortaucipir images from a large dataset of 202 subjects (55 Aβ- elderly cognitively normal, 43 Aβ-MCI, 54 Aβ+MCI, 16 Aβ-AD, and 34 Aβ+AD), the analysis yielded two dimensions (aka components).The first dimension (explaining 95% of the variance) provided the greatest separation of groups by diagnosis and amyloid status and was converted into a VOI now referred to as the MUBADAVOI (see, e.g., Devous et al., "Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F18," J. Nucl. Med. 2018;59:937-943 (2018)), which is incorporated herein by reference in its entirety).

[0291] The MUBADA VOI relative to the PERSI reference region was then applied to 204 subjects, and the resulting values ​​were divided into four tau burden quartiles: 1) very low, 2) low, 3) moderate, and 4) high. The cutoff SUVr values ​​separating very low and low were 1.10, low and moderate were 1.23, and moderate and high were 1.46. These values ​​were used to screen subjects according to the above algorithm.

[0292] Based on the hypothesis that cognitive decline in patients with high tau is primarily caused by tauopathy and therefore does not respond to anti-amyloid therapy, subjects with tAD+ and tAD++ scans with SUVr > 1.46 did not receive anti-N3pGlu Aβ antibodies. [Table 6]

[0293] As shown below in Figure 6A-C, the anti-N3pGlu Aβ antibody, donanemab, was found to be most effective in the treatment subgroup with the lowest baseline flortau signal. Based on Figure 6, it can be hypothesized that patients with high tau (>1.46 SUVr) are less likely to respond to treatment.

[0294] The data demonstrate that donanemab, an anti-N3pGlu Aβ antibody, was most effective in human subjects with tau levels of approximately 1.14 SUVr or less or approximately 1.27 SUVr or less (Figures 6A and 6B). Changes in scale scores, defined by baseline tau PET SUVr values ​​greater than 1.274 SUVr, were not statistically significant in the donanemab-treated group compared to placebo in the rightmost graph (Figure 6C). Figures 6A-C show baseline tau subgroup analysis based on the iADRS (FTP = F18-flortaucipitin).

[0295] Example 5: Efficacy and Safety Associated with Carriers of the Apolipoprotein E4 (APOE4) Allele A phase 2 clinical trial (NCT03367403, clinitritrials.gov) (disclosed above in Examples 2, 3, and 4) also included testing the efficacy and safety of an anti-N3pGlu Aβ antibody (donanemab) in a subgroup of participants with one or two alleles of APOE4.

[0296] This phase 2 clinical trial was a randomized, placebo-controlled, double-blind, multicenter study evaluating the safety, tolerability, and efficacy of donanemab in patients with early symptomatic AD. Clinical change from baseline to week 76 was assessed for all enrolled patients with intermediate tau pathology levels using the Integrated AD Rating Scale (iADRS, primary endpoint) and the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB, secondary endpoint), a composite tool measuring cognition and daily function. Baseline characteristics showed that 72.5% and 74.2% of patients treated with donanemab or placebo, respectively, were APOE4 carriers. Additional analyses of the iADRS and key secondary endpoints were conducted focusing on this subgroup.

[0297] Results: Compared to placebo, donanemab treatment resulted in a 49% slowing of cognitive decline measured by iADRS (p=0.004) (Figure 7A) and a 36% slowing of cognitive decline by CDR-SB (p=0.038) (Figure 7B) in APOE4 carriers at 76 weeks.

[0298] The difference in donanemab treatment between carriers and non-carriers was significantly greater in carriers (iADRS: p=0.001, CDR-SB: p=0.046). Additional key secondary endpoints demonstrated consistent and strong efficacy of donanemab compared to placebo in APOE4 carriers. See Tables G and H below. [Table 7] [Table 8]

[0299] The safety profile of APOE4 carriers was consistent with the overall donanemab-treated population. The slowing of tau PET increases after donanemab treatment was numerically greater in APOE4 carriers receiving donanemab than in non-carriers.

[0300] Amyloid-related imaging abnormalities (ARIA) with edema or exudates, most of which were asymptomatic, were more common in APOE4 carriers (33.7%) than in non-carriers (8.3%). ARIA with hemosiderin deposits such as microhemorrhages occurred in 34.5% of APOE4 carriers receiving donanemab. Controlling for carrier subjects with ARIA did not change the significance of the placebo-treatment differences for iADRS (p=0.020) and CDR-SB (p=0.050).

[0301] Analysis of the study population demonstrated greater efficacy of donanemab in APOE4 carriers than non-carriers, demonstrating a significant slowing of disease progression on both the iADRS and CDR-SB.

[0302] Figures 7A-B show that donanemab demonstrated greater efficacy in APOE4 carriers than non-carriers. Figure 7A shows that donanemab demonstrated greater efficacy in APOE4 carriers than non-carriers on the iADRS scale. Figure 7B shows that donanemab demonstrated greater efficacy in APOE4 carriers than non-carriers on the CDR-SB scale. Figure 7C shows amyloid change (centiloid) by patient APOE4 status in the treatment and placebo groups. Figure 7D shows tau PET SUVR change by patient APOE4 status. The left graph shows frontal lobe data for APOE4 carriers (referred to in the figure as E4 carriers) and non-carriers (referred to in the figure as E4 non-carriers). The right graph shows lateral temporal lobe data for APOE4 carriers (referred to in the figure as E4 carriers) and non-carriers (referred to in the figure as E4 non-carriers). Figures 7E-G show baseline tau subgroup analysis based on iADRS for APOE4 carriers in both the donanemab-treated and placebo groups. The bottom third shows patients with a baseline F18-flortaucipitin (FTP) SUVR ≤ 1.144 for both the placebo and donanemab groups. The middle third shows patients with a baseline FTP SUVR between 1.144 and 1.268 for both the placebo and donanemab groups. The top third shows patients with a baseline FTP SUVR > 1.268 for both the placebo and donanemab groups.

