TWI894689B - ANTI-N3pGlu AMYLOID BETA ANTIBODIES, DOSES, AND USES THEREOF - Google Patents

Abstract

The treatment or prevention of a disease characterized by deposition of amyloid beta (Aβ) plaques in the brain of a human subject, in particular intravenous and subcutaneous doses and dosing regimens of anti-N3pG antibodies.

Description

Anti-N3pGlu amyloid beta antibody, dosage and use thereof

The present invention relates to anti-N3pGlu Aβ antibodies, their dosages, their administration regimens, and methods of using such antibodies, including their use in treating or preventing diseases characterized by Aβ deposition in the brain. Diseases that can be treated or prevented using the antibodies, administration regimens, or methods disclosed herein include, for example, Alzheimer's disease (AD), Down syndrome, and cerebroamyloid angiopathy (CAA).

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by a progressive decline in cognitive function and the ability to perform activities of daily living, ultimately leading to death due to complications of the disease. Pathological hallmarks of AD identified at autopsy include the presence of neuroinflammatory Aβ plaques, neurofibrillary tangles (Selkoe, “The Molecular Pathology of Alzheimer's Disease,” Neuron 6(4):487-498 (1991); Hyman et al., “National Institute on Aging-Alzheimer's Association Guidelines on Neuropathologic Assessment of Alzheimer's Disease,” Alzheimers Dement. 8(1):1-13 (2012)), and neuronal loss in brain regions important for cognition, such as the hippocampus and temporal cortex (Padurariu et al., “Hippocampal Neuronal Loss in the CA1 and CA3 Areas of Alzheimer's Disease Patients,” Psychiatr Danub. 24(2):152-158). (2012)).

The amyloid hypothesis of AD proposes that the production and deposition of Aβ are early and essential events in the pathogenesis of AD (Hardy and Selkoe, "The Amyloid Hypothesis of Alzheimer's Disease: Progress and Problems on the Road to Therapeutics", Science 297(5580):353-356 (2002)). 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, but particularly in neuronal synapses. APP is cleaved by γ-secretase to release Aβ peptides, which encompass 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, protofibrils, and amyloid fibrils. Amyloid oligomers are soluble and diffuse throughout the brain, while amyloid fibrils are larger and insoluble and can further aggregate to form amyloid plaques. Amyloid plaques found in human patients consist of a heterogeneous mixture of Aβ peptides, some of which contain N-terminal truncations and may further include N-terminal modifications such as an N-terminal pyroglutamine residue (pGlu).

The role of amyloid plaques in driving disease progression has been supported by studies targeting uncommon genetic variants that 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)). In addition, the presence of amyloid plaques in the early stages of the disease increases the likelihood that mild cognitive impairment (MCI) will progress 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)). Another hallmark neuropathological lesion of AD includes intraneuronal neurofibrillary tangles composed of tau protein, which spread throughout the brain and mark disease progression (Braak and Braak, "Evolution of the Neuropathology of Alzheimer's Disease", Acta Neurol Scand Suppl. 165:3-12 (1996)). The presence of both is essential for the diagnosis of definite AD, but scientific understanding of the relationship between these 2 pathologies is still evolving.

It is hypothesized that interventions or therapies aimed at removing Aβ plaques could slow the clinical progression of AD. Antibodies targeting Aβ have shown promise as treatments for Alzheimer's disease in both preclinical and clinical studies. Despite this promise, many amyloid-beta-targeting antibodies have failed to meet therapeutic targets in multiple clinical trials. The history of clinical trials of anti-amyloids spans nearly two decades and, for the most part, has cast doubt on the potential of such therapies to be effective in treating 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)).

Furthermore, some anti-amyloid monoclonal antibodies carry significant safety risks. Administration of Aβ antibodies has been associated with adverse events in humans, including amyloid-associated imaging abnormalities (ARIAs), including vascular edema and cerebral sulci (ARIA-E), microbleeds and hemosiderin deposits (ARIA-H); infusion site reactions; and the risk of immunogenicity. See, e.g., 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 Being Investigated for the Treatment of Early Alzheimer's Disease”, The Journal of Prevention of Alzheimer's Disease 4.4: 255 (2017). ARIA is the most common side effect of this class of drugs. ARIA is usually asymptomatic and can be detected using brain MRI. ARIA can cause symptoms such as headache, confusion, dizziness, visual impairment, nausea, and seizures. The relationship between the stage of Alzheimer's disease progression, the target Alzheimer's disease patient population, the clearance of amyloid plaques with anti-amyloid antibody treatment, and the incidence of ARIA after treatment is not well understood.

Several therapeutic amyloid-targeted antibodies have demonstrated 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, the incidence of ARIA-E is higher in patients who carry the epsilon-4 allele of apolipoprotein E (referred to herein as APOE4, apoE4, or ApoE-e4).

To maintain plaque clearance while reducing the incidence of ARIA-E adverse events, some antibody treatment programs have implemented dose titration regimens that involve multiple dose escalations (3 to 4 steps) over a period of approximately 6 months until the effective dose level is reached. 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 treatments may not completely eliminate amyloid plaques or may delay their clearance.

Therefore, there is a need for improved dosages, dosing regimens, or methods that appropriately treat individuals without causing or increasing problematic adverse events.

The present invention relates to anti-N3pGlu Aβ antibodies that, upon administration to human subjects in need thereof, exhibit unexpectedly rapid clearance of amyloid-beta without causing or increasing problematic adverse events. In one embodiment, the anti-N3pGlu Aβ antibody of the present invention is remternetug (LY3372993). Remternetug is an IgG1 antibody that targets a pyroglutamine modification of the tertiary amino acid of the amyloid-beta peptide (N3pG Aβ), which is found exclusively in brain amyloid plaques. Remternetug's mechanism of action is to target and remove deposited amyloid plaques, a key pathological hallmark of AD, via microglial cell-mediated phagocytosis.

Remeneta has a relatively long half-life, reduced immunogenicity risk, and stable clearance of amyloid plaques, allowing for flexible dosing regimens. This flexibility is not achieved with other anti-amyloid antibodies, such as donanemab. Remeneta can be administered less frequently (with a longer window between dosings) while achieving stable and rapid clearance of amyloid plaques. In some embodiments, Remeneta can be administered intravenously (IV) at dosing intervals of 8 weeks (Q8W) to 12 weeks (Q12W). Such time intervals allow time for adverse events (such as asymptomatic ARIA) to resolve without interrupting dosing. In some embodiments, Remeneta can be administered subcutaneously (SC). SC dosing can be administered once a week (Q1W), once every two weeks (Q2W), or every two months. Overall, these dosing regimens provide rapid and stable clearance of amyloid plaques, reduce the risk of adverse events, and reduce participant burden by allowing for less frequent and/or fewer dosing times. Because Remeneta can be administered intravenously or subcutaneously, the dosing regimen can be selected based on patient preference or requirements, thereby potentially improving compliance and adherence to therapy. SC administration can also reduce the risk of ARIA due to the reduced Cmax observed with dosing. Another advantage of Remeneta is that it can be administered at a low dose and/or less frequently to achieve rapid and complete clearance of amyloid plaques. Large doses of remeneta can achieve population-wide amyloid plaque clearance levels exceeding 90%, representing a first-in-class treatment option. Both remeneta and donetumab target epitopes of amyloid peptides present only in brain amyloid plaques and can achieve robust clearance of amyloid plaques from the brain. Because amyloid plaques can be cleared by both of these antibodies, the dosing regimen is fixed, positively impacting dosing regimen compliance and adherence compared to treatments administered throughout a patient's lifetime. Given the stable clearance of amyloid plaques with Remeneta, a lower dose of Remeneta can be administered compared to any other amyloid plaque-reducing therapy currently being explored in clinical development.

In some embodiments, the disease characterized by Aβ plaques in the brain of a human subject is preclinical Alzheimer's disease (AD), clinical AD, prodromal AD, mild AD, moderate AD, severe AD, Down syndrome, clinical amyloid vascular disease, or preclinical amyloid vascular disease. In one embodiment, the disease is preclinical AD. In some embodiments, the disease is prodromal AD. In some embodiments, the disease is mild dementia caused by AD.

In some embodiments, the antibodies, methods, or administration regimens identified herein result in the treatment or prevention of Alzheimer's disease. In some embodiments, the antibodies, methods, or administration regimens identified herein result in: i) a reduction in Aβ plaques in the brain of a human subject; ii) a slowing of cognitive decline in a human subject; or iii) a slowing of functional decline in a human subject.

The anti-N3pGlu Aβ antibodies described in various aspects of the present invention include: An anti-N3pGlu Aβ antibody comprising: a light chain complementation determining region 1 (LCDR1) having the amino acid sequence of SEQ ID NO: 4, a light chain complementation determining region 2 (LCDR2) having the amino acid sequence of SEQ ID NO: 5, and a light chain complementation determining region 3 (LCDR3), wherein the light chain complementation determining region 3 (LCDR3) has the amino acid sequence of SEQ ID NO: 6 or an amino acid sequence having at least 95% homology to LCDR1 of SEQ ID NO: 4, an amino acid sequence having at least 95% homology to LCDR2 of SEQ ID NO: 5, and an amino acid sequence having at least 95% homology to LCDR3 of SEQ ID NO: 6; An anti-N3pGlu Aβ antibody comprising: a light chain complementation determining region 1 (LCDR1) having the amino acid sequence of SEQ ID NO: 4, a light chain complementation determining region 2 (LCDR2) having the amino acid sequence of SEQ ID NO: 5, and a light chain complementation determining region 3 (LCDR3). 1, a heavy chain determining region 1 (HCDR1) having the amino acid sequence of SEQ ID NO: 1, a heavy chain determining region 2 (HCDR2) having the amino acid sequence of SEQ ID NO: 2, and a heavy chain determining region 3 (HCDR3), wherein the heavy chain determining region 3 (HCDR3) has the amino acid sequence of SEQ ID NO: 3 or an amino acid sequence at least 95% homologous to the HCDR1 of SEQ ID NO: 1, an amino acid sequence at least 95% homologous to the HCDR2 of SEQ ID NO: 2, and an amino acid sequence at least 95% homologous to the HCDR3 of SEQ ID NO: 3; An anti-N3pGlu Aβ antibody comprising: a LCDR1 having the amino acid sequence of SEQ ID NO: 4, a LCDR2 having the amino acid sequence of SEQ ID NO: 5, a LCDR3 having the amino acid sequence of SEQ ID NO: 6, a LCDR4 having the amino acid sequence of SEQ ID NO: 7, a LCDR5 having the amino acid sequence of SEQ ID NO: 8, a LCDR6 having the amino acid sequence of SEQ ID NO: 9, a LCDR7 having the amino acid sequence of SEQ ID NO: 10, a LCDR8 having the amino acid sequence of SEQ ID NO: 11, a LCDR9 having the amino acid sequence of SEQ ID NO: 12, a LCDR10 having the amino acid sequence of SEQ ID NO: 13, a LCDR11 having the amino acid sequence of SEQ ID NO: 14, a LCDR12 having the amino acid sequence of SEQ ID NO: 15, a LCDR13 having the amino acid sequence of SEQ ID NO: 16 NO: 1, a HCDR1 having the amino acid sequence of SEQ ID NO: 1, a HCDR2 having the amino acid sequence of SEQ ID NO: 2, and a HCDR3 having the amino acid sequence of SEQ ID NO: 3, or an amino acid sequence at least 95% homologous to the LCDR1 of SEQ ID NO: 4, an amino acid sequence at least 95% homologous to the LCDR2 of SEQ ID NO: 5, an amino acid sequence at least 95% homologous to the LCDR3 of SEQ ID NO: 7, an amino acid sequence at least 95% homologous to the HCDR1 of SEQ ID NO: 8, an amino acid sequence at least 95% homologous to the HCDR2 of SEQ ID NO: 9, and an amino acid sequence at least 95% homologous to the HCDR3 of SEQ ID NO: 10; Anti-N3pGlu An Aβ antibody comprising: a LCVR and a HCVR, wherein the LCVR comprises: a LCDR1, a LCDR2, and a LCDR3, and the HCVR comprises: a HCDR1, a HCDR2, and a HCDR3 selected from the group consisting of: LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, LCDR3 of SEQ ID NO: 6, HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, and HCDR3 of SEQ ID NO: 3; or a LCVR and a HCVR, wherein the LCVR comprises: a LCDR1, a LCDR2, and a LCDR3, and the HCVR comprises: a HCDR1, a HCDR2, and a HCDR3 selected from the group consisting of: a LCDR1 at least 95% homologous to SEQ ID NO: 4, a LCDR2 at least 95% homologous to SEQ ID NO: 5, a LCDR3 at least 95% homologous to SEQ ID NO: 6, a LCDR3 at least 95% homologous to SEQ ID NO: 1 has a HCDR1 that is at least 95% homologous to SEQ ID NO: 1, a HCDR2 that is at least 95% homologous to SEQ ID NO: 2, and a HCDR3 that is at least 95% homologous to SEQ ID NO: 3. An N3pGlu Aβ antibody comprising a light chain (LC), the light chain comprising the amino acid sequence of SEQ ID NO: 10 or an amino acid sequence having at least 95% homology to SEQ ID NO: 10; An N3pGlu Aβ antibody comprising a heavy chain (HC), the heavy chain comprising the amino acid sequence of SEQ ID NO: 9 or an amino acid sequence having at least 95% homology to SEQ ID NO: 9; An anti-N3pGlu Aβ antibody comprising an LC and a HC, wherein the LC comprises the amino acid sequence of SEQ ID NO: 10 and the HC comprises the amino acid sequence of SEQ ID NO: 9, or wherein the LC comprises an amino acid sequence having at least 95% homology to SEQ ID NO: 10 and the HC comprises an amino acid sequence having at least 95% homology to SEQ ID NO: 9; An anti-N3pGlu Aβ antibody comprising two light chains and two heavy chains An Aβ antibody, wherein the LC comprises the amino acid sequence of SEQ ID NO: 10 or an amino acid sequence at least 95% homologous to SEQ ID NO: 10, and the HC comprises the amino acid sequence of SEQ ID NO: 9 or an amino acid sequence at least 95% homologous to SEQ ID NO: 9. An N3pGlu Aβ antibody comprising a LCVR comprising the amino acid sequence of SEQ ID NO: 8 or an amino acid sequence at least 95% homologous to SEQ ID NO: 8; An N3pGlu Aβ antibody comprising a HCVR comprising the amino acid sequence of SEQ ID NO: 7 or an amino acid sequence at least 95% homologous to SEQ ID NO: 7. An N3pGlu Aβ antibody comprising a LCVR and a HCVR, wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 8 or an amino acid sequence having at least 95% homology to SEQ ID NO: 8; and the HCVR comprises the amino acid sequence of SEQ ID NO: 7 or an amino acid sequence having at least 95% homology to SEQ ID NO: 7.

In some embodiments, the anti-N3pGlu Aβ antibodies of the present invention include κ LC and IgG HC. In a specific embodiment, the anti-N3pGlu Aβ antibodies of the present invention are of the human IgG1 isotype.

In one embodiment, the anti-N3pGlu Aβ antibody of the present invention is remeneta. Remeneta is a monoclonal antibody targeting N3pGlu Aβ, which is present only in deposited amyloid plaques. Remeneta comprises two light chains and two heavy chains, wherein the LC comprises the amino acid sequence of SEQ ID NO: 10 and the HC comprises the amino acid sequence of SEQ ID NO: 9. Remeneta is an IgG1 monoclonal antibody composed of two identical light chain polypeptides and two identical heavy chain polypeptides, each consisting of 214 amino acids and each consisting of 451 amino acids. Each heavy chain contains a single N-linked glycosylation site at Asn302. Remeneta specifically binds to aggregated N3pG Aβ peptides with high affinity (apparent dissociation constant of approximately 45.7 nM). Remeneta selectively targets AD plaques deposited in the brain and has been engineered to maximize plaque-mediated functions, including target engagement and microglial cell-mediated phagocytosis.

In some embodiments, an antibody of the present invention is administered to a subject in an amount of time sufficient to treat or prevent a disease. In some embodiments, the antibody is administered to a subject until Aβ plaques in the brain of the human subject are cleared. In some embodiments, the antibody is administered until at least one of the following occurs: i) Aβ plaques in the brain of the human subject are 24.1 percentile amyloid or less as measured by two consecutive amyloid PET imaging scans, wherein the two consecutive amyloid PET imaging scans are at least 6 months apart; or ii) Aβ plaques in the brain of the human subject are 11 percentile amyloid or less as measured by a single amyloid PET imaging scan. In some embodiments, the antibody is administered to the individual until the individual is negative for amyloid protein. In some embodiments, the antibody is administered to the individual until Aβ plaque levels reach <24.1 CL as measured by amyloid protein PET imaging scan.

In some embodiments, an anti-N3pGlu Aβ antibody as described herein is administered to a human subject of the present invention in one or more intravenous doses of about 200 mg to about 3000 mg. In some embodiments, an anti-N3pGlu Aβ antibody as described herein is administered to a human subject at least one of the following doses: 200 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2050 mg. mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, 2400 mg, 2450 mg, 2500 mg, 2550 mg, 2600 mg, 2650 mg, 2700 mg, 2750 mg, 2800 mg, 2850 mg, 2900 mg, 2950 mg or 3000 mg.

In some embodiments, an anti-N3pGlu Aβ antibody is administered intravenously to a human subject once a week, once every two weeks, once every four weeks, once every six weeks, once every eight weeks, once every twelve weeks, or once every 16 weeks. In some embodiments, the intravenous dose is administered once every twelve weeks. In some embodiments, the intravenous dose is administered once every eight weeks. In some embodiments, the intravenous dose is administered once every four weeks. In some embodiments, the intravenous dose is administered once every two weeks.

In some embodiments, about one to about twenty intravenous doses of an anti-N3pGlu Aβ antibody are administered to a human subject. In some embodiments, about one to about ten intravenous doses are administered to a human subject. In some embodiments, about one to about five intravenous doses are administered to a human subject. In some embodiments, at least one intravenous dose of an anti-N3pGlu Aβ antibody is administered to a subject. In some embodiments, two doses, three doses, four doses, five doses, six doses, seven doses, eight doses, nine doses, ten doses, eleven doses, twelve doses, thirteen doses, fourteen doses, fifteen doses, sixteen doses, seventeen doses, eighteen doses, nineteen doses, or twenty doses of an anti-N3pGlu Aβ antibody are administered to a human subject.

In some embodiments, the human subject suffers from early symptomatic AD and is administered i) about 1 to about 20 intravenous doses; ii) about 1 to about 10 intravenous doses; or iii) about 1 to about 5 intravenous doses of 2300 mg of an anti-N3pGlu Aβ antibody of the present invention once every 12 weeks (Q12W). In some embodiments, the human subject suffers from early symptomatic AD and is administered about three intravenous doses of 2300 mg of an anti-N3pGlu Aβ antibody of the present invention once every 12 weeks (Q12W).

In some embodiments, the human subject suffers from early symptomatic AD and is administered i) about 1 to about 20 intravenous doses; ii) about 1 to about 10 intravenous doses; or iii) about 1 to about 5 intravenous doses of 1500 mg of an anti-N3pGlu Aβ antibody of the present invention once every 12 weeks (Q12W). In some embodiments, the human subject suffers from early symptomatic AD and is administered about 4 intravenous doses of 1500 mg of an anti-N3pGlu Aβ antibody of the present invention once every 12 weeks (Q12W).

In some embodiments, the human subject suffers from early symptomatic AD and is administered i) about 1 to about 20 intravenous doses; ii) about 1 to about 10 intravenous doses; or iii) about 1 to about 5 intravenous doses of 800 mg of an anti-N3pGlu Aβ antibody of the present invention once every 8 weeks (Q8W). In some embodiments, the human subject suffers from early symptomatic AD and is administered about 7 intravenous doses of 800 mg of an anti-N3pGlu Aβ antibody of the present invention once every 8 weeks (Q8W).

In some embodiments, the human subject suffers from early symptomatic AD and is administered i) about 1 to about 20 intravenous doses; ii) about 1 to about 10 intravenous doses; or iii) about 1 to about 5 intravenous doses of 800 mg of an anti-N3pGlu Aβ antibody of the present invention once every 4 weeks (Q4W). In some embodiments, the human subject suffers from early symptomatic AD and is administered about 7 intravenous doses of 800 mg of an anti-N3pGlu Aβ antibody of the present invention once every 4 weeks (Q4W).

In some embodiments, the human subject suffers from early symptomatic AD and is administered about three intravenous doses of 2300 mg of an anti-N3pGlu Aβ antibody of the present invention once every 12 weeks (Q12W). In some embodiments, the human subject suffers from early symptomatic AD and is administered about four intravenous doses of 1500 mg of an anti-N3pGlu Aβ antibody of the present invention once every 12 weeks (Q12W). In some embodiments, the human subject suffers from early symptomatic AD and is administered about seven intravenous doses of 800 mg of an anti-N3pGlu Aβ antibody of the present invention once every 8 weeks (Q8W). In some embodiments, the human subject suffers from early symptomatic AD and the human subject is administered about 7 intravenous doses of 800 mg of the anti-N3pGlu Aβ antibody of the present invention once every 4 weeks (Q4W). In some embodiments, the human subject suffers from early symptomatic AD and the human subject is administered about 12 intravenous doses of 400 mg of the anti-N3pGlu Aβ antibody of the present invention once every 4 weeks (Q4W). In some embodiments, the human subject suffers from early symptomatic AD and the human subject is administered about 19 intravenous doses of 400 mg of the anti-N3pGlu Aβ antibody of the present invention once every 4 weeks (Q4W).

In some embodiments, the human subject suffers from early symptomatic AD and is administered approximately 36 subcutaneous doses of 400 mg of an anti-N3pGlu Aβ antibody of the present invention once weekly (Q1W). In some embodiments, the human subject suffers from early symptomatic AD and is administered approximately 52 subcutaneous doses of 400 mg of an anti-N3pGlu Aβ antibody of the present invention once weekly (Q1W). In some embodiments, the human subject suffers from early symptomatic AD and is administered approximately 76 subcutaneous doses of 400 mg of an anti-N3pGlu Aβ antibody of the present invention once weekly (Q1W). In some embodiments, the human subject suffers from early symptomatic AD and is administered approximately 36 subcutaneous doses of 400 mg of an anti-N3pGlu Aβ antibody of the present invention every two weeks (Q2W). In some embodiments, the human subject suffers from early symptomatic AD and is administered approximately 52 subcutaneous doses of 400 mg of an anti-N3pGlu Aβ antibody of the present invention every two weeks (Q2W). In some embodiments, the human subject suffers from early symptomatic AD and is administered approximately 76 subcutaneous doses of 400 mg of an anti-N3pGlu Aβ antibody of the present invention every two weeks (Q2W). In some embodiments, the human subject suffers from early symptomatic AD and is administered about 9 subcutaneous doses of 800 mg (or 2 x 400 mg, e.g., two 400 mg injections) of an anti-N3pGlu Aβ antibody of the present invention once every four weeks (Q4W). In some embodiments, the human subject suffers from early symptomatic AD and is administered about 12 subcutaneous doses of 800 mg (or 2 x 400 mg, e.g., two 400 mg injections) of an anti-N3pGlu Aβ antibody of the present invention once every four weeks (Q4W).

In some embodiments, the human subject suffers from preclinical AD and is administered i) about 1 to about 20 intravenous doses; ii) about 1 to about 10 intravenous doses; or iii) about 1 to about 5 intravenous doses of 2300 mg of an anti-N3pGlu Aβ antibody of the present invention once every 12 weeks (Q12W). In some embodiments, the human subject suffers from preclinical AD and is administered about 2 intravenous doses of 2300 mg of an anti-N3pGlu Aβ antibody of the present invention once every 12 weeks (Q12W).

In some embodiments, the human subject suffers from preclinical AD and is administered i) about 1 to about 20 intravenous doses; ii) about 1 to about 10 intravenous doses; or iii) about 1 to about 5 intravenous doses of 1500 mg of an anti-N3pGlu Aβ antibody of the present invention once every 12 weeks (Q12W). In some embodiments, the human subject suffers from preclinical AD and is administered about 3 intravenous doses of 1500 mg of an anti-N3pGlu Aβ antibody of the present invention once every 12 weeks (Q12W).

In some embodiments, the human subject suffers from preclinical AD and is administered i) about 1 to about 20 intravenous doses; ii) about 1 to about 10 intravenous doses; or iii) about 1 to about 5 intravenous doses of 800 mg of an anti-N3pGlu Aβ antibody of the present invention once every 8 weeks (Q8W). In some embodiments, the human subject suffers from preclinical AD and is administered about 5 or about 6 intravenous doses of 800 mg of an anti-N3pGlu Aβ antibody of the present invention once every 8 weeks (Q8W).

In some embodiments, the human subject suffers from preclinical AD and is administered i) about 1 to about 20 intravenous doses; ii) about 1 to about 10 intravenous doses; or iii) about 1 to about 5 intravenous doses of 800 mg of an anti-N3pGlu Aβ antibody of the present invention once every 4 weeks (Q4W). In some embodiments, the human subject suffers from preclinical AD and is administered about 5 or about 6 intravenous doses of 800 mg of an anti-N3pGlu Aβ antibody of the present invention once every 4 weeks (Q4W).

In some embodiments, an anti-N3pGlu Aβ antibody as described herein is administered to a human subject of the present invention in one or more subcutaneous doses of about 20 mg to about 1000 mg. In some embodiments, an anti-N3pGlu Aβ antibody as described herein is administered to a human subject of the present invention in one or more subcutaneous doses of about 250 mg to about 500 mg. In some embodiments, at least one subcutaneous dose of 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 mg, 560 mg, 580 mg, 600 mg, 620 mg, 640 mg, 660 mg, 680 mg, 700 mg, 720 mg, 740 mg, 760 mg, 780 mg, 800 mg, 820 mg, 840 mg, 860 mg, 880 mg, 900 mg, 1000 mg, 1000 mg, 1000 mg, 1000 mg, 1000 mg, 1000 mg, 1000 mg mg, 920 mg, 940 mg, 960 mg, 980 mg or 1000 mg.

In some embodiments, a subcutaneous dose of an anti-N3pGlu Aβ antibody is administered to a human subject once a week, once every two weeks, once every four weeks, once every six weeks, once every eight weeks, or once every twelve weeks. In some embodiments, the subcutaneous dose is administered once a week. In some embodiments, the subcutaneous dose is administered once every two weeks. In some embodiments, the subcutaneous dose is administered once every four weeks. In some embodiments, the subcutaneous dose is administered once every six weeks. In some embodiments, the subcutaneous dose is administered once every eight weeks.

In some embodiments, about one to about one hundred subcutaneous doses of an anti-N3pGlu Aβ antibody are administered to a human subject. In some embodiments, about one to about 90 subcutaneous doses are administered to a human subject. In some embodiments, about one to about 80 subcutaneous doses are administered to a human subject. In some embodiments, about one to about 70 subcutaneous doses are administered to a human subject. In some embodiments, about one to about 60 subcutaneous doses are administered to a human subject. In some embodiments, about one to about 50 subcutaneous doses are administered to a human subject. In some embodiments, about one to about 40 subcutaneous doses are administered to a human subject. In some embodiments, about one to about 30 subcutaneous doses are administered to a human subject. In some embodiments, about one to about 20 subcutaneous doses are administered to a human subject. In some embodiments, about one to about 10 subcutaneous doses are administered to a human subject. In some embodiments, at least one subcutaneous dose of an anti-N3pGlu Aβ antibody is administered to a human subject. In some embodiments, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 subcutaneous doses of an anti-N3pGlu Aβ antibody are administered to a human subject. In some embodiments, about 24 subcutaneous doses are administered to a human subject. In some embodiments, about 36 subcutaneous doses are administered to a human subject. In some embodiments, about 52 subcutaneous doses are administered to a human subject. In some embodiments, about 76 subcutaneous doses are administered to a human subject.

In some embodiments, the human subject suffers from early symptomatic AD and is administered i) about 1 to about 90 subcutaneous doses; ii) about 1 to about 60 subcutaneous doses; or iii) about 1 to about 30 subcutaneous doses of 400 mg of an anti-N3pGlu Aβ antibody of the invention once weekly (Q1W). In some embodiments, the human subject suffers from early symptomatic AD and is administered about 36 subcutaneous doses of 1500 mg of an anti-N3pGlu Aβ antibody of the invention once weekly (Q1W).

In some embodiments, the human subject suffers from early symptomatic AD and is administered i) about 1 to about 90 subcutaneous doses; ii) about 1 to about 60 subcutaneous doses; or iii) about 1 to about 30 subcutaneous doses of 400 mg of an anti-N3pGlu Aβ antibody of the present invention once every two weeks (Q2W). In some embodiments, the human subject suffers from early symptomatic AD and is administered about 52 subcutaneous doses of 400 mg of an anti-N3pGlu Aβ antibody of the present invention once every two weeks (Q2W). In some embodiments, the human subject suffers from early symptomatic AD and is administered about 76 subcutaneous doses of 400 mg of an anti-N3pGlu Aβ antibody of the present invention once every two weeks (Q2W).

In some embodiments, the human subject suffers from preclinical AD and is administered about two intravenous doses of 2300 mg of an anti-N3pGlu Aβ antibody of the present invention once every 12 weeks (Q12W). In some embodiments, the human subject suffers from preclinical AD and is administered about three intravenous doses of 1500 mg of an anti-N3pGlu Aβ antibody of the present invention once every 12 weeks (Q12W). In some embodiments, the human subject suffers from preclinical AD and is administered about five intravenous doses of 800 mg of an anti-N3pGlu Aβ antibody of the present invention once every 8 weeks (Q8W). In some embodiments, the human subject suffers from preclinical AD and the human subject is administered about six intravenous doses of 800 mg of the anti-N3pGlu Aβ antibody of the present invention once every eight weeks (Q8W). In some embodiments, the human subject suffers from preclinical AD and the human subject is administered about five intravenous doses of 800 mg of the anti-N3pGlu Aβ antibody of the present invention once every four weeks (Q4W). In some embodiments, the human subject suffers from preclinical AD and the human subject is administered about six intravenous doses of 800 mg of the anti-N3pGlu Aβ antibody of the present invention once every four weeks (Q4W).

In some embodiments, the human subject suffers from preclinical AD and is administered i) about 1 to about 60 subcutaneous doses; ii) about 1 to about 30 subcutaneous doses; or iii) about 1 to about 10 subcutaneous doses of 400 mg of an anti-N3pGlu Aβ antibody of the present invention once weekly (Q1W). In some embodiments, the human subject suffers from preclinical AD and is administered about 24 subcutaneous doses of 400 mg of an anti-N3pGlu Aβ antibody of the present invention once weekly (Q1W). In some embodiments, the human subject suffers from preclinical AD and is administered about 36 subcutaneous doses of 400 mg of an anti-N3pGlu Aβ antibody of the present invention once weekly (Q1W). In some embodiments, the human subject suffers from preclinical AD and the human subject is administered approximately 52 subcutaneous doses of 400 mg of the anti-N3pGlu Aβ antibody of the present invention once a week (Q1W). In some embodiments, the human subject suffers from preclinical AD and the human subject is administered approximately 24 subcutaneous doses of 400 mg of the anti-N3pGlu Aβ antibody of the present invention once a week (Q1W). In some embodiments, the human subject suffers from preclinical AD and the human subject is administered approximately 12 subcutaneous doses of 400 mg of the anti-N3pGlu Aβ antibody of the present invention once every two weeks (Q2W). In some embodiments, the human subject suffers from preclinical AD and the human subject is administered about 18 subcutaneous doses of 400 mg of an anti-N3pGlu Aβ antibody of the present invention once every two weeks (Q2W). In some embodiments, the human subject suffers from preclinical AD and the human subject is administered about 26 subcutaneous doses of 400 mg of an anti-N3pGlu Aβ antibody of the present invention once every two weeks (Q2W). In some embodiments, the human subject suffers from preclinical AD and the human subject is administered about 6 subcutaneous doses of 800 mg (or 2 x 400 mg, e.g., two 400 mg injections) of an anti-N3pGlu Aβ antibody of the present invention once every four weeks (Q4W). In some embodiments, the human subject suffers from preclinical AD and the human subject is administered about eight subcutaneous doses of 800 mg (or 2 x 400 mg, e.g., two 400 mg injections) of an anti-N3pGlu Aβ antibody of the present invention once every four weeks (Q4W). In some embodiments, the human subject suffers from preclinical AD and the human subject is administered about nine subcutaneous doses of 800 mg (or 2 x 400 mg, e.g., two 400 mg injections) of an anti-N3pGlu Aβ antibody of the present invention once every four weeks (Q4W). In some embodiments, the human subject suffers from preclinical AD and is administered about 12 subcutaneous doses of 800 mg (or 2 x 400 mg, e.g., two 400 mg injections) of an anti-N3pGlu Aβ antibody of the invention once every four weeks (Q4W).

In some embodiments, the human subject suffers from preclinical AD and is administered i) about 1 to about 60 subcutaneous doses; ii) about 1 to about 30 subcutaneous doses; or iii) about 1 to about 10 subcutaneous doses of 400 mg of an anti-N3pGlu Aβ antibody of the present invention once every two weeks (Q2W). In some embodiments, the human subject suffers from preclinical AD and is administered about 24 subcutaneous doses of 400 mg of an anti-N3pGlu Aβ antibody of the present invention once every two weeks (Q2W). In some embodiments, the human subject suffers from preclinical AD and is administered about 36 subcutaneous doses of 400 mg of an anti-N3pGlu Aβ antibody of the present invention once every two weeks (Q2W). In some embodiments, the human subject suffers from preclinical AD and the human subject is administered about 52 subcutaneous doses of 400 mg of an anti-N3pGlu Aβ antibody of the invention once every two weeks (Q2W).

In some embodiments, the dosing regimens of the present invention include one or more additional doses (also referred to as maintenance doses) that can be administered after completion of an IV dosing regimen or a subcutaneous dosing regimen as described herein (e.g., after the individual's amyloid beta has been cleared). For example, in some embodiments, one or more maintenance doses can be administered to an individual to reduce Aβ deposition in the individual's brain, prevent further Aβ deposition in the individual's brain, prevent further cognitive decline, prevent further memory loss, or prevent further functional decline. The intravenous maintenance dose can be about 250 mg to about 3000 mg of anti-N3pGlu Aβ antibody. In some embodiments, the subcutaneous maintenance dose may be about 20 mg to about 1000 mg of anti-N3pGlu Aβ antibody.

Some embodiments of the present invention include a method for treating or preventing a disease characterized by deposition of amyloid beta (Aβ) plaques in the brain of a human subject in need thereof, comprising: administering to the subject one or more intravenous (IV) doses of about 250 mg to about 3000 mg of an anti-N3pG Aβ antibody at a frequency of: i) about once every twelve weeks (Q12W); ii) about once every eight weeks (Q8W); or iii) about once every four weeks (Q4W); followed by one or more maintenance doses of about 250 mg to about 3000 mg of an anti-N3pGlu Aβ antibody; wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 8 and a nucleotide sequence comprising SEQ ID NO: The heavy chain variable region (HCVR) has a 7-amino acid sequence.

In some embodiments, the present invention includes a method for treating or preventing a disease characterized by deposition of amyloid beta (Aβ) plaques in the brain of a human subject in need thereof, comprising: administering to the subject one or more subcutaneous doses of about 20 mg to about 1000 mg of an anti-N3pG Aβ antibody at a frequency of about once a week, about once every two weeks, or once every four weeks; followed by administering one or more maintenance doses of about 20 mg to about 1000 mg of an anti-N3pGlu Aβ antibody; wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 8 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 7.

In some embodiments, a maintenance dose of an anti-N3pGlu Aβ antibody of the present invention may be administered to a subject one or more times every 2 weeks, every 4 weeks, every 8 weeks, every 12 weeks, monthly, every 1 year, every 2 years, every 3 years, every 4 years, every 5 years, or every 10 years. In some embodiments, a maintenance dose is administered annually. In one embodiment, a maintenance dose is administered every 2 years. In another embodiment, a maintenance dose is administered every 3 years. In another embodiment, a maintenance dose of the antibody is administered every 5 years. In another embodiment, a maintenance dose of the antibody is administered every 10 years. In another embodiment, a maintenance dose of the antibody is administered every 2 to 5 years. In another embodiment, a maintenance dose of the antibody is administered every 5 to 10 years.

In some aspects, the present invention relates to a method for treating or preventing a disease characterized by the deposition of amyloid beta (Aβ) plaques in the brain of a human subject, comprising: i) administering to the subject one or more doses of an anti-N3pGlu Aβ antibody as disclosed herein; ii) after administering a dose of the antibody and before administering a subsequent dose, evaluating the subject's brain for amyloid-associated imaging abnormality (ARIA) by magnetic resonance imaging (MRI); wherein if symptoms consistent with ARIA occur, administration of the subsequent dose is temporarily withheld; and wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR is represented by SEQ ID NO: In some embodiments, the subject is administered a 5-mg, ...