[0303] Example 6. Kinetics of amyloid reduction after donanemab treatment Donanemab treatment resulted in rapid 24-week amyloid reduction, the rate of which was directly proportional to baseline amyloid burden. After 6 months of donanemab treatment, participants with greater plaque clearance showed less tau progression in the frontal, parietal, and temporal brain regions, and greater amyloid plaque changes associated with less cognitive decline.

[0304] Figure 8A shows that donanemab induced rapid amyloid reduction in patients. This figure shows the individual 24-week amyloid reduction trajectories of patients treated with donanemab.

[0305] The individual amyloid trajectories shown in Figure 8A are based on baseline and 24-week amyloid measurements (centiloid units, CL) observed in the clinical study TRAILBLAZER-ALZ (AACG, Clinicaltrials.gov identifier NCT03367403). Participants (N = 115) were treated with donanemab and completed both baseline and 24-week F18-florbetapir PET scans. Complete amyloid clearance (also referred to herein as amyloid negativity and indicated by the dashed line in Figure 8A) was defined as an amyloid plaque level of <24.1 CL (Mintun et al., "Donanemab in Early Alzheimer's Disease," New England Journal of Medicine 384(18)(2021):1691-1704, 2021, incorporated herein by reference in its entirety). Donanemab induced rapid and significant amyloid plaque reduction. All participants demonstrated amyloid reduction ranging from -1.8 CL to -174.8 CL. The mean amyloid reduction rate across all participants was -2.9 CL / week. The group mean approached the complete amyloid clearance threshold of 24.1 CL over the first 24 weeks. As indicated by the upper dots on the plot, the individual trajectories also imply that individuals with higher baseline amyloid plaque levels were far from complete amyloid clearance over the first 24 weeks of treatment. Conversely, as indicated by the lower dots on the plot, participants with lower baseline amyloid plaque levels approached complete amyloid clearance over the first 24 weeks of treatment.

[0306] Figure 8B shows the association between baseline amyloid levels (X-axis) and change in amyloid levels over 24 weeks (Y-axis) for participants treated with donanemab in TRAILBLAZER-ALZ. Amyloid plaque reduction is associated with baseline amyloid plaque levels.

[0307] The relationship between baseline amyloid levels and change in amyloid levels over 24 weeks of treatment with donanemab, shown in Figure 8B, is based on baseline and 24-week amyloid measurements observed in the clinical study TRAILBLAZER-ALZ (AACG, Clinicaltrials.gov identifier NCT03367403). In this analysis, participants (N = 115) were treated with donanemab and underwent both baseline and 24-week F18-florbetapir PET scans. A robust correlation (Pearson correlation coefficient r = -0.57, p < 0.001) was observed between total amyloid plaque levels at baseline and the total amount of plaque removed during the first 24 weeks. Higher baseline amyloid plaque levels resulted in greater amyloid plaque removal. Conversely, lower baseline amyloid plaque levels resulted in less plaque removal.

[0308] Lower amyloid plaque levels at baseline correspond, on average, to earlier completion of amyloid clearance. Figure 8C shows the relationship between baseline amyloid levels (Y-axis) and amyloid clearance achieved at 24 weeks (X-axis) for participants treated with donanemab in TRAILBLAZER-ALZ. Participants who achieved complete amyloid clearance at 24 weeks had lower baseline amyloid plaque levels. In Figure 8C, bars indicate mean + / - standard deviation, where CL = centiloid, PET = positron emission tomography, and Q = quartile.

[0309] The relationship between baseline amyloid levels and amyloid clearance levels (partial or complete) obtained at 24 weeks, shown in Figure 8C, is based on baseline and 24-week amyloid measurements observed in the clinical study TRAILBLAZER-ALZ. In this analysis, participants (N=115) treated with donanemab and underwent both baseline and 24-week florbetapir PET scans were included in this analysis. Patients were divided into two groups based on their amyloid plaque levels at 24 weeks. Complete amyloid clearance (also referred to herein as amyloid negativity) was defined as an amyloid plaque level of less than 24.1 CL, and partial amyloid clearance was defined as an amyloid plaque level of 24.1 CL or greater. A two-sample t-test was used to compare the two groups. Participants who achieved complete amyloid clearance at 24 weeks had, on average, significantly (p<0.0001) lower baseline amyloid plaque levels than participants who had partial amyloid clearance at 24 weeks.

[0310] Participants with lower baseline levels of amyloid plaque were observed to achieve complete amyloid clearance more quickly (Figure 8D). Figure 8D shows the modeled relationship to achieving plaque clearance as a function of baseline amyloid plaque level. Figure 8D represents the time to achieving complete amyloid plaque clearance (defined as a PET measurement of less than 24.1 CL) in patients with various levels of amyloid deposition at baseline. The simulation shown in Figure 8D was performed using an exposure-response model developed using data from the clinical studies TRAILBLAZER-ALZ (AACG, Clinicaltrials.gov identifier NCT03367403) and AACD (Clinicaltrials.gov identifier NCT02624778). This model is an indirect response model, in which donanemab activity is modeled as increasing amyloid plaque level and the associated clearance rate constant. To conduct the simulation, 10,000 hypothetical patients received three doses of 700 mg donanemab IV four weeks apart, followed by 17 doses of 1400 mg donanemab Q4W, similar to the dosing regimen used in TRAILBLAZER-ALZ. Patients were divided into quartiles (Q1-Q4) based on their baseline amyloid-beta plaque load (CL) levels: Q1 = 38.7-81.6 cmcg, Q2 = 81.6-100.3 cmcg, Q3 = 100.3-126.3 cmcg, and Q4 = 126.4-251.4 cmcg. At the end of 76 weeks of treatment, the model-estimated percentages of patients who achieved amyloid clearance (by quartile) were 92.1% (Q1), 86.8% (Q2), 83.1% (Q3), and 76.0% (Q4).