In some aspects, the present invention relates to a method for treating or preventing a disease characterized by deposition of amyloid beta plaques in the brain of a human subject in need thereof, comprising: i) administering to the subject one or more doses of an anti-N3pGlu Aβ antibody as disclosed herein; ii) after administering a dose and before administering a subsequent dose, evaluating the subject's brain for ARIA by magnetic resonance imaging (MRI); wherein if symptoms consistent with severe or symptomatic ARIA occur, administration of the subsequent dose is interrupted; and 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: 8 and the HCVR consists of the amino acid sequence of SEQ ID NO: In some embodiments, the subject is administered one or more subsequent doses of a steroid. In some embodiments, the subject is administered a corticosteroid. In some embodiments, the disease characterized by the accumulation of amyloid beta (Aβ) plaques in the brain of the human subject is Alzheimer's disease. In some embodiments, the antibody is ramenitar.

In some embodiments, the present invention relates to a method for treating or preventing a disease characterized by the accumulation of amyloid beta plaques in a subject until symptoms consistent with ARIA-E develop, comprising: i) administering to the subject one or more doses of an anti-N3pGlu Aβ antibody as disclosed herein; 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: 8 and the HCVR consists of the amino acid sequence of SEQ ID NO: 7. In some embodiments, symptoms of ARIA are detected or manifested in the subject by MRI. In some embodiments, the disease characterized by the deposition of amyloid beta (Aβ) plaques in the brain of a human subject is Alzheimer's disease. In some embodiments, the antibody is ramelinexavar.

In some embodiments, the invention relates to a method of treating an individual suffering from Alzheimer's disease with Remeneta, comprising the steps of: a) administering Remeneta to the individual; b) determining whether the individual is symptomatic for ARIA-E by i) performing or having performed an MRI or ii) developing clinical symptoms consistent with ARIA-E; and c) temporarily interrupting Remeneta treatment if the patient has moderate symptoms of ARIA-E; and d) if the patient does not have symptomatic ARIA-E, administering Remeneta to the patient until brain amyloid is cleared, negative, or <24.1 CL. In some embodiments, subsequent dosing is discontinued and a corticosteroid is administered to the individual. In some embodiments, the disease characterized by the deposition of amyloid beta (Aβ) plaques in the brain of a human subject is Alzheimer's disease. In some embodiments, the antibody is ramelinexavar.

In some embodiments, the present invention relates to an improved method of treating an individual suffering from Alzheimer's disease with Remeneta, wherein the method comprises: a) administering Remeneta to the individual; b) determining whether the individual is symptomatic for ARIA-E by i) performing or having performed an MRI or ii) developing clinical symptoms consistent with ARIA-E; and c) temporarily interrupting Remeneta treatment if the patient has moderate symptoms of ARIA-E; and d) if the patient does not have symptomatic ARIA-E, administering Remeneta to the individual until brain amyloid is cleared, negative, or <24.1 CL. In some embodiments, subsequent dosing is discontinued, and a corticosteroid is administered to the individual. In some embodiments, the disease characterized by the deposition of amyloid beta (Aβ) plaques in the brain of a human subject is Alzheimer's disease. In some embodiments, the antibody is ramelinexavar.

In some embodiments, the present invention relates to an improved method of treating an individual suffering from Alzheimer's disease with Remeneta, wherein the method comprises: a) administering Remeneta to the individual; b) determining whether the individual is symptomatic for ARIA-E by i) performing or having performed an MRI or ii) developing clinical symptoms consistent with ARIA-E; and c) temporarily interrupting Remeneta treatment if the patient has moderate symptoms of ARIA-E; and d) if the patient does not have symptomatic ARIA-E, administering Remeneta to the individual until brain amyloid is cleared, negative, or <24.1 CL. In some embodiments, subsequent dosing is discontinued, and a corticosteroid is administered to the individual. In some embodiments, the disease characterized by the deposition of amyloid beta (Aβ) plaques in the brain of a human subject is Alzheimer's disease. In some embodiments, the antibody is ramelinexavar.

In some embodiments, the present invention relates to an improved method for treating an individual suffering from Alzheimer's disease with remeneta, wherein the method comprises: a) administering or having administered remeneta to the individual; b) determining whether the patient has symptoms of ARIA-E by i) performing or having performed an MRI or ii) the presence of clinical symptoms consistent with ARIA-E; and c) if the patient does not have symptomatic ARIA-E, further administering remeneta to the patient. In some embodiments, subsequent dosing is discontinued and a corticosteroid is administered to the individual. In some embodiments, the disease characterized by the accumulation of amyloid beta (Aβ) plaques in the brain of the human individual is Alzheimer's disease. In some embodiments, the antibody is remeneta.

In some embodiments, the present invention relates to an improved method of treating an individual suffering from Alzheimer's disease with Remeneta, wherein the method comprises: a) administering or having administered Remeneta to the individual; b) interrupting treatment if the patient has moderate symptoms of ARIA-E; and c) once ARIA-E resolves, continuing treatment by administering Remeneta to the patient until the brain is cleared, becomes negative for amyloid, <24.1 CL, or ARIA-E symptoms reappear. In some embodiments, symptoms or ARIA-E are confirmed or determined by MRI scan.

In some embodiments, treatment with Remeneta is discontinued or interrupted due to or after the development of severe or symptomatic ARIA-E. In some embodiments, treatment with Remeneta may be temporarily discontinued or interrupted after a subject develops mild or moderate asymptomatic ARIA-E. In some embodiments, the dose of Remeneta may be temporarily reduced after a subject develops mild or moderate asymptomatic ARIA-E. In some embodiments, supportive therapy including corticosteroids may be administered to a patient after the development of ARIA-E. In some embodiments, treatment with Remeneta may be resumed after resolution of symptoms or stabilization of abnormal brain MRI radiographic findings.

If symptoms of ARIA-H develop, ARIA-E is typically present and therefore managed as ARIA-E. In some embodiments, a brain MRI is obtained before administering Remeneta or upon the onset of symptoms consistent with ARIA-H. In some embodiments, treatment with Remeneta is stopped or interrupted due to or after the onset of ARIA-H. In some embodiments, treatment with Remeneta may be temporarily interrupted after a patient develops ARIA-H, for example, when ARIA-H symptoms are mild or moderate. In some embodiments, the dose of Remeneta may be temporarily reduced after a patient develops mild or moderate asymptomatic ARIA-H. In some embodiments, supportive therapy, including corticosteroids, may be administered to a patient after the onset of ARIA-H. In some embodiments, treatment with Remeneta may be temporarily interrupted until symptoms of ARIA-E or ARIA-H improve.

Some aspects of the present invention relate to the identification, monitoring, or assessment of amyloid-associated imaging abnormalities (ARIA) in human subjects before or after administration of an anti-N3pGlu Aβ antibody of the present invention to the subject. In some embodiments, the present invention relates to the identification, monitoring, or assessment of ARIA in human subjects while the subject is being treated with an anti-N3pGlu Aβ antibody of the present invention. In some embodiments, ARIA includes ARIA-E and ARIA-H. ARIA-E refers to cerebral edema, which involves the breakdown of the tight endothelial junctions of the blood-brain barrier and the subsequent accumulation of fluid. ARIA-H refers to cerebral microbleeds (mH), small bleeding in the brain, often accompanied by hemosiderosis.

In some embodiments, a brain MRI scan can be administered to a human subject to diagnose/assess/monitor one or more adverse events resulting from administration of an anti-N3pGlu Aβ antibody. For example, a brain magnetic resonance imaging (MRI) scan can be administered to a human subject to identify, monitor, or assess ARIA (including, for example, ARIA-E or ARIA-H).

In some embodiments, if the individual is identified as having ARIA at screening (ie, prior to treatment with the antibody), the methods of the invention include the step of excluding the individual from treatment with an anti-N3pGlu Aβ antibody.

In some embodiments, a baseline brain MRI is obtained or assessed prior to initiating treatment with an anti-N3pGlu Aβ antibody. A brain MRI scan may be administered to a human subject between doses of the anti-N3pGlu Aβ antibody (e.g., weekly, biweekly, every four weeks, or every 12 weeks). In some embodiments, a brain MRI scan is administered to a human subject prior to administering an intravenous or subcutaneous dose of the anti-N3pGlu Aβ antibody. In some embodiments, a brain MRI scan is administered to a human subject after the first dose of the anti-N3pGlu Aβ antibody is administered to the patient. In some embodiments, a brain MRI scan is administered to a human subject after two or three doses of the anti-N3pGlu Aβ antibody have been administered.

In some embodiments, a brain MRI scan is administered to a human subject after the first or first four weeks of treatment. In some embodiments, a brain MRI scan is administered to a human subject after 12 weeks prior to starting treatment. In some embodiments, a brain MRI scan is administered to a human subject after the last dose. In some embodiments, a brain MRI scan is administered to a human subject and evaluated for ARIA upon physician recommendation or when ARIA is suspected. In some embodiments, an antibody of the invention is not administered to a subject if a centrally read MRI shows the presence of ARIA-E, >4 cerebral microbleeds, more than 1 area of superficial siderosis, any major hemorrhage, or severe white matter disease during screening prior to the start of treatment.

In some embodiments, the anti-N3pGlu Aβ antibodies of the present invention can be administered simultaneously, separately, or sequentially in combination with an effective amount of a pharmaceutical agent to treat Alzheimer's disease. The symptomatic agent can be selected from cholinesterase inhibitors (ChEIs) and/or partial N-methyl-D-aspartate (NMDA) antagonists. In a preferred embodiment, the pharmaceutical agent is a ChEI. In another preferred embodiment, the pharmaceutical agent is an NMDA antagonist or a combination pharmaceutical agent comprising a ChEI and an NMDA antagonist. In some embodiments, the anti-N3pGlu Aβ antibodies of the present invention can be administered simultaneously, separately, or sequentially in combination with another anti-Aβ antibody or another anti-N3pGlu Aβ antibody. In some embodiments, the anti-N3pGlu Aβ antibody of the present invention is administered in combination with donetumab, solanezumab, aducanumab, lecanemab, or gantenerumab.

As used herein, "anti-N3pGlu Aβ antibody," "anti-N3pG antibody," or "anti-N3pE antibody," used interchangeably, refers to an antibody that preferentially binds to N3pGlu Aβ over Aβ1-40 or Aβ1-42. As used herein, an "antibody" is an immunoglobulin molecule comprising two HCs and two LCs interconnected by disulfide bonds. The amino-terminal portion of each LC and HC includes variable regions responsible for antigen recognition through the complementary determining regions (CDRs) contained therein. The CDRs are interspersed with more conserved regions known as framework regions. The amino acid assignments for the CDR domains within the LCVR and HCVR regions of the antibodies of the present invention are 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, 5th ed., U.S. Department 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 invention were identified using these methods.

The antibodies of the present invention are monoclonal antibodies ("mAbs"). Monoclonal antibodies can be produced, for example, by fusion tumor technology, recombinant technology, phage display technology, synthetic technology (e.g., CDR grafting), or a combination of such technologies, or other techniques known in the art. The monoclonal antibodies of the present invention 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 non-human antibodies. Human framework germline sequences can be obtained from ImunoGeneTics (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 012441351. Techniques for producing human or humanized antibodies are well known in the art. The present invention encompasses antibodies or nucleic acids encoding antibodies. In some embodiments, the antibodies or nucleic acids are provided in an isolated form. As used herein, the term "isolated" refers to a protein, peptide, or nucleic acid that is not found in nature and is free or substantially free of other macromolecular species found in the cellular environment. As used herein, "substantially free" means that the protein, peptide, or nucleic acid of interest comprises greater than 80% (on a molar basis) of the macromolecular species present, preferably greater than 90%, and even more preferably greater than 95%.

The anti-N3pGlu Aβ antibodies of the present invention can be administered in the form of pharmaceutical compositions. Pharmaceutical compositions comprising the antibodies of the present invention can be administered parenterally (e.g., subcutaneously, intravenously) to individuals at risk for or exhibiting a disease or condition as described herein. Subcutaneous and intravenous routes are preferred. In some embodiments, the anti-N3pGlu Aβ antibodies are administered by intravenous infusion. In some embodiments, the anti-N3pGlu Aβ antibodies are administered by subcutaneous infusion.

This application claims the benefit of U.S. Provisional Application Serial Nos. 63/384,224, filed November 17, 2022, and 63/490,544, filed March 16, 2023, under 35 U.S.C. §119(e); the disclosures of which are incorporated herein by reference .

This application contains a sequence listing, which has been submitted electronically in ST.26 XML format and is incorporated herein by reference in its entirety. The ST.26 XML sequence listing was created on October 23, 2023, is named 30394.xml, and is 15,353 bytes in size.

As used herein, the terms "treatment," "treating," or "to treat" include limiting, slowing, or stopping the progression or severity of an existing symptom, condition, disease, or disorder in a subject.

The term "individual" refers to human beings.

The term "prevention" refers to the prophylactic administration of an antibody of the present invention to an asymptomatic individual or an individual with preclinical Alzheimer's disease to prevent the onset or progression of the disease.

The terms "disease characterized by Aβ deposition" or "disease characterized by Aβ plaques" are used interchangeably and refer to diseases characterized pathologically by the presence of Aβ plaques in the brain or cerebral vasculature. Such diseases include conditions such as Alzheimer's disease, Down syndrome, and amyloid vasculopathy. The clinical diagnosis, stage, or progression of Alzheimer's disease can be readily determined by the attending physician or healthcare professional (who is skilled in the art) using known techniques and by observation of the findings. This typically includes brain plaque imaging, psychiatric or cognitive assessments (e.g., Clinical Dementia Rating - summary of boxes (CDR-SB), Mini-Mental State Exam (MMSE), or Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog)), or functional assessments (e.g., Alzheimer's Disease Cooperative Study-Activities of Daily Living (ACTS-DDS)). Living; ADCS-ADL). Cognitive and functional assessments can be used to identify cognitive changes (e.g., cognitive decline) and functional changes (e.g., functional decline) in patients. As used herein, "clinical Alzheimer's disease" is the diagnostic stage of Alzheimer's disease. Clinical Alzheimer's disease 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" is the stage before clinical Alzheimer's disease in which measurable changes in biomarkers (e.g., CSF High levels of Aβ42 or amyloid protein PET deposits (brain plaques) indicate the earliest signs of Alzheimer's disease pathology in individuals, often before symptoms such as memory loss and confusion become apparent. Preclinical Alzheimer's disease also includes individuals with pre-symptomatic chromosomal dominant disease and those at increased risk for developing AD due to carrying one or two copies of the APOE4 allele.

A decrease or slowing of cognitive decline can be measured using cognitive assessments such as the Clinical Dementia Rating Total Scale, the Mini-Mental State Examination, or the Alzheimer's Disease Assessment Scale-Cognitive. A decrease or slowing of functional decline can be measured using functional assessments such as the ADCS-ADL.

In some embodiments, the subject/patient of the present invention has extremely low tau burden. As used herein, a human subject has “very low tau” if the tau burden is less than 1.10 SUVr (<1.10 SUVr, normalized take-up ratio) using ^{a 18} F-flortaucipir-based quantification assay, where quantification refers to the calculation of the SUVr, and SUVr represents the relative abundance of a specific target region of interest in the brain (multiple block centroid discriminant analysis or MUBADA, see Devous et al., “Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir”) when compared to a reference region (parametric estimate of reference signal intensity or PERSI, see Southekal et al., “Flortaucipir F 18 Quantitation Using Parametric Estimation of Reference Signal Intensity”, J. Nucl. Med. 59:944-951 (2018)). F18", J. Nucl. Med. 59:937-943 (2018).

In some embodiments, the subject/patient of the present invention has very low to moderate tau burden. As used herein, a human subject has "very low to moderate tau" burden if the tau burden is less than or equal to 1.46 SUVr (i.e., ≤1.46 SUVr) using an ¹⁸ F-fluroxicillin-based quantitative assay, where quantitative assay refers to the calculation of SUVr, and SUVr represents the counts within a specific target region of interest in the brain (MUBADA, see Devous et al., "Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F18", J. Nucl. Med. 59:937-943 (2018)) when compared to a reference region (PERSI, see Southekal et al., "Flortaucipir F 18 Quantitation Using Parametric Estimation of Reference Signal Intensity", J. Nucl. Med. 59:944-951 (2018)).

In some embodiments, the subject/patient of the present invention has low to moderate tau burden. As used herein, a human subject has “low to moderate tau” if the tau burden is greater than or equal to 1.10 to less than or equal to 1.46 (i.e., ≥1.10 SUVr to ≤1.46 SUVr) using an ¹⁸ F-fluroxicillin-based quantitative assay, where quantitative assay refers to the calculation of SUVr, and SUVr represents the intensity of a particular target region of interest in the brain (MUBADA, see Devous et al., “Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F18”, J. Nucl. Med. 59:937-943 (2018)) when compared to a reference region (PERSI, see Southekal et al., “Flortaucipir F 18 Quantitation Using Parametric Estimation of Reference Signal Intensity”, J. Nucl. Med. 59:944-951 (2018)). (2018). "Low to moderate tau" burden may also be referred to as "moderate" tau burden.

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

The antibodies, dosages, administration regimens, or methods disclosed herein can be used to treat or prevent early symptomatic Alzheimer's disease. 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) created 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).

The term "long-term" means throughout the individual's lifespan.

As used herein, mild cognitive impairment is defined as cognitive performance that is below the expected range for that individual based on all available information. This can be based on clinical judgment and/or cognitive test performance. Cognitive performance is typically within the range of impairment/abnormal based on group norms, but this is not required, as long as performance is below the expected range for that individual. In addition to evidence of cognitive impairment, there must also be evidence of a decrease in cognitive performance from baseline. This can be reported by the individual or by an observer, or observed through changes in longitudinal cognitive tests/behavioral assessments, or a combination of these. During this stage, individuals perform activities of daily living independently, but cognitive difficulties result in detectable but mild functional impairment in the more complex activities of daily living, as self-reported or confirmed by a research partner.

As used herein, mild dementia is defined as substantial progressive cognitive impairment and/or neurobehavioral disturbances affecting several domains. This is reported by the individual or by an observer (e.g., a research partner) or documented by changes in longitudinal cognitive tests. This stage includes significant functional impairment in daily living, affecting primarily instrumental activities, and the individual is no longer completely independent/requires occasional assistance with activities of daily living. An individual is no longer considered to have mild AD dementia when AD worsens to the point of: a) widespread functional impairment in daily living, with impairment in basic activities of daily living, and b) no longer independent and requires frequent assistance with activities of daily living.

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

In the present invention, the terms "individual" and "patient" are used interchangeably.

In this disclosure, the phrases "slowing regression" and "slowing disease progression" are used interchangeably.

As used herein, "method of treatment" also applies to the use of a composition for treating a disease or condition described herein and/or the use of a composition for use and/or in the manufacture of a medicament for treating a disease or condition described herein .

The following examples further illustrate the present invention. However, it should be understood that the examples are described in an illustrative rather than a restrictive manner and that various modifications can be made by those skilled in the art.

The following table provides some examples of dosing regimens for Remeneta provided by the present invention: Delivery Dosage (mg) Dosage frequency Dose number Dosage administration time shown by weeks instruct IV 2300 Q12W 3 0, 12, 24 Treat or prevent early symptomatic ^AD IV 1500 Q12W 4 0, 12, 24, 36 IV 800 Q8W 7 0, 8, 16, 24, 32, 40, 48 IV 400; 800 ^c Q4W; Q8W 3; 5 0, 4, 8, 16, 24, 32, 40, 48 IV 400 Q4W 13 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 SC 400 Q1W 36 0, 1, 2, 3, ..., 36 SC 800 Q4W 13 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 SC 400; 800 ^days Q4W 3;10 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 IV 200 400 800 Q8W 2; 2; 3 (or 6) 0, 8, 16, 24, 32, 40, 48 (or up to 72 weeks) SC 400 800 800 Q8W Q8W Q4W 3;3;7 0, 8, 16, 24, 32, 40, 48, 52, 56, 60, 64, 68, 72 IV 2300 Q12W 2 0, 12 Treat or prevent preclinical AD ^b IV 1500 Q12W 3 0, 12, 24 IV 800 Q8W 5 0, 8, 16, 24, 32 IV 400; 800 ^e Q4W; Q8W 3;3 0, 4, 8, 16, 24, 32 IV 400; 800 ^f Q4W; Q8W 3; 4 0, 4, 8, 16, 24, 32, 40 IV 400 Q4W 10 0, 4, 8, 12, 16, 20, 24, 28, 32, 36 SC 400 Q1W 36 0, 1, 2, 3...35 SC 800 Q4W 13 0, 4, 8, 12, 16...48 SC 400; 800 ^g Q4W 3;8 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40 SC 100 400 800 800 Q8W Q8W Q8W Q4W 2 2 2 7 0, 8, 16, 24, 32...72 SC 200 400 800 800 Q8W Q8W Q8W Q4W 1 2 1 9-11 0, 8, 16, 24, 32, 36, 40, 44, 48, 52, 56, 60, 64 (or up to 72) SC 400 800 800 Q8W Q8W Q4W 2 1 7-13 0, 8, 16, 24, 28, 32, 36, 40, 44, 48 (or up to 72) SC 400 800 800 Q12W Q8W Q4W 2 1 9-11 0, 12, 24, 32, 36, 40, 44, 48, 52, 56, 60, 64 (or up to 72) "a" treatment or prevention also causes i) a reduction in Aβ plaques in the brain of a human subject, ii) a slowing of cognitive decline in a human subject, or iii) a slowing of functional decline in a human subject. "b" treatment or prevention also causes i) a reduction in Aβ plaques in the brain of a human subject, ii) a slowing of cognitive decline in a human subject, or iii) a slowing of functional decline in a human subject. "c" indicates that the patient is to be administered 400 mg once every 4 weeks (Q4W) for a total of three doses, followed by 800 mg for a total of five doses, each dose administered once every 8 weeks (Q8W). "d" indicates that the patient will be given 400 mg once every 4 weeks (Q4W) for a total of three doses, followed by 800 mg for a total of 10 doses, each dose delivered once every 4 weeks (Q4W). "e" indicates that the patient will be given 400 mg once every 4 weeks (Q4W) for a total of three doses, followed by 800 mg for a total of three doses, each dose delivered once every 8 weeks (Q8W). "f" indicates that the patient was given three doses of 400 mg every four weeks (Q4W), followed by four doses of 800 mg, each dose delivered every eight weeks (Q8W). "g" indicates that the patient was given three doses of 400 mg every four weeks (Q4W), followed by eight doses of 800 mg, each dose delivered every four weeks (Q4W). Example 1 : Nonclinical study.

Nonclinical ADME: Nonclinical pharmacokinetics (PK) of remenetal were characterized in cynomolgus monkeys following a single intravenous (IV) or subcutaneous (SC) dose. Multiple-dose toxicokinetics were characterized in cynomolgus monkeys following twice-weekly IV dosing for 6 weeks. Serum concentrations of remenetal were measured by a validated ELISA using immobilized ligand N3pG Aβ to capture remenetal.

In monkeys, the PK profile of remenetal is characterized by a low CL, a small Vss, and a terminal elimination _t½ of 329 to 390 hours (approximately 14 to 16 days). Subcutaneous bioavailability in monkeys was approximately 74%. Following twice-weekly IV dosing in cynomolgus macaques for 6 weeks, remenetal exposure increased in a roughly dose-proportional manner with increasing doses between 20 and 200 mg/kg. Accumulation of approximately 3- to 4-fold the observed exposure was observed. No anti-drug antibodies were detected following remenetal administration in single or repeated-dose studies.

Single-dose pharmacokinetics: The serum PK of remenetal in cynomolgus monkeys was characterized following a single bolus administration of 1 mg/kg (IV) or 40 mg/kg (IV and SC) as shown in Table 1. Table 1. Summary of pharmacokinetic parameters of remenetal in cynomolgus monkeys following a single IV or SC administration Parameter ^a IV IV SC 1 mg/kg 40 mg/kg 40 mg/kg N=2 animals N=3 animals N=3 animals C ₀ (mg/mL) 28 984 ± 108 NA T _max (hours) NA 6.00 ± 0.00 ^b 128 ± 36.7 C _max (mg/mL) 27 915 ± 68.2 372 ± 45.3 AUC _0-∞ (mg·h/mL) 7380 282,000 ± 52,200 20,6000 ± 15,800 t _1/2 (hour) 390 377 ± 128 329 ± 75.2 CL (ml/h/kg) 0.14 0.145 ± 0.0280 NA CL/F (ml/hour/kg) NA NA 0.195 ± 0.0156 V _ss (mL/kg) 69 ND ND %F NA NA 74 Abbreviations: AUC _0-∞ = area under the concentration-time curve from time zero to infinity; C ₀ = estimated serum concentration at time zero; CL = clearance; CL/F = relative clearance; C _max = maximum observed serum concentration; %F = percent bioavailability; IV = intravenous; SC = subcutaneous; N3pG Aβ = pyroglutamine modification of the third amino acid of amyloid-β peptide; N = number of measurements; NA = not applicable; ND = not determined; t _1/2 = terminal half-life; T _max = time to maximum serum concentration; V _ss = steady-state distribution volume. ^Parameters are calculated based on concentrations determined by N3pG Aβ antigen-capture enzyme-linked immunosorbent assay. Presented values are mean values (n=2) or mean values +/- standard deviation (n=3). ^bThe first time point collected was 6 hours after administration.

Serum concentrations of remeneta were determined by ELISA using an immobilized ligand, N3pG Aβ, to capture remeneta. Samples were collected from two or three animals for each time point. Remeneta PK demonstrated a low CL and small Vss, consistent with blood volumes reported in cynomolgus macaques, indicating that remeneta is primarily distributed within the vascular system. Mean elimination t1 _/2 ranged from 329 to 390 hours (approximately 14 to 16 days). Cmax and AUC were dose-proportional when comparing IV doses of 1 mg/kg and 40 mg/kg; bioavailability after subcutaneous administration was 74%. Injection site reactions were absent (clinical observations at the injection site and microscopic evaluation of skin biopsies).

Multiple-Dose Toxicokinetics: Toxicity studies were conducted in cynomolgus macaques with twice-weekly dosing for 6 weeks. Repeated-dose serum toxicity of remenetal was determined as part of a GLP toxicology study. Six animals per group were administered 20 or 200 mg/kg of remenetal. Serum concentrations of remenetal were determined by a validated ELISA using immobilized ligand N3pG Aβ to capture remenetal and detection by horseradish peroxidase-labeled anti-human IgG. Serum toxicokinetics in cynomolgus macaques are described in Table 2. Table 2 : Serum Toxicokinetic Parameters of Remenetal in Cynomolgus Mascots Following 6 Weeks of Twice-Weekly Intravenous Administration ( Mean ± SD) Dosage (mg/kg) 20 200 N 6 6 Day 1 C ₀ (µg/mL) 541 ± 73.3 5290 ± 506 C _max (µg/mL) 519 ± 67.0 5070 ± 401 T _max (hours) 1.00 ± 0.00 1.00 ± 0.00 AUC _0-96 (µg□h/mL) 29,300 ± 2200 288,000 ± 11,500 Day 39 C ₀ (µg/mL) 1590 ± 258 13,900 ± 695 C _max (µg/mL) 1580 ± 254 13,600 ± 751 T _max (hours) 2.17 ± 2.86 1.00 ± 0.00 AUC _0-96 (µg□h/mL) 123,000 ± 23,800 941,000 ± 54,300 Abbreviations: AUC _0-96 = area under the curve during the dosing interval; C ₀ = back-extrapolated concentration at time 0; C max = maximum observed concentration; F = female; M = male; MF = combined males and females; N = number of animals; SD = standard deviation; T max = time to maximum observed concentration.

Samples from all study animals were tested for the presence of ADA, and no treatment-induced ADA was detected after 6 weeks of administration of Remeneta.

Exposure to remeneta increased with dose on all evaluated days, as assessed by the area under the curve (AUC096) during the dosing interval, the back-extrapolated concentration at time 0 (C0), and Cmax. The Cmax and _AUC0-96 values on Day 39 were approximately 3- to 4-fold higher than those on Day 1, indicating that remeneta accumulated in monkey serum after multiple dosing. Pre-dose and 1-hour post-dose concentrations on Day 22 were comparable to those on Day 39 for the corresponding groups and time points. Anti-drug antibodies were not detected in any samples.

Nonclinical safety pharmacology and toxicology:

The safety of Remeneta was assessed through safety pharmacology and toxicology evaluations in a six-week toxicity study in cynomolgus macaques. No adverse or important drug-related findings were observed.

The overall nonclinical safety profile of Remeneta will be confirmed in clinical studies conducted in humans (see Tables 3 and 4). Table 3 : Safety margins of Remeneta following a single intravenous dose based on dose and exposure Species dose level Human dose (mg/kg) Dosage multiple ^a AUC (μg • h/mL) AUC exposure ^multiplesb C _max (μ g/mL) Cmax exposure ^multipleb Crab-eating macaque 200 mg/kg twice weekly NOAEL ^c - - 941,000 - 13,600 - Human starting dose 20 mg (single dose) 0.29 690× 3450 273× 6.39 2128× Maximum human dose 2800 mg (maximum dose) 10 20× 152,000 6.2× 631 22× Abbreviations: AUC = serum concentration relative to the area under the time curve; AUC _0-96h = AUC from time zero to 96 hours postdose; AUC _0-∞ = concentration relative to the area under the time curve from time zero to infinity; C _max = maximum serum concentration; NOAEL = no observed adverse effect level. ^a Dose multiples are the dose at the NOAEL in monkeys (200 mg/kg) divided by the human dose in mg/kg (assuming a 70 kg individual weight). For intravenously administered biological products with a molecular weight >100,000 Da, scaling the dose in mg/kg is preferred (FDA 2005). ^bExposure multiples are calculated as AUC _0-96h (or C max ) in animals after 6 weeks of treatment (Day 36)/AUC _0-∞ (or C _max ) in humans following a single dose from Study LAKB ( _NCT04451408 , clinicaltrials.gov). ^cNOAELs were determined in a 6-week, repeated-dose toxicity study in cynomolgus macaques. Table 4 : Safety Margins of Repeated Intravenous or Subcutaneous Administration of Remeneta . Species dose level Dosage mg / kg / week Weekly dose multiple ^a C _av,ss ^b (mg/mL) C _av,ss ^c exposure multiple C _max ^b (mg/mL) _Cmax exposure ^c times Cynomolgus macaques 200 mg/kg ^twice a week 400 NA 9802 NA 13,600 NA Human SC dose, 400 mg QW 5.7 70 242 41 252 54 Human IV Dosage (Adjustment) ^e 1.4 286 70 140 351 39 Human IV dose, 2300 mg Q12W 2.7 146 202 49 1010 13 The highest human dose is 2800 mg Q4W (Study LAKB) ^f 10 40 368 27 834 16 Abbreviations: C _av,ss = mean steady-state serum concentration; C _max = maximum serum concentration; C _max,ss = maximum drug concentration observed at steady-state; NA = not applicable; NOAEL = no observed adverse effect level; PK = pharmacokinetics; Q4W = every 4 weeks; Q12W = every 12 weeks; SC = subcutaneous. ^a The dose multiple is the total weekly dose at the NOAEL in monkeys (200 mg/kg twice weekly, a total of 400 mg/week) divided by the human weekly dose in mg/kg (assuming a 70 kg body weight and dividing the human dose by the number of weeks in the dosing interval). ^b Cynomolgus macaque C _av,ss was calculated by dividing the mean AUC _0-96 values from the Day 39 toxicity study by 96 hours; monkey C _max is the mean C _max value observed on Day 39. Human C _av,ss and C _max values for SC and IV dosing were derived from a population PK model with a data cutoff of May 30, 2022. ^c Exposure multiples of C _av,ss or C _max were calculated by dividing the monkey C _av,ss or C _max on Day 36 by the model-predicted human C _av,ss (or C _max,ss ). ^d NOAEL was determined in a 6-week, repeated-dose toxicity study in cynomolgus macaques. e IV doses were adjusted to 200 mg Q8W x 2, 400 mg Q8W x 2, and 800 mg Q8W x 3. ^f Maximum clinical dose (2800 mg intravenously every 4 weeks)

Cross-reactivity studies were also conducted in human and cynomolgus macaque tissues. Remeneta produced immunoreactivity in plaques in the cerebellum and cerebrum, in extracellular material in the walls of small blood vessels, and in collage cells in the human brain. Furthermore, binding to remeneta was observed in several epithelial cell types and spermatogenic cells in the human testes. In cynomolgus macaque tissues, binding to remeneta was limited to epithelial cells in the skin and to stromal cells in the lamina of the placenta. The immunoreactivity observed in plaques in human brain using Remeneta was expected based on the known AD diagnosis of one donor and the age of the other (86 years old), even though AD had not been diagnosed. Plaques were not expected to be present in cynomolgus macaque brain samples, as these samples were obtained from adolescent macaques. All other immunoreactivity observed with Remeneta in human and macaque tissues was unexpected, as the target antigenic determinant is specific for AD plaques and has not been reported to be expressed in normal tissues or demonstrated in physiological fluids. However, in the current study, all cell binding sites in both human and macaque tissues were cytoplasmic in nature. Monoclonal antibodies that bind to cytoplasmic sites are generally considered to have little toxicological significance because the cytoplasm/cytoplasmic structure is considered unavailable for monoclonal antibodies in vivo. Example 2 : Clinical Study. Dosing Considerations for Participants with Early Symptomatic AD and / or Presymptomatic AD ( Preclinical AD)

The dose selected for administration to human participants attempts to address one or both of the following: (i) achieve stable amyloid plaque clearance in participants, i.e., achieve amyloid plaque clearance (<24.1 percentile amyloid value) in approximately 80 to 90% of participants (i.e., within 52 or 72 weeks of treatment or less); and (ii) reduce the risk of ARIA development while maintaining stable plaque clearance. Dosing at intervals of 4, 8, and 12 weeks, or a combination thereof, is contemplated to allow time for any asymptomatic ARIA to resolve without interrupting dosing and also to reduce the risk of ARIA worsening. This paper also considers regulatory options to reduce the incidence and severity of observed ARIA (Salloway et al., 2022).

Subcutaneous administration is contemplated herein to allow for a slower increase in serum concentrations and a lower Cmax compared to IV administration. It has been hypothesized that a lower Cmax and slower increase in serum concentrations may reduce the risk of ARIA. (Hayato et al., 2020; Salloway et al., 2022) Dosing intervals of 4, 8, and 12 weeks, or combinations thereof, are contemplated herein to allow time for any asymptomatic ARIA to resolve without interrupting dosing and potentially reduce the risk of ARIA worsening. Also contemplated herein are dosing regimens for subcutaneous administration to reduce the incidence and severity of observed ARIA.

Intravenous and subcutaneous dosing regimens also seek to provide acceptable formulations and convenience for patients. The dosing regimens provided herein result in a relatively long half-life for Remeneta, reduced risk of immunogenicity, and stable clearance of amyloid plaques, properties not applicable to other anti-N3pGlu Aβ antibodies. These properties seek to achieve stable clearance of amyloid plaques with less frequent dosing (e.g., 4-week, 8-week, and 12-week dosing intervals, or a combination thereof, for IV or SC dosing); a dosing interval that allows any asymptomatic ARIA to resolve without interruption; and SC dosing, which reduces the risk of ARIA due to the lower Cmax observed with dosing and reduces the burden on participants.

Remeneta targets the amyloid beta peptide, modified with pyroglutamine at the third position. Pyroglutamine-modified Aβ is found exclusively in brain amyloid plaques. Remeneta can achieve robust clearance of amyloid plaques from the brain. The dosing regimen provided herein can be of fixed duration, which has a positive impact on dosing regimen compliance and adherence compared to treatments administered throughout a patient's life. Example 3 : Single-dose and dose-escalation studies evaluating the safety, tolerability, and pharmacokinetics of Remeneta in healthy participants.

Study LAKA (NCT03720548, clinicaltrials.gov) represents the first-in-human administration of Remenetal. This complete single-ascending dose (SAD) Phase 1 study in healthy participants evaluated the safety, tolerability, pharmacokinetics (PK), and immunogenicity of Remenetal. Study LAKA was designed as a single- and multiple-ascending dose study, but only the SAD portion was conducted.

Summary of Trial Design: Participants received a single dose of Remeneta or placebo and were monitored for approximately 12 weeks post-dose for safety assessments and collection of PK and immunogenicity samples. Four dose levels (i.e., 20, 75, 250, and 700 mg) were evaluated.