[0311] Analysis of Figure 8D shows that patients with lower baseline amyloid levels were more likely to achieve amyloid clearance within 76 weeks of treatment than patients who initiated therapy with higher baseline amyloid levels. For example, 92.1% of patients achieved complete amyloid clearance in Q1, while 76.0% of patients achieved amyloid clearance in Q4. As the time required for 50% of patients in each quartile to achieve amyloid clearance corresponds to the relative amount of amyloid at baseline in each quartile, patients with lower baseline amyloid appear to achieve plaque clearance more quickly than patients with higher baseline amyloid.

[0312] The association between baseline amyloid levels and donanemab dosing regimens is shown in Figure 8E. This figure shows the association between baseline amyloid levels (Y-axis) and the donanemab dosage used. Participants with lower baseline levels of amyloid plaques were eligible for earlier dose reduction. In Figure 8E, bars indicate mean + / - standard deviation; CL = centiloid, Max = maximum value, PET = positron emission tomography; ***p<0.001.

[0313] In participants treated with donanemab, if amyloid plaque levels (assessed by F18-florbetapir PET performed at weeks 24 and 52) were less than 11–25 CL, indicating amyloid plaque clearance, the dose was reduced to 700 mg. If amyloid plaque levels were less than 11 CL on an individual scan or less than 11–25 CL on two consecutive scans, donanemab-treated participants were switched to placebo. Figure 8E includes two subgroups: participants who continued on the maximum dose until the end of the study and participants eligible for dose reduction at week 24. Two-sample t-tests were used to compare the two groups. Participants who met the dose modification criteria had significantly lower baseline amyloid plaque levels than participants who continued on maximum treatment until the end of the study.

[0314] Response rates to donanemab treatment depended on baseline amyloid plaque levels, and discontinuing medication did not result in significant amyloid re-accumulation over a one-year period. Figure 8F shows the model-predicted changes in amyloid plaque levels after treatment cessation in patients who achieved amyloid clearance within six months.

[0315] Using the model described above in Figure 8F, we simulated the evolution of amyloid plaque levels in 2,000 patients using the dosing regimen utilized in TRAILBLAZER-ALZ. The subset of these 2,000 patients who achieved amyloid plaque levels of 11 CL or less was examined graphically to assess the predicted time course of amyloid plaque levels over the remainder of the study. A value of 11 CL was used as the cutoff for this simulation because this was the criterion used in TRAILBLAZER-ALZ for discontinuing donanemab treatment. Median values ​​(solid lines) and 90% prediction intervals (shaded regions) are plotted for the on-treatment and off-treatment periods.

[0316] The impact on plaque re-accumulation of discontinuing treatment after patients reached <11 CL was investigated by simulation using a treatment-exposure-response model (Figure 8F). In the simulated patient population achieving a PET signal <11 CL by week 24, discontinuing donanemab treatment did not result in a significant increase in PET signal until the end of the simulation (week 76), attributable to the model-estimated plaque accumulation (approximately 6.7 CL / year). The model assumption is that the rate of plaque formation / accumulation after donanemab treatment is similar to the baseline rate. This model implies that continued donanemab treatment after complete amyloid clearance is limited in its additional benefit, as the relatively low amyloid accumulation rate (6.7 CL / year) suggests that patients who achieved 11 CL while on donanemab would require more than 13 years to return to the model-estimated baseline of 101 CL.

[0317] Donanemab treatment reduced tau accumulation over 76 weeks, and in participants who achieved complete amyloid plaque clearance at 24 weeks. Figure 8G shows the effect on tau PET in participants who achieved complete amyloid plaque clearance at 24 weeks compared with participants who had partial amyloid clearance or placebo. At baseline and week 76, [ 18 [F] TRAILBLAZER-ALZ study participants who underwent flortaucipir PET scans are included in the analysis. Participants who received donanemab (green bars in Figure 8G) are designated as having partial or complete amyloid clearance based on amyloid plaque levels at 24 weeks. Complete amyloid clearance was defined as an amyloid plaque level <24.1 CL, and the partial amyloid clearance cohort included donanemab-treated participants who did not reach that threshold by week 24. Tau PET accumulation is measured by flortaucipir regional SUVR in the temporal, parietal, and frontal brain regions, using the cerebellar crus as the reference region. P values ​​indicate statistical significance relative to placebo regional tau PET changes over 76 weeks (gray). In Figure 8G, bars indicate the mean + / - standard error, LS = least squares, PET = positron emission tomography, SUVR = standardized uptake value ratio, *p<0.05, **p<0.01 vs. placebo.

[0318] In TRAILBLAZER-ALZ study participants treated with donanemab, less accumulation of aggregated tau was observed across the temporal, parietal, and frontal brain regions as measured by F18-flortaucipir PET at week 76. Numerically greater effects on tau change (even less accumulation) were observed in participants who achieved complete amyloid clearance at week 24 of the study. These data highlight the value of rapid amyloid plaque removal and support the relevance of these biomarkers to models of amyloid-induced tauopathy and the development and / or progression of Alzheimer's disease.

[0319] Figure 8H shows percent change in amyloid plaque levels versus iADRS change from baseline at week 24. Greater amyloid clearance at week 24 was associated with less clinical decline.

[0320] The percentage change from baseline in CL values ​​for each patient was calculated at week 24 and plotted against the change from baseline in iADRS scores for TRAILBLAZER-ALZ at weeks 52, 64, and 76 (indicating a reduction in clinical disease progression) (Figure 8H). Both donanemab- and placebo-treated patients were included in the plot. A simple linear regression line was fitted to demonstrate the relationship between plaque reduction at week 24 and iADRS clinical outcome, and Pearson correlation coefficients were calculated. A negative correlation coefficient indicates a linear relationship between increasing amyloid plaque removal and reduced clinical decline. At weeks 52, 64, and 76, the correlation coefficients were -0.15, -0.13, and -0.09, respectively. This analysis shows a moderate correlation, suggesting that greater amyloid plaque removal is associated with less clinical decline.