Primary Objective: The primary objective of Study LAKA is to evaluate the safety and tolerability of Remenita in healthy participants and patients with Alzheimer's disease (AD).

Secondary Objectives: The secondary objectives of Study LAKA were to: i) assess the serum PK of remenetal after a single intravenous (IV) infusion in healthy participants and multiple IV infusions in patients with AD; and ii) evaluate the effect of remenetal on brain amyloid load in patients with AD.

Patient Population: Study LAKA consisted of healthy men and women aged 18 to 45 years (inclusive), with a body mass index (BMI) between 18.0 kg/m² and 32.0 kg/m² (inclusive). Participants with evidence of cognitive impairment (Mini-Mental State Examination [MMSE] total score less than 29), clinically significant brain magnetic resonance imaging (MRI) scans, or a family history of early-onset AD were excluded.

Safety and Tolerability Results: There were no deaths or other serious adverse events (SAEs), and no participants discontinued due to adverse events (AEs). Twelve participants (33.3%) reported a total of 15 AEs, with no apparent treatment-related trend. All reported AEs were mild in intensity. Only one AE (dizziness after administration of 700 mg of remeneta) was considered related to study treatment. No infusion-related reactions or allergic reactions were observed.

Immunogenicity Results: No participant developed treatment-emergent anti-drug antibodies (treatment-induced or treatment-enhanced) following administration of Remeneta.

Pharmacokinetic (PK) Results: In Study LAKA, the PK of remenetal was assessed in healthy participants for up to 12 weeks following a single IV dose of 20 to 700 mg. The PK parameters of remenetal are presented in Table 5 below. Table 5 : Mean (CV%) Non-Ventricular Pharmacokinetic Parameters Following a Single Intravenous Dose of remenetal in Healthy Participants . Single-dose group treatment 20 mg IV 75 mg IV 250 mg IV 700 mg IV N 7 7 7 7 Cmax 6.39 23.4 77.3 208 (μg/mL) (29) (15) (twenty two) (28) t _1/2 28.2 23.0 22.3 24.2 (sky) (17.3-61.6) (6.27-41.0) (18.7-30.7) (20.0-30.6) AUC(0-∞) 3450 9860 32,700 73,300 (μg•h/mL) (38) (48) (17) (14) CL 0.139 0.183 0.183 0.229 (liters/day) (38) (48) (17) (14) Abbreviations: AUC(0-∞) = area under the concentration-versus-time curve from time zero to infinity; _Cmax = maximum observed drug concentration; CV = coefficient of variation; CL = total clearance of drug calculated after IV administration; IV = intravenous; N = number of participants; t1 _/2 = half-life related to the terminal rate constant.

Pharmacodynamic Results: Study LAKA was designed to have a multiple ascending dose (MAD) component to investigate pharmacodynamic (PD) outcomes; however, only the SAD component was conducted. Therefore, no PD results are available for this study.

Conclusion: Single IV doses of up to 700 mg of remeneta were safe and well tolerated in healthy participants. No participant developed treatment-emergent anti-drug antibodies up to 12 weeks after a single dose of remeneta. The PK profile of remeneta was generally linear and exhibited a long _t½ , typical of monoclonal antibodies. Example 4 : A study evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of remeneta in participants with Alzheimer's disease and healthy subjects.

Study LAKB (NCT04451408, clinicaltrials.gov) is an ongoing, two-part Phase 1 study. Part A of the study is investigating the safety and tolerability of remeneta in participants with AD, including those of Japanese ancestry, following single and multiple doses (IV or subcutaneous (SC)) and the effects of remeneta on brain amyloid plaque levels.

Part B of the study was conducted in healthy participants, including those of Japanese ancestry, to evaluate the safety, tolerability, and PK of remeneta up to 2800 mg after IV and SC administration and to investigate any risk of immunogenicity. Table 6 below describes the cohorts of Study LAKB: Table 6 : Summary of Clinical Pharmacology Studies. Test alias nation Participants exposed the situation LAKB United States, Japan Multiple-dose IV doses of Remeneta in participants with AD ^a : Group 1 (250 mg or PBO Q4W): 6 Group 2 (700 mg or PBO Q4W): 18 Group 3 (1400 mg or PBO Q4W): 16 Group 4 (2800 mg or PBO Q4W): 6 Group 7 (700 mg to 1400 mg or PBO Q4W) ^b : 5 Group 12 (2800 mg or PBO single dose): 6 Multiple-dose SC doses of Remeneta in participants with AD: Group 14 (400 mg or PBO): 18 Single-dose dose of Remeneta in healthy participants: Group 5 (2800 mg or PBO IV): 12 Japanese: 8 Non-Japanese: 4 Group 8 (400 mg or PBO Group 9 (2000 mg or PBO SC): 14 Group 10 (2800 mg or PBO IV): 18 Japan: 6 Non-Japanese: 12 Abbreviations: AD = Alzheimer's disease, IV = intravenous; PBO = placebo; Q4W = every 4 weeks; SC = subcutaneous. ^a All groups in Part A were randomly assigned to remenitastatin in a 5:1 ratio to placebo. ^b Group 7 was administered 700 mg IV every 4 weeks in two doses, followed by a 1400 mg IV every 4 weeks adjustment group.

As shown herein, Remeneta demonstrated rapid and stable clearance of amyloid plaques in patients with AD, with an acceptable safety and tolerability profile.

Part A Trial Design Summary: Part A consists of multiple cohorts, each with a 5:1 randomized allocation ratio of remenita to placebo. Dose escalation decisions will be made after at least six participants in a given cohort have been dosed and safety data for at least four participants who have received the study intervention have been assessed by Day 29. Additional participants may be added to existing cohorts based on review of safety, tolerability, PK, and PD data. All potential participants in Part A will undergo screening procedures, including the MMSE, screening magnetic resonance imaging (MRI), and screening positron emission tomography (PET) scan with florbetapir.

Participants in Cohorts 1 through 4, 7, and 12 received their first dose of the study intervention via IV infusion on Day 1 of the treatment period and were observed as inpatients overnight after the first dose. Participants were monitored as outpatients and underwent repeat neurological examinations and MRI approximately four weeks after the first dose of the study intervention. The remaining doses of the study intervention were administered IV to outpatients approximately every four weeks (Q4W), with the exception of participants randomized to Cohort 12, who received a single dose of 2800 mg.

Participants in Cohort 14 received their first dose of the study intervention via subcutaneous injection on Treatment Day 1. Participants were observed approximately 6 hours after completing each of the initial 4 subdoses and for at least 2 hours after completing all subsequent dosing visits. Participants were monitored as outpatients and underwent repeat neurological examinations and MRIs after the first dose of the study intervention.

All participants in Part A were monitored for safety, particularly amyloid-associated imaging abnormalities (ARIA) and allergic reactions, and had regular outpatient visits for at least 12 weeks after the last dose of the study intervention.

Part B Study Design Summary: Part B is a SAD study conducted in healthy participants receiving either IV or SC administration of Remeneta. Participants received a single dose of Remeneta or placebo and were monitored for approximately 12 weeks post-dose for safety assessments and collection of PK and immunogenicity samples.

Primary Objective: The primary objective of Part B of Study LAKB was to evaluate the safety and tolerability of remenita in participants with AD and healthy participants, including participants of Japanese ancestry, following IV or SC administration.

Secondary Objectives: The secondary objectives of Study LAKB Part B were to: i) assess the serum PK of remenetal in participants with AD (including participants of Japanese ancestry) after single or multiple IV infusions, or SC injections, and in healthy participants (including participants of Japanese ancestry) after a single IV infusion and a single SC dose; and ii) evaluate the effect of remenetal on brain amyloid plaque levels in participants with AD (including participants of Japanese ancestry).

Patient Population: Study LAKB Part A included men and women between the ages of 55 and 85 years (inclusive) with gradual and progressive changes in memory function and a clinical diagnosis of mild cognitive impairment due to AD or AD dementia. Participants also had evidence of amyloid brain pathology as measured by amyloid PET scan and an MMSE score greater than or equal to 16. Participants were required to have a research partner to participate. Participants were excluded if they had a serious illness (other than AD) that could interfere with study analysis or affect the participant's ability to complete the study. Participants were excluded if a centrally read MRI demonstrated ARIA-E, >4 cerebral microbleeds, >1 area of superficial siderosis, any major hemorrhage, or severe white matter disease.

Study LAKB Part B included healthy men and women aged 18 to 45 years (inclusive) with a BMI between 18.0 kg/m² and 32.0 kg/m². Participants with clinically significant findings on brain magnetic resonance imaging scans or a family history of early-onset AD were excluded.

Safety and Tolerability Results in Participants with Alzheimer's Disease: As of August 2023, a total of 75 participants with AD received at least one dose of Remeneta or placebo.

Forty participants with AD (53.3%) reported at least one treatment-emergent AE (TEAE); most TEAEs were mild or moderate in severity. ARIA-E (n = 16; 21.3%) was the most commonly reported TEAE. The incidence of ARIA-E appeared to be related to the intravenous dose. ARIA-H was reported in 12 participants (16.0%). No major bleeding was observed. Three ARIA-Es (out of 16 identified) were symptomatic. All but six patients who experienced ARIA were managed with temporary medication interruption (six patients discontinued the study). Follow-up MRI performed after temporary study intervention discontinuation showed partial or complete resolution of ARIA-E.

No participant with AD experienced injection site pain, itching, or edema. Two infusion-related reactions and one allergic event, contact dermatitis, were observed; all three events were considered mild.

Safety and Tolerability Results in Healthy Participants: As of May 2022, a total of 64 healthy participants (20 of Japanese ancestry) have received one dose of Remeneta or placebo.

No deaths, SAEs, or early discontinuations due to AEs were observed. Twelve (18.8%) healthy participants reported at least one TEAE. At least two participants reported TEAEs related to COVID-19 infection. The overall TEAE incidence was similar between Japanese and non-Japanese participants. No TEAEs were considered by the investigator to be related to study treatment.

Injection site reactions were prospectively assessed in 34 participants after a single subcutaneous injection. Preliminary analysis showed mild injection site reactions. Findings included mild injection site erythema and induration in approximately 50% of healthy participants; mild injection site pain in two participants; and/or pruritus and edema in one participant each. Most injection site reactions lasted up to four hours after administration.

Immunogenicity Results: As of August 2023, no participants in this ongoing study had treatment-emergent anti-drug antibodies (treatment-induced or treatment-enhanced) following single or multiple doses of remeneta.

Pharmacokinetic Results: In Study LAKB, PK was evaluated in healthy participants following single doses of 2800 mg IV and 400 mg SC for up to 56 days post-dosing. A bioavailability of 61% was observed following SC administration. This was based on the geometric mean AUC _0-∞ observed in healthy volunteers following a single dose of 2800 mg IV or 400 mg SC. PK results are presented in Table 7 below. Table 7 : Mean (CV%) non-compartmental pharmacokinetic parameters following a single dose of 2800 mg IV or 400 mg SC of remeneta in healthy participants. Parameters Geometric mean (CV%) Single dose IV 2800 mg (N=9) Single dose SC 400 mg (N=10) C _max (µg/mL) 984 (24) 37.1 (29) T _max ^a (hours) 0.70 (0.68-6.02) 168 (96.15-339.1) AUC _(0-672) (µg·h/mL) 212000 (21) 17400 (24) AUC _(0-1344) (µg·h/mL) 308000 (25) 26800 (24) AUC _(0-∞) (µg·h/mL) 394000 (24) 32100 (25) CL (liters/day) 0.171 (24) 0.299 (25) V _z (L) 6.13 (47) 6.98 (26) Bioavailability (F%) 61 Abbreviations: AUC _(0-672) = dosing interval 672 hours (month 1); AUC _(0-1344) = dosing interval 672 hours = month 2; AUC _(0-∞) = area under the concentration-time curve from time zero to infinity; bioavailability = (dose-normalized geometric mean AUCτ SC/dose-normalized geometric mean AUCτ IV) × 100; C _max = maximum observed drug concentration; CL = total body clearance after intravenous administration; CV = coefficient of variation; IV = intravenous; N = number of participants; SC = subcutaneous; t max = time to maximum observed drug concentration; V _z = apparent volume of distribution during the terminal phase. ^aMedian (range).

As of the data cutoff date of March 24, 2023, PK data from participants with AD from the ongoing LAKB and LAKC studies (described in Examples 4 and 5) are reported below. Both Cmax,ss and AUCτ,ss increased with dose. In Study LAKB, cumulative effects occurred with repeated monthly administration of remeneta, with cumulative ratios of approximately 1.6, 1.3, 1.0, and 1.9 following Q4W IV doses of 250 mg, 700 mg, 1400 mg, and 2800 mg, respectively. A primary population PK analysis (n=451 participants) was conducted using all observed LAKB and LAKC data. Intravenous and subcutaneous PK data were best described by a first-order absorption, two-compartment model with clearance and volume terms proportional to patient weight, with fixed exponents of 0.8 and 1, respectively (based on an allometric growth principle). Longevity of the Phase 1 (20 mg/mL) drug product was identified as a significant covariate in exposure. At the start of treatment (day 0), drug longevity in the Phase 1 study ranged from 182 to 621 days. Exposure (LAKB) decreased linearly with drug longevity over the range of 180 to 423 days. Studies investigating the effect of drug longevity suggest that age-related increases in oxidation contribute to the PK changes. Phase 3 drug formulation modifications were incorporated, including increasing the concentration of remenitatinib and incorporating methionine for oxidative stabilization.

Based on LAKC PK data, no changes in serum exposure were observed over the life of the Phase 3 material. Based on preliminary population PK modeling, bioavailability was estimated to be 60%, and the mean absorption rate of remeneta after subcutaneous administration was 0.008 h-1. Maximum concentration (Cmax) was reached at the end of the IV infusion (30 minutes to 3 hours) or approximately 7 days after IV or SC administration, respectively. The central volume of distribution was 2.74 L with an inter-subject variability of 38%, while the peripheral volume of distribution was 2.73 L with an inter-subject variability of 28%. Serum clearance was 0.0053 L/h with an inter-participant variability of 54%.

Remeneta PK was dose proportional over the 250 mg to 2800 mg IV dose range. A dose-dependent increase in serum exposure was also observed following 400 mg and 800 mg SC dosing (limited data).

Pharmacodynamic Results: In Study LAKB, ^18F -flubetapyr PET scans were performed prior to dosing and approximately 12 and 24 weeks after starting IV administration of remenetal or placebo every 4 weeks or a single dose of remenetal or placebo. For SC administration of remenetal, ^18F -flubetapyr PET scans were performed 4, 12, and 24 weeks after starting weekly dosing of remenetal or placebo.

Flubetadine images of the available cohort were prepared essentially as described herein. Composite SUVr was calculated using six target cortical regions and the entire cerebellum as a reference region (Clark et al., 2011). This composite SUVr measure of brain Aβ plaques was converted to percentage isoform units (IFUs) using the following formula: IFUs = 183.07 * SUVr - 177.26 (Navitsky et al., 2018). As previously reported (Navitsky et al., 2018), a threshold of 24.1 IFUs (CL) distinguished between no or sparse plaques verified by neuropathology and moderate to frequent plaques in necropsy-confirmed data. The 0 CL threshold represents the average value of “high-certainty” amyloid-negative individuals (i.e., young (≤45 years) controls) (Klunk et al., 2015).

Figure 1 depicts changes in brain amyloid plaques from baseline to day 169, by individual participant and time point. Time-dependent and dose-/concentration-dependent reductions in amyloid plaques were observed for both the IV and SC groups. Amyloid clearance was defined as an amyloid plaque level <24.1 CL (Navitsky et al., 2018; Mintun et al., 2021). The proportion of participants achieving amyloid clearance increased with increasing dose and duration of remenitar (see Error ! Reference source not found ). Similar trends were observed when an amyloid plaque level <0 CL was used as the cutoff value (see Tables 8a and 8b). Table 8a : Overall Percentage of Participants Achieving Amyloid Clearance (CL < 24.1) in Study LAKB treatment Day 85 ( n /s ) Day 169 (n/ s ) Day 253 (n/ s ) Placebo (N=13) 0/9 (0.00%) 0/9 (0.00%) 0/6 (0.00%) LY 250 mg Q4W (N=5) 0/4 (0.00%) 0/4 (0.00%) 1/4 (25.00%) LY 700 mg Q4W (N=15) 4/15 (26.67%) 8/14 (57.14%) 3/5 (60.00%) LY 1400 mg Q4W (N=13) 6/12 (50.00%) 10/10 (100.00%) 5/7 (71.43%) LY 2800 mg Q4W (N=5) 4/4 (100.00%) 4/4 (100.00%) 4/4 (100.00%) LY 700 mg × 2 + 1400 mg 2/3 (66.67%) 2/2 (100.00%) 0/- LY 2800 mg SD (N=5) 3/5 (60.00%) 2/5 (40.00%) 3/5 (60.00%) LY 400 mg SC QW (N=15) 0/3 (0.00%) 2/2 (100.00%) 0/- Table 8b : Overall Percentage of Participants Achieving Negative % Isotype Starch Levels in Study LAKB treatment Day 85 ( n /s ) Day 169 (n/ s ) Day 253 (n/ s ) Placebo (N=13) 0/9 (0.00%) 0/9 (0.00%) 0/6 (0.00%) LY 250 mg Q4W (N=5) 0/4 (0.00%) 0/4 (0.00%) 0/4 (00.00%) LY 700 mg Q4W (N=15) 1/15 (6.67%) 1/14 (7.14%) 1/5 (20.00%) LY 1400 mg Q4W (N=13) 3/12 (25.00%) 6/10 (60.00%) 3/7 (42.86%) LY 2800 mg Q4W (N=5) 4/4 (100.00%) 3/4 (75.00%) 4/4 (100.00%) LY 700mg×2 + 1400 mg 1/3 (33.33%) 1/2 (50.00%) 0/- LY 2800mg SD (N=5) 2/5 (40.00%) 2/5 (40.00%) 1/5 (20.00%) LY 400 mg SC QW (N=15) 0/3 (0.00%) 1/2 (50.00%) 0/- Abbreviations: LY = lymenastatin; N = number of subjects randomly assigned; n = subjects with flubeta-18 PET levels meeting the criteria; s = number of subjects with available flubeta-18 PET scans; Q4W = every 4 weeks; SD = single dose; SC = subcutaneous; QW = once a week.