[0321] Figure 8I shows the relationship between amyloid plaque reduction and delayed rate of disease progression using a model integrating PK, PET, and clinical endpoint (iADRS) data, where iADRS = integrated Alzheimer's Disease Rating Scale, mean and 90% CI, CI = confidence interval, PET = positron emission tomography, and PK = pharmacokinetics.

[0322] A model was developed to describe the relationship between changes in amyloid plaque levels and changes in the rate of disease progression as measured by the iADRS scale. This model is based on the disease progression model described by Conrado et al., "An Updated Alzheimer's Disease Progression Model: Incorporating Nonlinearity, Beta Regression, and a Third-Level Random Effect in NONMEM," Journal of Pharmacokinetics and Pharmacodynamics 41(6)581-598, 2014 (incorporated herein by reference in its entirety). In this study, the Conrado model was modified to include a drug effect modeled as moderating the slope of disease progression correlated with the percent change in amyloid plaque levels from baseline, as predicted by the exposure-response model for donanemab and amyloid plaques. Figure 8I was generated using the model-estimated slope of disease progression in the TRAILBLAZER-ALZ population along with the model-estimated effect of amyloid plaque reduction on the disease slope. The 90% confidence intervals for the relationships were estimated using the standard errors of each of the model parameters. The model's predicted relationships are plotted as solid lines, and the 90% confidence intervals are represented by the shaded areas in Figure 8I.

[0323] Figure 8I shows the modeled relationship between the change in amyloid with donanemab treatment and the change in disease progression rate relative to placebo patients. This relationship is based on an exposure-response model that relates serum donanemab concentrations to changes in amyloid levels and subsequent changes in disease progression as a result of changes in amyloid levels. The model suggests that complete removal of amyloid plaques could reduce the rate of disease progression by >40%. The model suggests that there is a continuous relationship between the reduction in amyloid plaque levels and the change in disease progression rate. The continuous nature of this relationship suggests that less than complete plaque removal could slow the rate of disease progression in patients and increase the period during which they can maintain sufficient cognitive and functional activity to enable them to maintain an independent lifestyle.

[0324] Example 7: Amyloid clearance results in a rapid and sustained reduction in plasma levels of human tau phosphorylated at threonine 217 (P-tau217) Clearance of amyloid in subjects resulted in a rapid and sustained reduction in plasma P-tau217 levels. Plasma P-tau217 correlated with baseline amyloid plaque levels and baseline neurofibrillary tangles measured by F18-florbetapir PET. Treatment with donanemab drove a rapid reduction in plasma P-tau217, detected within 12 weeks. As demonstrated by the Conrado model, changes in plasma P-tau217 positively correlated with reductions in amyloid plaques by PET, slower growth of tau neurofibrillary tangles by PET, and slower clinical progression. Furthermore, similar to the trends observed in local tau-PET declines, early and complete clearance of amyloid plaques suggests a significant reduction in plasma P-tau217.

[0325] An immunoassay for human tau phosphorylated at threonine residue 217 (P-tau217) was used to measure tau loading in human K2EDTA plasma from patients on TRAILBLAZER-ALZ (see, e.g., International Patent Application Publication No. WO2020 / 242963, which is incorporated herein by reference in its entirety). The anti-tau antibodies disclosed in WO2020 / 242963 are directed against isoforms of human tau expressed in the CNS (e.g., they recognize isoforms expressed in the CNS, but not isoforms of human tau expressed only outside the CNS).

[0326] A Quanterix Simoa® HD-X Analyzer™ was used for the p-tau217 immunoassay. The analyzer uses p-tau217 immunoassay reagents (capture antibody: a Fab clone against p-tau217; detection antibody: an antibody clone against tau protein; calibrator and control: two synthetic peptides linked with a PEG linker representing the epitopes recognized by the capture and detection antibodies). See, for example, International Patent Application Publication No. WO 2020 / 242963 (incorporated herein by reference in its entirety), which uses single molecule array (Simoa®) technology. This assay can detect low levels of p-tau217 in human plasma and is a fully automated immunoassay.

[0327] In the first step, target antibody-coated capture beads were combined with a human plasma sample. Target molecules present in the sample were captured by the antibody-coated capture beads. After washing, a biotinylated detection antibody was mixed with the capture beads. The detection antibody bound to the captured target. After a second wash, a streptavidin-β-galactosidase (SBG) conjugate was mixed with the capture beads. SBG bound to the biotinylated detection antibody, resulting in enzymatic labeling of the captured target. After a third wash, the capture beads were resuspended in a resorufin β-D-galactopyranoside (RGP) substrate solution and transferred to a Simoa® disk. Individual capture beads were then sealed into the array's microwells. Once the target was captured and labeled, the β-galactosidase hydrolyzed the RGP substrate, producing a fluorescent product that provided a signal for measurement. Single-labeled target molecules produced sufficient fluorescent signals to be detected and counted within 30 seconds by the Simoa® optical system. At low target concentrations, the percentage of bead-containing wells in the array with a positive signal is proportional to the amount of target present in the sample. At higher target concentrations, when most of the bead-containing wells have one or more labeled target molecules, the total fluorescent signal is proportional to the amount of target present in the sample. The concentration of target in an unknown sample is interpolated from the standard curve using unweighted log-log power regression.

[0328] Figures 9A-B show that baseline plasma P-tau217 correlates with baseline amyloid plaque levels and neurofibrillary tangles. Figure 9A shows a scatterplot of baseline amyloid PET centroids and baseline plasma P-tau217. Open circles represent TRAILBLAZER-ALZ patients receiving placebo, and solid green lines represent TRAILBLAZER-ALZ patients receiving donanemab. P-tau217 values ​​were normalized by log10 transformation. Correlation between the two variables was assessed using Spearman's rank correlation. At baseline, β-amyloid measured by F18-florbetapir PET positively correlated with plasma P-tau217 levels (R = 0.147, p = 0.026). Figure 9B shows a scatterplot of baseline tau PET centroids and baseline plasma P-tau217. Open circles indicate patients on TRAILBLAZER-ALZ who received placebo, and solid green lines indicate patients on TRAILBLAZER-ALZ who received donanemab. P-tau217 values ​​were normalized by log10 transformation. Correlation between the two variables was assessed using Spearman's rank correlation. At baseline, brain tau measured by F18-florbetapir PET positively correlated with plasma P-tau217 levels (R = 0.383, p < 0.0001). In Figures 9A-9B, CL = centiroid, SUVR = standardized uptake value ratio, PET = positron emission tomography, p = p-value, R = correlation coefficient, and SUVR = standardized uptake value ratio.

[0329] Immunoassay data demonstrate that donanemab treatment significantly reduced plasma P-tau 217 in human subjects. Figure 9C shows a mixed model with repeated measures (MMRM) model comparing the change in P-tau 217 from baseline between treatment groups. This figure demonstrates that donanemab rapidly reduced plasma P-tau 217. Figure 3A (provided above) demonstrates that donanemab treatment significantly reduced amyloid plaques. P-tau 217 showed rapid clearance after treatment, starting at the 12-week measurement. At week 76, the donanemab-treated group showed a 24% reduction compared to baseline (P<0.0001), while the placebo-treated group showed a 6% increase (p=0.03). Compared to the placebo-treated group, the donanemab-treated group showed a 29% reduction in P-tau 217 accumulation. In Figure 9C, LS = least squares, p = p-value, **p<0.01, ****p<0.0001 vs. placebo.

[0330] Changes in plasma P-tau217 were associated with amyloid plaque clearance status after 24 weeks. Figure 9D shows a mixed model with repeated measures (MMRM) to compare changes in P-tau217 from baseline across the placebo group, the donanemab group treated with partial amyloid clearance, and the donanemab group treated with complete amyloid clearance. Complete amyloid clearance was defined as a florbetapir PET centimeter level <24.1 (also referred to herein as amyloid negative). Amyloid clearance status was measured using an F18-florbetapir PET scan at 24 weeks. In Figure 9D, bars indicate mean + / - standard error, LS = least squares, p = p-value, ****p<0.0001 vs. placebo.

[0331] Consistent with findings from brain tau PET, amyloid clearance was associated with a reduction in P-tau217. Complete amyloid clearance at 24 weeks showed a numerically greater P-tau217 reduction than partial amyloid clearance, although this was not statistically significant at 76 weeks (p=0.34). Both treatment groups showed a statistically significant reduction in P-tau217 accumulation compared to the placebo group (p<0.0001).

[0332] Figures 9E and 9F show that reductions in plasma P-tau217 are associated with amyloid clearance. Figures 9E and 9F show scatterplots of amyloid PET centiloid change from baseline with changes in P-tau217 from baseline values ​​at 24 and 76 weeks, respectively. P-tau217 values ​​were normalized by log10 transformation. Correlation between the two sets of variables was assessed using Spearman's rank correlation. In the figures, open circles represent TRAILBLAZER-ALZ patients who received placebo, and solid green lines represent TRAILBLAZER-ALZ patients who received donanemab. CL = centiloid, PET = positron emission tomography, p = p-value, r = correlation coefficient.

[0333] At both time points (24 and 76 weeks), the change from baseline in β-amyloid as measured by F18-florbetapir PET was positively correlated with P-tau217 levels (r=0.349 and 0.482 for both correlation coefficients, respectively; p<0.001).

[0334] Reductions in plasma P-tau217 were associated with reductions in neurofibrillary tangles at week 76. Figures 9G and 9H show scatterplots of tau PET regional SUVR (frontal and parietal) change from baseline with change in P-tau217 from baseline values ​​at week 76. P-tau217 values ​​were normalized by log10 transformation. Correlation between the two sets of variables was assessed using Spearman's rank correlation. In the figures, open circles represent TRAILBLAZER-ALZ patients who received placebo, and closed circles represent TRAILBLAZER-ALZ patients who received donanemab. PET = positron emission tomography, p = p-value, r = correlation coefficient.

[0335] Changes from baseline in SUVR in the frontal and parietal lobes were positively correlated with changes from baseline in P-tau217 (r=0.171, p=0.031 and r=0.257, p=0.0011, respectively).

[0336] The PK / PD model shows the relationship between plasma P-tau217 and slowing of clinical decline. This model was developed to describe the relationship between changes in plasma P-tau217 levels and changes in the rate of disease progression as measured by the iADRS scale. This model is based on the disease progression model described by Conrado et al. (Conrado et al., "An Updated Alzheimer's Disease Progression Model: Incorporating Non-linearity, Beta Regression, and a Third-Level Random Effect in NONMEM," Journal of Pharmacokinetics and Pharmacodynamics 41(6)581-598, 2014, which is incorporated herein by reference in its entirety).

[0337] The model shows that reduction in P-tau217 is statistically significant as a predictor of delayed clinical decline (p<0.001). In Figure 9I, iADRS = integrated Alzheimer's Disease Rating Scale, mean and 90% CI, CI = confidence interval, PK = pharmacokinetics, p = p-value.

[0338] Example 8: TRAILBLAZER-ALZ3 Study Design and Rationale Objective: TRAILBLAZER-ALZ3 (referred to herein as TB3, NCT05026866) is a multicenter, randomized, double-blind, placebo-controlled, event-driven, phase 3 study with a centrally assessed, decentralized design designed to evaluate the effects of donanemab versus placebo in cognitively unimpaired participants with evidence of AD pathology (preclinical AD). Figure 10 shows the study design of the clinical protocol. SP stands for Study Period. Participants randomized to placebo and who complete SPIII may have access to donanemab in SPIV, an open-label extension, if donanemab meets defined success factors.