Amyloid clearance was rapid and stable in some participants. Figure 2 depicts an example of amyloid clearance as a representative example from Study LAKB, where participants received a single dose of 2800 mg and achieved amyloid clearance at the Day 85 visit. The X-axis of Figure 2 provides the standardized uptake value (SUV) and reflects that the participant experienced a 144 percent reduction in amyloid clearance (CL) at Day 85.

Pharmacokinetics/Pharmacodynamics: PK/PD analysis of the relationship between serum remenetastatin concentrations and amyloid plaques (measured using ^18F -flubetapyr PET) revealed that a linear model best described the treatment effect on the reduction of amyloid plaque levels over time. The time to achieve amyloid plaque clearance (levels <24.1 CL) depended on dose and baseline amyloid plaque levels. An exposure-response model was used to fit the time-dependent amyloid plaque data. The model was parameterized based on the natural degradation half-life of amyloid plaques, treatment effect, and baseline. A linear model of the degradation rate that stimulated plaque removal was used to describe the PK effects of remenetastatin. The treatment effect, as indicated by the slope, was also found to be correlated with baseline amyloid plaque levels. The exposure-amyloid plaque model indicated that with increasing exposure, there was a proportional increase in the rate of plaque clearance. Although data available at the time of application did not allow estimation of the relevant serum concentrations required for maximal and half-maximal responses, the observation that the highest plaque clearance within the dose range studied was achieved with 2800 mg IV every 4 weeks is notable. The time to achieve clearance of amyloid plaques (<24.1 CL units) depended on baseline amyloid plaque levels. Higher baseline values increased the time required to achieve clearance of amyloid plaques. ApoE4 carrier status (limited data) was tested as a potential covariate at baseline and slope, but was not identified as a significant covariate in this primary exposure-amyloid plaque model. Example 5 : Evaluating the safety and efficacy of Remenita in early symptomatic Alzheimer's disease as measured by amyloid reduction

Study LAKC (NCT04451408, clinicaltrials.gov) is an ongoing Phase 3 study comprised of an open-label appendix and a double-blind, placebo-controlled, randomized clinical trial (i.e., the primary protocol). The open-label appendix is collecting open-label safety data in participants with early symptomatic AD who have evidence of amyloid pathology and receive IV or SC remeneta. The primary protocol is evaluating IV and SC remeneta compared to placebo to measure the clearance of amyloid plaques in participants with early symptomatic AD.

Open-Label Appendices Trial Design Summary: The purpose of these appendices is to assess the open-label safety of participants receiving Remeneta IV or SC; no placebo will be administered in these appendices.

Appendices 1, 3 and 4 have been started as described below. Participants were assigned to receive 2300 mg of ramunetide IV every 12 weeks for 3 doses, 1500 mg of ramunetide IV every 12 weeks for 4 doses, 800 mg of ramunetide IV every 8 weeks for 7 doses, 400 mg of ramunetide IV every 4 weeks for 3 doses at Weeks 0, 4, and 8; and 800 mg of ramunetide IV every 8 weeks for 5 doses at Weeks 16, 24, 32, 40, and 48, 400 mg of ramunetide IV every 8 weeks for 2 doses at Weeks 0 and 8; and 800 mg of ramunetide IV every 8 weeks for 8 doses. IV for 5 consecutive doses at Weeks 16, 24, 32, 40, and 48; 200 mg IV for 2 consecutive doses every 8 weeks at Weeks 0 and 8; 400 mg IV for 2 consecutive doses every 8 weeks at Weeks 16 and 24; and 800 mg IV for 3 consecutive doses every 8 weeks at Weeks 32, 40, and 48; 400 mg subcutaneously weekly for 36 consecutive doses, or 400 mg subcutaneously every 4 weeks for 13 consecutive doses.

A summary of the study related to Appendix 1 is provided in Figure 3 , a summary of the study related to Appendix 3 is provided in Figure 4 , and a summary of the study related to Appendix 4 is provided in Figure 5 .

Assessment of the SC group can also be performed substantially as provided herein and in accordance with Appendix 5 (study summary provided in Figure 6). Therefore, participants will be randomly assigned (1:1:1) to one of the following three open-label subcutaneous dosing regimens: Treatment Group 1 ( total 13 dosings ) 100 mg Q8W for 2 dosings, followed by 400 mg Q8W for 2 dosings, followed by 800 mg Q8W for 2 dosings, followed by 800 mg Q4W for up to 7 dosings. Treatment Group 2 ( 15 dosings total ) : 200 mg Q8W once, followed by 400 mg Q8W twice, followed by 800 mg Q8W once, followed by 800 mg Q4W for up to 11 dosings. Treatment Group 3 ( 16 dosings total ) : 400 mg Q8W twice, followed by 800 mg Q8W once, followed by 800 mg Q4W for up to 13 dosings. Alternatively, treatment group 4 ( 14 dosing doses total ) could also be initiated essentially as described below : 400 mg for 2 doses every 12 weeks, followed by 800 mg every 8 weeks for 1 dose, followed by 800 mg every 4 weeks for up to 11 doses.

Summary statistics and statistical analyses will be provided for the safety and exposure data collected in the appendix as defined in the statistical analysis plan. The analyses in the appendix will generally follow those described in the statistical analysis plan of the primary protocol, except that no testing related to the remenita or placebo groups will be conducted during the double-blind treatment phase.

Open-Label Appendix Objectives: The primary objective of this Appendix is to describe the safety profile of remeneta. Secondary objectives in this Appendix are to assess peripheral PK and the presence of anti-remeneta antibodies. Additionally, secondary objectives in Appendix 4 are to assess the proportion of participants achieving brain amyloid clearance and the mean absolute change from baseline in brain amyloid plaques on an amyloid PET scan.

Open-label Appendix Patient Population: In general, individuals may participate in the open-label appendix if they meet the following criteria: are 60 to 85 years of age (inclusive); have gradual and progressive changes in cognitive function; have an MMSE score of 20 to 28 (inclusive) (Appendixes 1, 3, and 4) or an MMSE score of 22 to 30 (inclusive) (Appendix 5); and have an amyloid PET scan consistent with the presence of brain amyloid pathology (e.g., more than 24 cL of Aβ plaques in the brain).

In LAKC Appendix 5, participants must also have a CDR-GS of 0.5 or 1 to be selected.

In general, individuals may be excluded from study participation if they: Have a significant neurologic disorder or psychiatric diagnosis other than Alzheimer's disease that could interfere with analysis or the ability to complete the study; Have any clinically significant abnormality at screening that could adversely affect participation, could compromise the study, or demonstrate evidence of another etiology of dementia; Have a current serious or unstable illness or condition that could interfere with analysis of the study; and/or Be a female of childbearing potential.

Study LAKC (primary protocol) Trial Design Summary: Study LAKC is an ongoing, multicenter, randomized, double-blind, placebo-controlled Phase 3 study of remeneta in participants with early symptomatic AD. Participants meeting the eligibility criteria will be enrolled in one of the SC QW, SC Q4W, or IV cohorts and randomly assigned to remeneta in a 3:1 ratio to placebo. IV group (N = approximately 200) Remenetal 800 mg IV every 8 weeks for up to 7 doses, or Placebo IV SC QW group (N = approximately 200)* Remenetal 400 mg SC weekly for 36 doses, or Placebo SC SC Q4W group (N = approximately 200) Remenetal 800 mg SC Q4W for 13 doses, or Placebo SC

Participants were previously enrolled and randomized to the SC QW group, and after a minimum 4-week treatment pause, their dose was adjusted to 800 mg SC Q4W or placebo. A study summary of the primary protocol is provided in Figure 7.

Random assignment will be sought in a 3:1 ratio of Remeneta to placebo. Analyses of each of the trial's primary and key secondary endpoints will be conducted for each cohort. The primary endpoint will be the proportion of participants achieving plaque clearance at Week 52, which is superior to placebo, for each dosing regimen.

Study LAKC (Primary Protocol) Study Objectives: The primary objective of the study was to test the hypothesis that at least one dosing regimen of Remenetal (SC or IV) is superior to placebo in clearing brain amyloid plaques in participants with early symptomatic AD. Secondary objectives of the study were to: i) test the hypothesis that at least one dosing regimen of Remenetal (SC or IV) is superior to placebo in reducing brain amyloid plaques; ii) test the hypothesis that at least one dosing regimen of Remenetal (SC or IV) is superior to placebo in clearing brain amyloid plaques in participants with early symptomatic AD; and iii) test the hypothesis that at least one dosing regimen of Remenetal (SC or IV) is superior to placebo in reducing brain amyloid plaques. Other secondary objectives of the study include: i) describing the safety profile of remeneta and ii) assessing peripheral PK and the presence of anti-remeneta antibodies.

Study LAKC (Primary Protocol) Patient Population: In general, individuals were eligible for participation in Study LAKC (Primary Protocol) if they met the following criteria: were 60 to 85 years of age, inclusive; had gradual and progressive changes in cognitive function; had an MMSE score of 20 to 28, inclusive; had P-tau findings consistent with the presence of brain amyloid pathology; and had amyloid PET scan findings consistent with the presence of brain amyloid pathology.

In general, individuals were excluded from participation in studies if they: had a significant neurological disorder or psychiatric diagnosis other than AD that could affect cognition, interfere with study analysis, or ability to complete the study; had any clinically important abnormality at screening that could adversely affect participation, could compromise the study, or indicate evidence of another etiology of dementia; had a current serious or unstable illness or condition that could interfere with study analysis; and/or were females of childbearing potential.

Study LAKC Dose Adjustment: The dose selection will take into account the following factors: safety and tolerability data from the Phase 1 study in participants with early symptomatic AD; safety data from the open-label appendix of LAKC in participants with early symptomatic AD; bioavailability of the SC drug product observed in healthy volunteers; and PK exposure-amyloid plaque-analysis of all available data across a wide dose range.

The inventors of the invention provided herein propose that: Seven infusions of 800 mg of remeneta administered intravenously every 8 weeks (at Weeks 0, 8, 16, 24, 32, 40, and 48) are expected to result in ≥80% of participants achieving amyloid plaque clearance by 52 weeks from the start of dosing, while still allowing for built-in pauses to reduce the risk of ARIA. Three infusions of 2300 mg of remeneta administered every 12 weeks (at Weeks 0, 12, and 24) are expected to result in approximately 90% of participants achieving amyloid plaque clearance by 52 weeks from the start of dosing. Three infusions of 1500 mg of Remenetal administered every 12 weeks (at Weeks 0, 12, 24, and 36) are expected to result in approximately 90% of participants achieving amyloid plaque clearance by 52 weeks from the start of dosing. Three infusions of 400 mg of remeneta given intravenously every four weeks (at Weeks 0, 4, and 8), followed by five infusions of 800 mg of remeneta given intravenously every eight weeks (at Weeks 16, 24, 32, 40, and 48), are expected to result in amyloid plaque clearance in ≥80% of participants by Week 52 from the start of dosing, while still allowing for built-in suspension at the higher dose (i.e., 800 mg) to reduce the risk of ARIA. Two infusions of 400 mg of remeneta given intravenously every four weeks (at Weeks 0 and 8), followed by five infusions of 800 mg of remeneta given intravenously every eight weeks (at Weeks 16, 24, 32, 40, and 48) are expected to result in amyloid plaque clearance in ≥80% of participants by Week 52 from the start of dosing, while still allowing for internal pauses to reduce the risk of ARIA. Two infusions of 200 mg of remenergic intravenously every four weeks (at Weeks 0 and 8), followed by two infusions of 400 mg of remenergic intravenously every eight weeks (at Weeks 16 and 24), and then three infusions of 800 mg of remenergic intravenously every eight weeks (at Weeks 32, 40, and 48) are expected to result in amyloid plaque clearance in ≥60% of participants at Week 52. An alternative regimen would be to administer 800 mg of remeneta intravenously every 8 weeks for six infusions (at Weeks 32, 40, 48, 56, 64, and 72) after 200 mg and 400 mg infusions. This dosing schedule is expected to result in amyloid plaque clearance in ≥90% of participants by 76 weeks from the start of dosing, while still allowing for built-in dosing pauses to reduce the risk of ARIA. Fixed IV dosing schedules include built-in dosing pauses (2 to 3 months between infusions). These IV dosing schedules are also expected to result in stable plaque clearance, with dosing pauses used to minimize the risk of ARIA. The expected exposure range will be within the range explored in the previous Phase 1 study. It was hypothesized that an 8- to 12-week dosing interval would allow time for potential asymptomatic ARIA to resolve and reduce the risk of ARIA worsening (Salloway et al., 2022). The titrated IV dosing regimen included a built-in dosing pause (2 months between infusions). It was hypothesized that the titrated regimen would reduce the severity of observed ARIA, and the 8-week dosing pause was used to minimize the risk of ARIA associated with dose escalation. An alternative IV dosing regimen of 400 mg of remenitamine intravenously every 4 weeks for thirteen infusions (at Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48) was also considered, with an expected rate of amyloid plaque clearance in ≥80% of participants by 52 weeks from the start of dosing. It is anticipated that the SC dosing regimen of 400 mg administered weekly for 36 doses or 800 mg administered once every four weeks for 13 doses will result in approximately 80 to 90% of participants achieving amyloid plaque clearance by week 52 from the start of dosing. It is hypothesized that the SC dosing regimen will result in a slower increase in serum concentrations and a lower _Cmax compared to serum concentrations and _Cmax achieved after IV administration. For both SC dosing regimens, the steady-state _Cmax after subcutaneous administration will be achieved after approximately four months, providing a slower increase in serum concentrations similar to the titrated regimen. It is hypothesized that a lower _Cmax and slower increase in serum concentration may reduce the risk of ARIA (Hayato et al., “OC14: BAN2401 and ARIA-E in Early Alzheimer's Disease: Pharmacokinetic/pharmacodynamic Time-to-event Analysis from the Phase 2 Study in Early Alzheimer's Disease”, J. Prev. Alzheimer's Dis. 7(Suppl 1): 2-54 (2020); Salloway et al., “Amyloid-related Imaging Abnormalities in 2 Phase 3 Studies Evaluating Aducanumab in Patients with Early Alzheimer's Disease”, JAMA Neurol. 79(1): 13-21 (2022); both of which are incorporated herein by reference in their entirety). Both SC dosing regimens are expected to achieve monthly serum exposures within the range of steady-state exposures observed after 700 and 1400 mg IV Q4W in the Phase 1 study. Every four weeks and weekly SC dosing will approach the lower and upper exposure ranges, respectively. If _Cmax is not a primary factor in the development of ARIA, a titration-based SC dosing regimen with a built-in hold is being evaluated. The titration regimen may reduce the severity of observed ARIAs, and an initial 8- to 12-week dosing hold is intended to minimize the risk of ARIA associated with dose escalation. The following titrated dosing regimens may be evaluated: 400 mg SC of Remenetal every 8 weeks for two doses at Weeks 0 and 8, titrated up to 800 mg SC of Remenetal once at Week 16, and 800 mg SC of Remenetal every 4 weeks for 13 doses at Weeks 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, and 72. Administer 400 mg SC of Remeneta every 12 weeks for two doses at Weeks 0 and 12, adjusted to a maximum of 800 mg SC of Remeneta once at Week 24, and 800 mg SC of Remeneta every four weeks for 11 doses at Weeks 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, and 72. Administer 200 mg SC of Remeneta once at Week 0 and titrate every 8 weeks up to 400 mg SC of Remeneta twice at Weeks 8 and 16, and titrate up to 800 mg SC of Remeneta once at Week 24, and 800 mg SC of Remeneta every 4 weeks for 11 doses at Weeks 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, and 72. Administer 100 mg SC of Remeneta every 8 weeks for two doses at Weeks 0 and 8, and titrate up to 400 mg SC of Remeneta every 8 weeks for two doses at Weeks 16 and 24, and titrate up to 800 mg SC of Remeneta every 8 weeks for two doses at Weeks 32 and 40, and 800 mg SC of Remeneta every 4 weeks for seven doses at Weeks 48, 52, 56, 60, 64, 68, and 72. 400 mg SC of Remeneta every 8 weeks for 3 doses at Weeks 0, 8, and 16, adjusted to a maximum of 800 mg SC of Remeneta for 3 doses at Weeks 24, 32, and 40, and 800 mg SC of Remeneta every 4 weeks for 7 doses at Weeks 48, 52, 56, 60, 64, 68, and 72.

Safety Results from the Ongoing Phase 3 LAKC Study: To date (53.4%), participants have reported at least one treatment-emergent adverse event (TEAE). Among the TEAEs, ARIA-E and ARIA-H have occurred in 10 or more of 100 participants. Other TEAEs observed (occurring in 1 to 9 of 100 participants) included, but were not limited to, headache, COVID-19, falls, upper respiratory tract infection, dizziness, urinary tract infection, diarrhea, and confusional state. Symptomatic ARIA-E has occurred in 1 to 9 of 100 participants. Headache has been reported in approximately half of the symptomatic cases. ARIA has been associated with SAEs and deaths in participants receiving Remeneta. The incidence of ARIA-related SAEs was higher in participants with pre-existing superficial siderosis. Studies LAKB and LAKC were amended to exclude additional participants with baseline superficial siderosis, and all randomized participants with baseline superficial siderosis were discontinued from further study treatment.

If ARIA-E occurred in participants receiving study treatment, it usually developed within the first 12 weeks of dosing. The incidence of ARIA-E was higher in the groups testing higher doses of remeneta given intravenously and lower in participants receiving less frequent subcutaneous dosing (e.g., 800 mg Q4W versus 400 mg QW), even though the initial dose in the Q4W dosing regimen was higher. The incidence of ARIA-E was higher in participants with APOE ε4/ε4 compared to those who were heterozygous or non-carriers of the APOE ε4 allele. Although major bleeding has been observed in participants taking remeneta, these events were uncommon (fewer than 1 in 100).

Fewer than 1 in 100 participants experienced an allergic reaction. One infusion-related reaction was reported. No systemic allergic reactions were observed. Among participants receiving SC Remeneta or placebo, 1 to 9 in 100 participants experienced injection site reactions. Injection site reactions were mild to moderate in severity, with erythema being the predominant sign and symptom.