[0339] Overview and Primary Endpoint: Approximately 3,300 participants who meet the inclusion criteria will be randomized in a 1:1 ratio to either donanemab (700 mg intravenously (IV) every four weeks (Q4W) for the first three doses, followed by 1,400 mg IV Q4W for the next six doses) or placebo (9 doses IV Q4W). Approximately 434 participants will be followed until they experience the primary outcome event of clinical progression (an increase in Clinical Dementia Rating-Global Score (CDR-GS or gCDR) from baseline CDR-GS = 0 at two consecutive visits). Total study participation will vary by participant, with continuous follow-up for 3 to 5 years. Donanemab treatment will be stratified by APOE4 allele dose, ranging from 0 to 2. For example, individuals may have 0, 1, or 2 copies of the E4 allele. Zero copies of the APOE4 allele are APOE4 negative, one copy of the APOE4 allele is heterozygous, and two copies of the APOE4 allele are homozygous. Rather than categorizing individuals by APOE4 carrier status, this stratification by APOE4 dose allows for equal amounts of homozygous and heterozygous APOE4 carriers in each treatment group.

[0340] The study will use a decentralized clinical trial (DCT) model in which all or some of the visits are conducted remotely, with the goal of increasing the number of eligible participants, including those from underrepresented populations. All clinical and cognitive assessments will be conducted remotely by a central rater. The DCT model includes the use of technology, flexible locations, and centralized staffing to optimize the potential for strong participant retention and enhanced standardization through centralized raters for clinical assessments. Participants and partners will be assigned a central study coordinator (CSC) who will serve as a central point of contact throughout the study.

[0341] Inclusion / Exclusion Criteria: Selection criteria included: ●Men and women aged 55 to 80 years old Telephone Interview for Cognitive Status - Complete Cognitive Function Modification (TICS-m) score, and • Qualified plasma P-tau217 result (SIMOA assay).

[0342] Exclusion criteria included: Mild cognitive impairment (MCI) / dementia or other neurodegenerative diseases that affect cognition, current or previous use of prescription medications for the treatment of MCI or dementia; -Current serious or unstable illness, • a history of cancer with a high risk of recurrence that would prevent completion of the study; • Clinically significant multiple or severe drug allergies or a history of severe hypersensitivity reactions following treatment; previous treatment with anti-amyloid immunotherapy, Any clinically significant abnormality on screening MRI or clinical examination, Any contraindications to MRI, and • Central-read MRI showing the presence of ARIA-E (amyloid-related imaging abnormality with exudate or edema), >4 cerebral microbleeds, >1 superficial siderosis, macroscopic hemorrhage, or severe white matter disease at screening.

[0343] Other efficacy assessments: Secondary endpoints to assess clinical progress include the International Shopping List Test, Serial Paired Associate Learning, International Everyday Symbol Substitution Test-Medications, Category Fluency, Face-Name Association Test, Behavioral Pattern Separation-Object Test, Cog-State Brief Battery, CDR-Sum of Boxes, Cognitive Function Index, Montreal Cognitive Assessment, and Cognitive Composite Score (including a combination of individual assessments). Optional additions may include florbetapir-18F PET scan (N=200), flortaucipir-18F PET scan (N=500), and APOE disclosure.

[0344] Safety Assessment: To evaluate the safety and tolerability of donanemab, this study will monitor spontaneously reported adverse events (AEs), MRIs (for ARIA and urgent radiological findings), infusion-related reactions, and the Columbia Suicide Severity Rating Scale. MRIs to assess / monitor ARIA may be performed at baseline, after the first dose, before dose escalation from 700 mg to 1400 mg, during the dosing period (e.g., double-blind treatment period), at weeks 4, 12, and 20, and every 1-2 weeks, or as determined by the investigator. MRI scheduling may resume during the open-label extension period to assess / monitor ARIA.

[0345] Biomarkers: Serum, plasma, and whole blood RNA samples for biomarker studies will be collected at screening and throughout the study. Biomarker analysis will be performed to address questions of relevance to drug disposition, target engagement, pharmacodynamics, mechanism of action, and participant response variability (including safety). Plasma P-tau217 and other blood-based biomarkers will be used to further inform clinical outcomes and response to therapy. A subset of participants will undergo florbetapir and / or flortaucipir PET imaging to evaluate the effect of donanemab on cerebral amyloid plaque burden and cerebral neurofibrillary tangle burden versus placebo in a preclinical Alzheimer's disease population.

[0346] Potential Impact / Conclusions: TB3 represents an innovative, centrally assessed, decentralized trial design that includes a time-to-clinical-event model, blood-based AD biomarker selection criteria, and potentially supportive AD biomarker endpoints. Results from this trial may help address the question of whether donanemab treatment, coupled with rapid reduction in cerebral amyloid plaques, can delay or even prevent progression to the clinical stage of AD.