Pharmacodynamic Results: In a subset of study participants, flubeta-18 PET scans were performed before and 24 weeks after starting open-label IV dosing of remeneta. As of September 22, 2023, the following crude mean changes from baseline at Week 24 were observed: -81.9 CL (n = 12) for participants taking 2300 mg IV Q12W remeneta, -66.3 CL (n = 7) for participants taking 1500 mg IV Q12W remeneta, and -53.4 CL (n = 14) for participants taking 800 mg IV Q8W remeneta. Flubeta-18 PET scans were performed before and 8 weeks after starting open-label SC dosing of remeneta. As of September 22, 2023, the following crude mean changes from baseline at Week 8 were observed: -26.5 CL (n=25) for participants administered 400 mg SC QW remenetal, and -22.3 CL (n=23) for participants administered 800 mg SC Q4W remenetal. Example 6 : Evaluation of the Safety and Efficacy of Subcutaneous Remenetal in Early Symptomatic Alzheimer's Disease.

Study LAKD (EU Trial Number: 2022-501473-38-00) is an upcoming, multicenter, randomized, double-blind, placebo-controlled Phase 3 study evaluating the safety and efficacy of Remeneta in participants with early symptomatic AD who have evidence of brain amyloid and tau pathology. The primary objective of Study LAKD will assess whether treatment with subcutaneous administration of Remeneta can slow disease progression, as assessed by double-blind observational clinical outcomes of cognition and function over 76 weeks.

Study LAKD Trial Design Summary: Study LAKD is a multicenter, randomized, double-blind, placebo-controlled Phase 3 study of Remeneta in participants with early symptomatic AD. A summary of the study is depicted in Figure 8. Participants meeting the eligibility criteria will be randomly assigned in a 1:1 ratio to receive either Remeneta 400 mg subcutaneous (SC) weekly for 36 doses or placebo subcutaneously.

The primary objective of this study was to test the hypothesis that treatment with Remeneta SC would slow the progression of AD compared to placebo, as measured by the change from baseline in the iADRS score at Week 76, the primary endpoint. Based on prior research expectations, approximately two-thirds of the randomized participants would fall into the intermediate tau group. It is conceivable that certain aspects of the trial design, such as the primary analysis groups (intermediate tau vs. intermediate and high tau, APOE ε4 carriers only vs. carriers and non-carriers), sample size, and other aspects of the design (such as the randomization ratio) could be varied.

Study LAKD (Master Protocol) Study Objectives: The primary objective of the study was to test the hypothesis that Remeneta SC is superior to placebo in reducing clinical progression (as measured by the iADRS) in participants with early symptomatic AD. Key secondary objectives were to test the hypothesis that Remeneta SC is superior to placebo in reducing clinical progression as measured by the CDR-SB (Clinical Dementia Rating-Summary Scale); the ADAS-Cog13 (13-point Alzheimer's Disease Assessment Scale - Cognitive Subscale); the ADCS-iADL (Alzheimer's Disease Cooperative Study - Activities of Daily Living Scale); and/or the MMSE (Mini-Mental State Examination). Another secondary objective was to describe the safety profile of Remeneta.

Study LAKD (Main Protocol) Patient Population: In general, individuals are eligible for Study LAKD if they: are 60 to 85 years of age, inclusive; have gradual and progressive changes in cognitive function; have an MMSE score of 20 to 28, inclusive; have biomarkers consistent with the presence of brain amyloid pathology (if any); and have tau positron emission tomography scan results consistent with the presence of tau pathology.

In general, individuals were excluded from participation in studies if they: had a significant neurological disorder or psychiatric diagnosis other than AD that could affect cognition, interfere with study analysis, or ability to complete the study; had any clinically important abnormality at screening that could adversely affect participation, could compromise the study, or indicate evidence of another etiology of dementia; had a current serious or unstable illness or condition that could interfere with study analysis; and/or were females of childbearing potential.

LAKD Amyloid and Tau Substudy: This substudy aims to collect additional amyloid and tau PET scans in participants enrolled in the LAKD study. These additional PET scans will provide data on the effects of Remenetal on brain amyloid plaques and tau pathology over time to inform the effects of Remenetal on PD. Approximately 250 participants are planned to be enrolled in the study.

Study LAKD Dose Adjustment: The 400 mg dose administered SC weekly for 36 doses was selected based on the following: Safety and tolerability data from a Phase 1 study in participants with early symptomatic AD. Observed SC drug product bioavailability in healthy volunteers. PK/PD (amyloid plaque) analysis of all available data across a wide dose range. The inventors of the invention presented herein propose that a weekly SC dosing regimen for 36 doses is expected to result in amyloid plaque clearance in approximately 90% of participants, with a slower increase in serum concentrations and a lower _Cmax compared to _those achieved following IV administration. Following SC administration, steady-state _Cmax is achieved after approximately 4 months of weekly dosing, providing a slower increase in serum concentrations similar to that observed with the titrated regimen. It is hypothesized that the lower _Cmax and slower increase in serum concentrations may reduce the risk of ARIA. (Hayato et al., “OC14: BAN2401 and ARIA-E in Early Alzheimer's Disease: Pharmacokinetic/pharmacodynamic Time-to-event Analysis from the Phase 2 Study in Early Alzheimer's Disease”, J. Prev. Alzheimer's Dis. 7(Suppl 1): 2-54 (2020); Salloway et al., “Amyloid-related Imaging Abnormalities in 2 Phase 3 Studies Evaluating Aducanumab in Patients with Early Alzheimer's Disease”, JAMA Neurol. 79(1):13-21 (2022); which are incorporated herein by reference in their entirety). Weekly SC dosing of Aducanumab is expected to achieve monthly serum exposures within the range of steady-state exposures observed after 700 and 1400 mg IV Q4W in the Phase 1 study. Alternatively, Remeneta can be administered as an 800 mg subcutaneous (SC) dose every 4 weeks for 13 doses at Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48. It is anticipated that a subcutaneous dosing regimen of 800 mg administered every 4 weeks for 13 doses will result in approximately 90% of participants achieving amyloid plaque clearance by Week 52 from the start of dosing. If _Cmax is not a primary factor in the development of ARIA, a titrated SC dosing regimen with a built-in hold is being evaluated in Study LAKC. Adjustment of the regimen reduced the severity of observed ARIAs, and an initial 8- to 12-week dosing hold was used to minimize the risk of ARIA associated with dose escalation. Therefore, based on the ongoing results in LAKC, one of the following alternative dosing regimens can be evaluated: an adjusted dose of 400 mg SC of remenezeta every 8 weeks for 2 doses at Weeks 0 and 8, with an adjusted dose of up to 800 mg SC of remenezeta once at Week 16, and 800 mg SC of remenezeta every 4 weeks for 13 doses at Weeks 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, and 72. Administer 400 mg SC of Remeneta every 12 weeks for two doses at Weeks 0 and 12, adjusted to a maximum of 800 mg SC of Remeneta once at Week 24, and 800 mg SC of Remeneta every four weeks for 11 doses at Weeks 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, and 72. Administer 200 mg SC of Remeneta once at Week 0 and titrate every 8 weeks up to 400 mg SC of Remeneta twice at Weeks 8 and 16, and titrate up to 800 mg SC of Remeneta once at Week 24, and 800 mg SC of Remeneta every 4 weeks for 11 doses at Weeks 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, and 72. Administer 100 mg SC of remeneta every 8 weeks for two doses at Weeks 0 and 8, and up to 400 mg SC of remeneta every 8 weeks for two doses at Weeks 16 and 24, and up to 800 mg SC of remeneta every 8 weeks for two doses at Weeks 32 and 40, and 800 mg SC of remeneta every 4 weeks for seven doses at Weeks 48, 52, 56, 60, 64, 68, and 72. Case 7 : A study to investigate the safety, tolerability, and pharmacokinetics of a single dose of Remeneta in healthy Chinese participants .

Study LAKE is an upcoming, single-site, randomized, participant- and investigator-blinded, placebo-controlled, parallel-group, single-dose Phase 1 study. Study LAKE will investigate the safety, tolerability, and PK of a single dose of Remeneta administered intravenously or subcutaneously in healthy Chinese participants. To date, Remeneta has not been evaluated in the Chinese population. This study will support the future clinical development and registration of Remeneta in China.

Study LAKE Trial Design Summary: This study aims to evaluate the safety, tolerability, and PK of Remenetal compared to placebo following a single IV or SC dose in healthy Chinese participants. The study will include three cohorts, with participants randomly assigned to Remenetal or placebo in a 5:1 ratio. A summary of the study is provided in Figure 9.

Approximately 36 participants will be enrolled in the study. The primary objective of the study is to evaluate the safety and tolerability of Remeneta in healthy Chinese participants following a single IV or SC dose.

Study LAKE Objectives: The primary objective of Study LAKE is to evaluate the safety and tolerability of Remenetal in healthy Chinese participants following a single IV or SC dose. Secondary objectives are to assess the serum PK of Remenetal in healthy Chinese participants following a single IV infusion or SC dose.

Study LAKE Patient Population: The study included healthy men and women from mainland China aged 18 to 28 years (inclusive) with a body mass index (BMI) between 18.0 kg/m² and 32.0 kg/m² (inclusive). Participants with evidence of cognitive impairment, clinically significant brain MRI scans, or a family history of early-onset Alzheimer's disease were excluded. Example 8 : To evaluate the safety and efficacy of intravenous Neremenetal in early symptomatic Alzheimer's disease.

Study LAKF (EU Trial Number: 2022-501886-38-00) is an upcoming, multicenter, randomized, double-blind, placebo-controlled Phase 3 study evaluating the safety and efficacy of Remeneta in participants with early symptomatic AD who have evidence of brain amyloid and tau pathology. The primary objective of Study LAKF will assess whether treatment with Remeneta IV can slow disease progression, as assessed by double-blind observational clinical outcomes of cognition and function over 76 weeks.

Study LAKF Trial Design Summary: Study LAKF is a multicenter, randomized, double-blind, placebo-controlled Phase 3 study of Remeneta in participants with early symptomatic AD. A summary of the study is provided in Figure 10. Participants meeting the inclusion criteria will be randomly assigned in a 1:1 ratio to receive either Remeneta 2300 mg IV every 12 weeks for three doses (approximately N=1300) or placebo IV (approximately N=1300).

The primary objective of this study is to test the hypothesis that treatment with Remeneta IV will slow the progression of AD compared to placebo, as measured by the change from baseline in the iADRS score at Week 76, the primary endpoint. Approximately two-thirds of the randomized participants are expected to fall into the intermediate tau group.

It is conceivable that some aspects of the trial design, such as the primary analysis groups (intermediate tau vs. intermediate and high tau, APOE ε4 carriers only vs. carriers and non-carriers), sample size, and other aspects of the design (such as the randomization ratio) could be varied.

Study LAKF (Primary Protocol) Study Objectives: The primary objective of this study is to test the hypothesis that Remeneta IV is superior to placebo in reducing clinical progression (as measured by the iADRS) in participants with early symptomatic AD. Key secondary objectives of this study are to test the hypothesis that Remeneta IV is superior to placebo in reducing clinical progression as measured using the rating scales defined above: CDR-SB, ADAS-Cog 13, ADCS-iADL, and/or MMSE.

Another secondary objective of the study was to describe the safety of Remeneta.

Study LAKF (Main Protocol) Patient Population: In general, individuals may participate in Study LAKF if they: are 60 to 85 years of age, inclusive; have gradual and progressive changes in cognitive function; have an MMSE score of 20 to 28, inclusive; have biomarkers consistent with the presence of brain amyloid pathology (if available); or have tau positron emission tomography scan results consistent with the presence of tau pathology.

In general, individuals were excluded from participation in studies if they: had a significant neurological disorder or psychiatric diagnosis other than AD that could affect cognition, interfere with study analysis, or ability to complete the study; had any clinically important abnormality at screening that could adversely affect participation, could compromise the study, or indicate evidence of another etiology of dementia; had a current serious or unstable illness or condition that could interfere with study analysis; and/or were females of childbearing potential.

LAKF Amyloid and Tau Substudy: The purpose of this substudy is to collect additional amyloid and tau PET scans in participants enrolled in the LAKF study. These additional PET scans will provide data on the effects of remenitinib on brain amyloid plaques and tau pathology over time to inform the impact of remenitinib in PD.

Study LAKF Dose Adjustment: The dose of 2300 mg IV every 12 weeks for 3 doses was selected based on the following factors: Safety and tolerability data from a Phase 1 study in participants with early symptomatic AD; Bioavailability of the SC drug product observed in healthy volunteers; PK exposure-amyloid plaque analysis of all available data across a wide dose range; The inventors of the invention provided herein propose that 2300 mg IV every 12 weeks for 3 doses be administered. mg of Remeneta, administered as three infusions (at Weeks 0, 12, and 24), is expected to result in approximately 90% of participants achieving amyloid plaque clearance by Week 52 from the start of dosing; and/or an IV dosing regimen that includes a built-in dosing pause (3 months between infusions). This IV dosing regimen is also expected to result in stable plaque clearance, with pauses between doses used to minimize the risk of ARIA. The expected exposure range is within the range explored in the previous Phase 1 study. It is hypothesized that a 12-week dosing interval will allow time for potential asymptomatic ARIA to resolve and may reduce the risk of ARIA worsening (Salloway et al., “Amyloid-related Imaging Abnormalities in 2 Phase 3 Studies Evaluating Aducanumab in Patients with Early Alzheimer's Disease”, JAMA Neurol. 79(1):13-21 (2022), which is incorporated herein by reference in its entirety).

One or more of the following alternative dosing schedules and adjusted dosing schedules with built-in holds may be implemented as protocol addenda to minimize the risk of ARIA while anticipating that ≥80% of participants will achieve amyloid plaque clearance after completing the full dosing regimen: 800 mg IV every 8 weeks for 7 doses administered at Weeks 0, 8, 16, 24, 32, 40, and 48. 400 mg IV every 4 weeks for 13 doses at Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48. 400 mg IV every 4 weeks for 3 doses at Weeks 0, 4, and 8; and 800 mg IV every 8 weeks for 5 doses at Weeks 16, 24, 32, 40, and 48. 400 mg IV every 4 weeks for 3 doses at Weeks 0, 4, and 8, and 800 mg IV every 8 weeks for 5 doses at Weeks 12, 20, 28, 36, and 44. 400 mg IV every 8 weeks for 2 doses at Weeks 0 and 8, and 800 mg IV every 8 weeks for 5 doses at Weeks 16, 24, 32, 40, and 48. 200 mg IV every 8 weeks for two doses, administered at Weeks 0 and 8, titrated up to 400 mg IV every 8 weeks for two doses, administered at Weeks 16 and 24, and titrated up to 800 mg IV every 8 weeks for six doses, administered at Weeks 32, 40, 48, 56, 64, and 72. Example 9 : Utilization of Baseline Tau in Participant Screening.

Participants can be screened for baseline tau levels substantially as described herein. For the stratification in Study LAKD and Study LAKF, tau levels can be determined based on an initial visual assessment of a flortaucipir scan, followed by a quantitative analysis. An example is shown in FIG11 . As illustrated in FIG11 , the visual assessment can be graded based on the presence of tracer uptake in specific regions of the neocortex (AD-, AD+, AD++). Quantitative analysis can be determined based on the calculation of SUVr, which represents the count within a specific target area of interest in the brain (e.g., multi-block centroid discriminant analysis or MUBADA) when compared to a reference area (parametric estimate of reference signal intensity or PERSI). Participants may be stratified based on screening substantially as described herein and as illustrated, for example, in Figure 11. Example 10 : Management of ARIA .

The development of ARIA-E (cerebral edema/effusion) and/or ARIA-H (cerebral microhemorrhages [MCH], cortical superficial siderosis [cSS], or cerebral hemorrhage) is an expected event in the setting of amyloid plaque-clearing antibodies such as ramenitar.

MCH is known to occur during aging and in individuals with AD, and its presence may or may not be present in ARIA-H associated with ramenitide (Goos et al., 2010, Carlson et al., 2016, Sperling et al., 2012, Poels et al., 2011). Risk factors associated with an increased risk of ARIA during treatment with amyloid plaque-clearing antibodies include APOE ε4 status and baseline MCH/cSS/white matter disease (WMD) (Arrighi et al., 2016).

MRI-identified ARIA-E and ARIA-H have been associated with the administration of Remeneta. The incidence of ARIA-E was higher in participants with APOE ε4/ε4 compared with heterozygotes or non-carriers of the APOE ε4 allele. The incidence of SAEs associated with ARIA was higher in participants with pre-existing superficial siderosis. Ongoing studies are excluding additional participants with baseline superficial siderosis from the current study dosing regimen.

ARIA was observed in the fixed-dose and titrated groups and was generally asymptomatic and resolved with treatment discontinuation. ARIA was usually observed with the initial dose of Remeneta (e.g., within three months of treatment).

The IV dosing regimen for Remeneta includes a built-in dosing pause (2 or 3 months between infusions). Due to Remeneta's relatively long half-life, these IV dosing regimens are expected to not only result in stable plaque clearance, but also minimize the risk of ARIA by allowing the pause between doses. The pause may also allow MRI-identified ARIA observed between doses to resolve and/or stabilize before the next dose. The incidence of ARIA-E was generally higher in groups testing higher doses of remenitar administered intravenously; therefore, a titrated dosing regimen may reduce the incidence and severity of observed ARIA at a lower initial dose and induce stable amyloid plaque clearance at higher doses later in the titrated regimen.

The fixed-dose SC dosing regimen is expected to reach a steady-state Cmax after approximately 4 months of dosing. The SC dosing regimen provides a slower increase in serum concentrations compared to the IV dosing regimen and is similar to the serum concentrations of the adjusted regimen. It has been hypothesized that the lower Cmax and slower increase in serum concentrations may reduce the risk of ARIA (Hayato et al., 2020; Salloway et al., 2022); however, the incidence of ARIA-E was lower in participants who received less frequent subcutaneous dosing (800 mg Q4W compared to 400 mg QW), even though the initial dose was higher in the Q4W dosing regimen. Therefore, a titrated dosing regimen with subcutaneous administration was also investigated; it was hypothesized that a titrated dosing regimen initially with a lower starting dose and less frequent dosing might reduce the incidence and severity of observed ARIAs and, later in the titrated phase, lead to stable amyloid plaque clearance at higher doses and more frequent dosing. Example 11 : MRI Scheduling in a Phase 3 Clinical Trial of Participants with Early Symptomatic AD .

In all clinical trials investigating Remeneta, scheduled MRI brain scans were performed routinely to monitor for ARIA. In addition, unscheduled MRIs were performed when ARIA was suspected by the investigator.

All participants were required to have an MRI at screening to be eligible. Considering potential risk factors for ARIA, participants were excluded if their centrally read MRI at screening showed ARIA-E, major bleeding, more than 4 MCH, superficial cortical siderosis, or severe white matter disease (WMD).