[0347] Example 9: TRAILBLAZER - Biomarkers of ALZ Additional biomarker data was generated using the Simoa® Neurology4-Plex E Advantage Kit (additional information regarding the assay / kit is provided at "quanterix.com / wp-content / uploads / 2020 / 12 / Neurology-4-Plex-E-Data-Sheet-HD-X.pdf," which is incorporated herein by reference in its entirety). Briefly, the Simoa® Neuro4-plexE assay measures amyloid beta 40 (Aβ) in human plasma. 40 ), amyloid beta 42 (Aβ 42This is a digital immunoassay for quantitatively measuring NF-κB, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). The Simoa® HD-X Analyzer™ uses ready-to-use Neuro4-plexE immunoassay reagents to perform jobs using single molecule array (SiMoA) technology (one job equals one value, so a duplicate run results in two jobs). In the two-step Simoa® Neuro4-plexE assay, paramagnetic beads coated with a target antibody are combined with the sample and a biotinylated detection antibody in the same incubation. Target molecules present in the sample are captured by the antibody-coated beads and simultaneously bind to the biotinylated antibody detector. After washing, a streptavidin-β-galactosidase (SBG) complex is mixed with the beads. SBG binds to the biotinylated detection antibody, resulting in enzymatic labeling of the captured target. After a final wash, the beads were resuspended in resorufin β-D-galactopyranoside (RGP) substrate solution and transferred to a Simoa® disk. Individual beads were then sealed into the microwells of the array. If the target was captured and labeled on the bead, β-galactosidase hydrolyzed the RGP substrate in the microwell, producing a fluorescent product that provided a signal for measurement. A single-labeled target molecule produced a fluorescent signal sufficient to be detected and counted by the Simoa® optical system within 30 seconds. At low target concentrations, the percentage of bead-containing wells in the array with a positive signal is proportional to the amount of target present in the sample. At higher target concentrations, when most of the wells containing beads have one or more labeled target molecules, the total fluorescent signal is proportional to the amount of target present in the sample. The concentration of target in an unknown sample is expressed as 1 / y 2 is interpolated from the calibration curve using a 4 / 5 parameter logistic regression with weighting.

[0348] Neurofilament light chain (NfL) Neurofilament light chain (NfL) is an important biomarker (plasma or CSF) that can indicate neuronal damage due to many disease mechanisms, but is also elevated in Alzheimer's disease in particular. Therapies that can reduce NfL are predicted to mitigate neuronal damage and portend improved disease outcomes. Data from the Simoa® Neuro4-plexE assay demonstrate that NfL in the overall donanemab-treated population can be reduced by at least 4% compared to placebo over the course of the treatment / dosing regimen (Figure 11A shows plasma NfL reduction). This reduction effect may be enhanced in APOE4 carriers, as shown in Figure 11B, with significant declines at later time points in the study. The plasma data in this figure are the first to demonstrate NfL reduction with an anti-Aβ antibody in Alzheimer's disease in an APOE4 carrier population. Figure 11B shows the change from baseline in NfL in APOE4 carriers (LS mean estimates from the MMRM model).

[0349] Amyloid beta (Aβ) Aβ 42 / 40 The ratio is known to slowly decrease over time in plasma and CSF when amyloid plaques are deposited in the brain parenchyma. Treatments that remove amyloid plaques may normalize this ratio, which translates to an increase toward higher levels. Data from TRAILBLAZER-ALZ show that donanemab treatment increases this ratio, demonstrating significant improvement at at least one time point (Figure 12). Figure 12 shows an increase in the Aβ42 / 40 ratio.

[0350] It is noteworthy that, unlike other antibodies, donanemab does not interact with any soluble species, and therefore, an increase in this ratio provides a definitive result regarding its ability to clear amyloid plaques to normalize this biomarker without the confounding effects of binding to other soluble blood species previously demonstrated with other antibodies.

[0351] Glial fibrillary acidic protein (GFAP) Normalization and reduction of the GFAP biomarker is an important first step for plaque-lowering antibodies. GFAP is an intermediate cytoskeletal protein upregulated in reactive astrocytes and is recognized as a pathological hallmark of many diseases, including AD. GFAP is associated with amyloidosis, and recent studies have linked circulating GFAP to amyloid deposition. The data shown in Figure 13A demonstrate for the first time the ability of a therapeutic agent (donanemab) to reduce the pathological response of astrocytes to amyloid through reduction of GFAP measured in the blood. Figure 13A shows that GFAP is significantly reduced with donanemab treatment. Additionally, P-tau217 and GFAP show a similar relationship with amyloid plaque clearance in TRAILBLAZER-ALZ....

Claims

1. 1. A medicament for preventing or treating a disease characterized by the deposition of amyloid beta plaques in the brain of a human subject, comprising: (i) administering to the human subject one or more first doses of about 100 mg to about 700 mg of an anti-N3pGlu Aβ antibody, wherein each first dose is administered about once every four weeks; (ii) about four weeks after administering the one or more first doses, administering to the human subject one or more second doses of greater than 700 mg to about 1400 mg of the anti-N3pGlu Aβ antibody, wherein each second dose is administered about once every four weeks; The anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 1, and the HCVR comprises the amino acid sequence of SEQ ID NO:

2.

2. 10. The method of claim 1, wherein the human subject receives one, two, or three doses of the first dose before receiving the second dose.

3. 3. The method of claim 1 or 2, wherein the human subject is administered a first dose of about 700 mg.

4. 4. The method of claim 1, wherein the human subject is administered one or more second doses of about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, or about 1400 mg.

5. The method of any one of claims 1 to 4, wherein the human subject is administered one or more second doses of about 1400 mg.

6. 6. The method of claim 1, wherein the anti-N3pGlu Aβ antibody is administered to the human subject (i) for a period of up to 72 weeks, (ii) until normal levels of amyloid are achieved, or (iii) until reduction / clearance of Aβ from the subject's brain has ceased.

7. The method of any one of claims 1 to 6, wherein the anti-N3pGlu Aβ antibody is administered to the human subject until the amyloid plaque level in the patient is about 25 centiloids or less.

8. The agent of any one of claims 1 to 6, wherein the anti-N3pGlu Aβ antibody is administered to the human subject until the amyloid plaque level in the human subject is about 25 centiloids or less in two consecutive PET imaging scans (optionally, the two consecutive PET imaging scans are separated by at least 6 months), or 11 centiloids or less in one PET imaging scan.

9. 7. The method of claim 1, wherein the human subject receives a first dose of 700 mg three times every four weeks, followed by a second dose of 1400 mg once every four weeks for a period of up to 72 weeks.

10. 7. The method of claim 1, wherein the human subject is administered three first doses of 700 mg once every four weeks, followed by a second dose of 1400 mg once every four weeks until the amyloid plaque level in the subject is about 25 centiloids or less.

11. 7. The agent of any one of claims 1 to 6, wherein the human subject is administered three 700 mg first doses once every four weeks, followed by a 1400 mg second dose once every four weeks until the subject has amyloid plaque levels of about 25 centiloids or less on two consecutive PET imaging scans (optionally, the two consecutive PET imaging scans are separated by at least six months), or 11 centiloids or less on one PET imaging scan.

12. The method of any one of claims 1 to 11, wherein the human subject is administered the second dose for a period of time sufficient to treat or prevent the disease.

13. 13. The agent according to any one of claims 1 to 12, wherein the treatment or prevention of the disease involves i) reducing Aβ plaques in the brain of the human subject, and / or ii) slowing cognitive or functional decline in the human subject.

14. The method of claim 13, wherein the reduction of Aβ plaques in the brain of the human subject is determined by amyloid PET brain imaging or a diagnostic that detects an Aβ biomarker.

15. The method of claim 13 or 14, wherein the second dose is administered to the human subject until Aβ plaques in the brain of the human subject are reduced by about 20 to 100%.

16. 16. The agent of claim 15, wherein Aβ plaques in the brain of the human subject are reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 75%, or about 100%.

17. 15. The pharmaceutical agent of any one of claims 1 to 14, wherein the second dose is administered to the human subject until Aβ plaques in the brain of the human subject are reduced by: i) about an average of about 25 centiloids to about 100 centiloids; ii) about an average of about 50 centiloids to about 100 centiloids; iii) about 100 centiloids; or iv) about 84 centiloids.

18. 18. The method of claim 1, wherein the disease characterized by Aβ deposition in the brain of the human subject is selected from preclinical Alzheimer's disease (AD), clinical AD, prodromal AD, mild AD, moderate AD, severe AD, Down's syndrome, clinical cerebral amyloid angiopathy, or preclinical cerebral amyloid angiopathy.

19. The method of claim 18, wherein the human subject has prodromal AD.

20. The method of any one of claims 1 to 18, wherein the human subject is a preclinical AD patient.

21. 20. The agent according to any one of claims 1 to 19, wherein the human subject i) has been determined to have a very low to moderate tau load or has a very low to moderate tau load, ii) has been determined to have a low to moderate tau load or has a low to moderate tau load, iii) has been determined to have a very low to moderate tau load or has a very low to moderate tau load and has one or two alleles of APOE4, iv) has a low to moderate tau load or has been determined to have a low to moderate tau load and has one or two alleles of APOE4, or v) has one or two alleles of APOE4.

22. 22. The agent of claim 21, wherein the human subject has i) a very low to moderate tau burden when the tau burden measured by PET brain imaging is ≦1.46 SUVr, or ii) a low to moderate tau burden when the tau burden measured by PET brain imaging is 1.10 SUVr to 1.46 SUVr.

23. 21. The agent according to any one of claims 1 to 20, wherein the human subject i) does not have a high tau burden or has been determined not to have a high tau burden, or ii) carries one or two alleles of APOE4 and does not have a high tau burden or has been determined not to have a high tau burden.

24. 24. The agent of claim 23, wherein the human subject has a high tau burden if the tau burden measured by PET brain imaging is greater than 1.46 SUVr.

25. 23. The agent of claim 21 or 22, wherein the tau burden of the human subject is determined using PET brain imaging or a diagnostic that detects a tau biomarker.

26. 26. The agent of any one of claims 1-25, further comprising the step of evaluating a magnetic resonance imaging (MRI) scan of the subject's brain for amyloid-related imaging abnormalities (ARIA) after said administration of the three first doses, and modifying one or more of the dosing steps until ARIA-E resolves.

27. 27. The method of claim 26, wherein administration of the anti-N3pGlu Aβ antibody is temporarily withheld or discontinued if symptoms consistent with ARIA occur.

28. 28. The method of claim 27, wherein administration of the anti-N3pGlu Aβ antibody is temporarily withheld if symptoms consistent with mild to moderate ARIA occur.

29. 28. The method of claim 27, wherein administration of the anti-N3pGlu Aβ antibody is discontinued if symptoms consistent with severe or symptomatic ARIA occur.

30. The agent according to any one of claims 1 to 29, wherein the administration of the anti-N3pGlu Aβ antibody comprises: a) slowing disease progression by at least 15% compared to untreated as predicted by a disease progression model (DPM) as measured by iADRS or CDR-SB; b) slowing disease progression by at least 15% compared to untreated as measured by iADRS or CDR-SB as estimated by mixed model repeated measures analysis (MMRM); c) slowing disease progression by at least 15% compared to untreated patients as measured by the integrated Alzheimer's Disease Rating Scale (iADRS); d) slowing disease progression by at least 3 compared to untreated patients as measured by the integrated Alzheimer's Disease Rating Scale (iADRS); e) slowing the progression of the disease by at least 20% compared to untreated, as measured by the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB); f) reducing the level of Aβ plaques in the brain of said subject by at least 40% as measured by amyloid PET imaging; g) slowing tau accumulation in the frontal lobe by at least 50% compared to untreated; h) limiting the increase in frontal lobe tau in said subject to less than 0.04 SUVr (standardized uptake value ratio) over 72 weeks as measured by tau PET imaging; or i) reducing plasma P-tau217 by at least 5% from baseline; or j) Agents that reduce glial fibrillary acidic protein (GFAP) by at least 5% from baseline.

31. The agent according to any one of claims 1 to 30, wherein the anti-N3pGlu Aβ antibody comprises a light chain (LC) and a heavy chain (HC), wherein the LC comprises the amino acid sequence of SEQ ID NO: 3, and the HC comprises the amino acid sequence of SEQ ID NO:

4.

32. The agent of claim 31 , wherein the anti-N3pGlu Aβ antibody comprises two light chains and two heavy chains, the LC comprising the amino acid sequence of SEQ ID NO: 3, and the HC comprising the amino acid sequence of SEQ ID NO: 4.

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