MRI scans are read locally and sent to a centralized MRI provider for analysis. Specific analyses of the scans are interpreted by the centralized MRI provider for data analysis and reporting. Results of the centrally read MRIs related to participant care and safety are reported back to the investigators.

Study LAKC Open Label Appendix: The MRI schedules for Study LAKC (Appendix 1), Study LAKC (Appendix 3), Study LAKC (Appendix 4), and Study LAKC (Appendix 5) are listed below (Tables 9, 10, 11, and 12). Table 9 : Study LAKC ( Appendix 1) - Scheduled MRIs . Visit 1 2 5 6 7 8 9 10 11 ED 801 Weeks after random assignment screening 0 4 8 12 16 twenty four 36 52 Scheduled MRI X X X X X ED = Early Discontinuation; V801 is the scheduled MRI that must be performed before dosing and analyzed at the dosing visit. Table 10 : Study LAKC ( Appendix 3) - Scheduled MRI Visit 1 2 5 6 7 8 9 10 11 12 13 ED 801 Weeks after random assignment screening 0 4 8 12 16 twenty four 32 40 48 52 800 mg every 8 weeks X X X X X X X IV Setup #1 X X X X X X X IV Setup #2 X X X X X X X IV Setup #3 X X X X X X X X X ED = early discontinuation; V801 is follow-up. IV schedule 1 = 400 mg Q4W x 2; 400 mg Q8W x 1; 800 mg Q8W x 5. IV schedule 2 = 400 mg Q8W x 2; 800 mg Q8W x 5. IV schedule 3 = 200 mg Q8W x 2; 400 mg Q8W x 2; 800 mg Q8W x 3. A scheduled MRI must be performed before dosing and analyzed at the dosing visit. Table 11 : Study LAKC ( Appendix 4) - Scheduled MRI . Visit 1 2 3 4 5 6 7 9 10 11 ED 801 Weeks after random assignment screening 0 1 2 4 8 12 twenty four 36 52 Scheduled MRI X X X X X X ED = Early Discontinuation; V801 is Follow-up Visit; Must be performed before dosing and analyzed at the scheduled on-site dosing visit. Table 12 : Study LAKC ( Appendix 5) - SC Dosing Schedule and Scheduled MRI Visit 1 2 3 4 5 6 7 8 9 10 11 12 13 ED 801 Weeks after random assignment screening 0 4 8 12 16 twenty four 32 40 48 56 64 76 Scheduled MRI X X X X X X x X X ED = early discontinuation; V801 = follow-up visit; a scheduled MRI must be performed before dosing and analyzed at the on-site dosing visit.

The Study LAKC open-label appendix MRI schedule is designed to monitor participants for potential ARIA for safety and to inform dosing decisions for IV and SC dosing. An MRI performed at the 12-week pre-dose visit will provide information on the potential development of ARIA shortly after study drug administration and the impact of the initial dose. This early analysis will also provide information if a dosing hold is established to allow time for asymptomatic ARIA to resolve and/or stabilize before subsequent scheduled dosing.

For dosing schedules based on adjustments, MRIs were performed at visits before and after dose escalation or dosing frequency increases. These MRIs served a dual purpose: (1) to monitor for potential ARIA prior to dosing and to inform final dosing decisions as described in the ARIA Management Plan (next section), and (2) to examine the impact of dose escalation or frequency increases on the dosing schedule based on adjustments. Investigators were permitted to perform unscheduled MRIs if ARIA was suspected.

Study LAKC (primary protocol): The MRI schedule for Study LAKC (primary protocol) is listed below (Tables 13a and 13b). Table 13a : MRI schedule for Study LAKC ( primary protocol ; SC group ) . Visit 601 1 2 3 4 5 6 7 8 9 10 11 Weeks after random assignment screening 0 1 2 4 8 12 16 twenty four 36 52 Scheduled MRI X X X X X X Visit 12 13 14 15 16 17 18 19 20 ED 801 Weeks after random assignment 54 55 56 58 62 66 78 90 106 Scheduled MRI X X X X X A scheduled MRI must be performed before dosing and analyzed at the dosing visit. Table 13b : MRI Schedule for Study LAKC ( Primary Protocol ; Cohort IV ) . Visit 601 1 5 6 7 8 9 10 11 12 13 Weeks after random assignment screening 4 8 12 16 twenty four 32 40 48 52 Scheduled MRI X X X X X Visit 14 15 16 17 18 19 20 twenty one twenty two twenty three twenty four ED 801 Weeks after random assignment 54 58 62 66 70 78 86 90 94 102 106 -- -- Scheduled MRI X X X X A scheduled MRI must be performed prior to dosing and analyzed at the dosing visit.

The Study LAKC MRI schedule was designed to safely monitor participants for potential ARIA for both IV and SC dosing regimens; the effects of dose and frequency on the development of ARIA were previously described in the open-label safety appendix.

An MRI after the initial dosing visit will monitor for potential ARIA prior to dosing and inform final dosing decisions as described in the ARIA Management Plan (next section). These MRIs will also be used to continue monitoring for ARIA during the SC dosing regimen. Prior to crossover to the second 52-week study, an MRI at Week 52 will inform current ARIA status.

There were no scheduled MRIs after Visit 18 (Week 78, 24 weeks after crossover). As demonstrated in Studies LAKB and LAKC described herein, the potential risk of ARIA primarily occurs in the months prior to dosing. Investigators were permitted to perform unscheduled MRIs for suspected ARIA.

Study LAKD (Subcutaneous Administration): The MRI schedule for Study LAKD is listed below (Table 14). Table 14 : MRI Schedule for Study LAKD (SC Administration ) . Visit 601 1 2 3 4 5 6 7 8 9 10 11 12 Weeks after random assignment screening 0 1 2 4 8 12 twenty four 36 52 64 76 Scheduled MRI X X X X X Visit 13 14 15 16 17 18 19 20 twenty one ED 801 Weeks after random assignment 78 79 80 82 86 90 102 114 130 Scheduled MRI X X X

The study LAKD MRI schedule was designed to safely monitor potential ARIA in participants receiving the SC dosing regimen. Prior to crossover into the second 52 weeks of the study, an MRI at Week 76 informed the current ARIA status.

There were no scheduled MRIs after Visit 19 (Week 102, 24 weeks after crossover). As described in Studies LAKB and LAKC, the risk of ARIA primarily occurred in the months before dosing. Investigators were permitted to perform unscheduled MRIs for suspected ARIA.

Study LAKF (IV Administration): The MRI schedule for Study LAKF is listed below (Table 15). Table 15 : MRI Schedule for Study LAKF (IV Administration ) . Visit 601 1 2 3 4 5 7 9 12 13 14 Weeks after random assignment screening 0 4 8 12 twenty four 36 52 64 76 Scheduled MRI X X X X Visit 15 16 17 18 20 twenty two 25 ED V801 Weeks after random assignment 78 82 86 90 102 114 130 Scheduled MRI X X X MRI must be performed before dosing and analyzed at Visits 5, 7, 18, and 20.

The study LAKF MRI schedule was designed to safely monitor participants for potential ARIA during the IV dosing regimen. MRIs were performed prior to the second and third dosing of participants. These MRIs monitored for potential ARIA prior to dosing and informed the final dosing decision as described in the ARIA Management Plan (next section). Prior to crossover to dosing during the second 52 weeks of the study, an MRI at Week 76 informed participants of current ARIA status.

There were no scheduled MRIs after Visit 20 (Week 102, 24 weeks after crossover). As demonstrated in Studies LAKB and LAKC, the potential risk of ARIA primarily occurs in the months prior to dosing. Investigators were permitted to perform unscheduled MRIs for suspected ARIA. Example 12 : ARIA Management Plan for Studies LAKD and LAKF .

The development of ARIA-E and/or ARIA-H is an expected event and has occurred in some participants treated with Remeneta (observed in Studies LAKB and LAKC). Monitoring for ARIA (as detailed in the preceding section) is determined, in part, by scheduled MRIs. At the investigator's discretion, a single symptom suggestive of ARIA may warrant an unscheduled MRI. If a participant experiences more than one symptom suggestive of ARIA simultaneously, an unscheduled MRI will be performed.

Participants with SAEs related to treatment-emergent ARIA-E and/or ARIA-H and those who experienced one or more major bleeding episodes required permanent discontinuation of treatment.

Participants with treatment-emergent ARIA-E and/or ARIA-H may permanently discontinue study intervention therapy at the investigator's discretion and based on the severity of clinical and radiological findings.

The administration of the ARIA is fully detailed in the protocols for each clinical trial. The administration of the ARIA may be modified based on additional clinical trial data and/or changes in standard care; changes will be reflected in updates to the protocols and/or amendments to the clinical trial protocols. The ARIA administration plan for the ARIA-E is detailed in Table 16 below. Table 16 : ARIA-E administration plan. discover Symptoms MRI severity measure ARIA-E Asymptomatic Any severity The study intervention will be discontinued permanently after complete resolution of the disease. The study intervention may be restarted at the investigator's discretion. If there is no resolution before the end of the main study period, the study intervention will be permanently discontinued. Symptoms Any severity Study intervention will be discontinued after ARIA-E and related clinical symptoms have completely resolved. Study intervention may be restarted at the investigator's discretion. If ARIA-E or related symptoms have not resolved before the end of the primary study period, study intervention will be permanently discontinued. If ARIA-E or related symptoms are reported as a serious adverse event (SAE), study intervention will be permanently discontinued.

Complete resolution of ARIA-E (Table 14) is determined by the first MRI scan showing the absence of ARIA-E. In participants receiving the SC dosing regimen, injections should be resumed after resolution of ARIA-E and continued until the end of the study period. In participants receiving the IV dosing regimen, the investigator should consult with Lilly personnel on the time to resume IV dosing. Depending on the dosing regimen, infusions should not be performed less than 4 to 12 weeks apart, and all infusions must be completed before the end of the study period. Unscheduled visits may be required to administer missed infusions. The ARIA Management Plan for ARIA-H is detailed in Table 17 below. Table 17 : Management Plan for ARIA-H and Major Bleeding. discover Symptoms MRI severity measure ARIA-H MCH, superficial siderosis Asymptomatic ≤ 4 new MCH and/or 1 superficial siderosis relative to baseline If the intervention is stopped within 16 weeks of the start of drug administration, the intervention can be restarted at the discretion of the investigator after the ARIA-H imaging stabilizes. If the drug is administered 16 weeks or more after the start of the study, the drug may be continued at the discretion of the investigator. >4 new MCH and/or ≥2 superficial siderosis compared to baseline Study intervention discontinued. Study intervention may be restarted at the investigator's discretion after ARIA-H imaging stabilizes. If not stable before the end of the primary study period, study intervention will be permanently discontinued. Note: Participants who develop any treatment-emergent superficial siderosis during the primary study period are excluded from the extension period. Symptoms Any severity Study intervention discontinued. Study intervention may be restarted at the investigator's discretion after ARIA-H stabilizes and related clinical symptoms resolve. If ARIA-H is unstable or related symptoms do not resolve before the end of the primary study period, study intervention will be permanently discontinued. If ARIA-H or related symptoms are reported as a SAE, SI will be permanently discontinued. heavy bleeding Asymptomatic or symptomatic Any severity Permanently discontinue research intervention NOTE: Participants who developed any treatment-emergent superficial siderosis during the main study period were excluded from the extension period.

Stability of ARIA-H and/or major hemorrhage (Table 15) was defined as the first MRI scan showing the following: no new cSS or no increase in cSS size; no more than one new MCH; and/or no increase in size of major hemorrhage.

For mild to moderate symptoms associated with ARIA-E, oral or IV steroids may be considered on an outpatient basis. In cases of severe symptoms associated with ARIA-E, hospitalization for close observation is recommended, and IV steroids, such as high-dose dexamethasone, methylprednisolone, or similar agents (which can be converted to oral administration during outpatient care), may be considered. The following steroids were selected based on their high anti-inflammatory effects and lack of saliva-producing effects. Final treatment decisions are ultimately made by the investigator or treating physician. Example 13 : Evaluation of the safety, efficacy, and tolerability of Remeneta in preclinical Alzheimer's disease.

Remenetal will be studied in participants with preclinical Alzheimer's disease either as an addendum to Study AACM or as a standalone Phase 3 clinical trial. Study AACM (NCT05026866, clinicaltrials.gov, TRAILBLAZER-3) is an ongoing, multicenter, randomized, double-blind, placebo-controlled Phase 3 study evaluating the safety, tolerability, and efficacy of donetumab in participants with preclinical Alzheimer's disease.

The primary objective will be to assess whether treatment with Remeneta reduces clinical progression in participants with preclinical AD. Clinical progression will be assessed by a reduction in the progression from normal cognition to mild cognitive impairment (MCI)/dementia, measured using the Clinical Dementia Rating Global Score (CDR-GS) and time-to-event analysis. The primary outcome event will be time to clinical progression, measured by an increase in the CDR-GS from baseline between two consecutive visits (conversion). Participants will be tracked until a pre-specified number of participants experience the primary outcome event of clinical progression; therefore, the total duration of study participation will vary among participants and depend on the overall conversion rate.

Trial Design Summary: The clinical trial will be a multicenter, randomized, double-blind, placebo-controlled Phase 3 study of Remeneta in participants with preclinical AD. Participants meeting the inclusion criteria will be randomly assigned in a 1:1 ratio to receive either Remeneta or placebo.

Participants will receive the drug during the double-blind treatment phase until the end of the dosing period. Participants will then enter a double-blind observation phase with visits every 26 weeks for a maximum of 150 weeks.

Study Objective: The primary objective of this study will be to test the hypothesis that Remeneta is superior to placebo in reducing the time to clinical progression (as measured by the CDR-GS) in participants with preclinical AD. Key secondary objectives included describing the safety of Remeneta and testing the hypothesis that Remeneta is superior to placebo in slowing clinical progression as measured by the following scales: Statistical Analysis Plan (SAP), International Shopping List Test (ISLT), Continuous Paired Associate Learning (CPAL), International Daily Symbol Substitution Test (iDSSTm), Category Fluency, Face Name Association Test (FNAME), Behavioral Pattern Separation-Object Test (BPS-O), Cogstate Brief Scale (CBB), Clinical Dementia Rating-Sum (CDR-SB), Cognitive Functioning Index (CFI), and/or Montreal Cognitive Assessment (MoCA score).

Patient Population: In general, individuals are eligible for study participation if they: are 55 to 80 years old (inclusive), have TICS-M scores reflecting intact cognitive function, have biomarkers consistent with the presence of brain amyloid pathology, and/or have reliable research partners.

In general, individuals are excluded from study participation if they: Have mild impairment, dementia, or other CNS disease that affects cognition; Have any clinically important abnormality at screening that could adversely affect participation or potentially harm the study; and/or Have a current serious or unstable disease or condition that could interfere with study analysis.

Dose Adjustment: The dosing schedule for Remeneta will be selected based on the following factors: Safety and tolerability data from Phase 1 and Phase 3 studies, PK exposure-amyloid plaque analysis of all available data across a broad dose range, and/or The expectation that the fixed or adjusted dosing schedule will result in approximately 80% to 90% of participants achieving amyloid plaque clearance during treatment.

As part of the clinical trial, one of the following dosing schedules for Remeneta was administered: 2300 mg IV for two consecutive doses every 12 weeks, administered at Weeks 0 and 12. 1500 mg IV for three consecutive doses every 12 weeks, administered at Weeks 0, 12, and 24. 800 mg IV for five consecutive doses every 8 weeks, administered at Weeks 0, 8, 16, 24, and 32. 400 mg IV every 4 weeks for 3 consecutive doses at Weeks 0, 4, and 8, titrated up to 800 mg IV every 8 weeks for 3 or 4 consecutive doses at Weeks 16, 24, 32, and/or 40. 400 mg IV every 8 weeks for 2 consecutive doses at Weeks 0 and 8, titrated up to 800 mg IV every 8 weeks for 3 or 4 consecutive doses at Weeks 16, 24, 32, and/or 40. 400 mg IV every 4 weeks for 10 doses, administered at Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, and 36. 200 mg IV every 8 weeks for 2 doses, administered at Weeks 0 and 8, and adjusted every 8 weeks to a maximum of 400 mg IV for 2 doses, administered at Weeks 16 and 24, and adjusted every 8 weeks to a maximum of 800 mg IV for 3 or 4 doses, administered at Weeks 32, 40, 48, and/or 56. 100 mg SC every 8 weeks for 2 doses at Weeks 0 and 8, followed by 400 mg SC every 8 weeks for 2 doses at Weeks 16 and 24, followed by 800 mg SC every 8 weeks for 2 doses at Weeks 32 and 40, followed by 800 mg SC every 4 weeks for up to 7 doses (e.g., doses administered at Weeks 44, 48, 52, 56, 60, 64, 68, and 72). 200 mg SC once every 8 weeks, administered at Week 0, followed by 400 mg SC twice every 8 weeks, administered at Weeks 8 and 16, followed by 800 mg SC once every 8 weeks, administered at Week 24, followed by 800 mg SC every 4 weeks for 9 to 11 doses (e.g., administered at Weeks 28, 31, 36, 40, etc., until at least Week 64 or up to Week 72). 400 mg SC every 8 weeks for 2 doses at Weeks 0 and 8, followed by 800 mg SC every 8 weeks for 1 dose at Week 16, followed by 800 mg SC every 4 weeks for 8 to 13 doses (e.g., administered at Weeks 20, 24, 28, 32, 36, 40, etc. until at least Week 48 or up to Week 72). 400 mg SC every 12 weeks for 21 doses, administered at Weeks 0 and 12, followed by 800 mg SC every 8 weeks for 1 dose at Week 20, followed by 800 mg SC every 4 weeks for 9 to 11 doses (e.g., administered at Weeks 24, 28, 32, 36, 40, etc. until at least Week 64 or up to Week 72). 400 mg SC weekly for 25 doses at Weeks 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24. 800 mg SC every 4 weeks for 10 doses at Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, and 36. 400 mg SC every 4 weeks for 3 doses at Weeks 0, 4, and 8, and titrated every 4 weeks to a maximum of 800 mg SC for 8 doses at Weeks 12, 16, 20, 24, 28, 32, 36, and 40.

In a trial design of Remeneta in preclinical AD, MRI scheduling can be designed to safely monitor participants for potential ARIA in one or more IV or SC dosing regimens. Investigators will be able to perform unscheduled MRIs to test for ARIA at any time throughout the study or after suspected ARIA. Example 14. Use of Remeneta for preventing or delaying the onset of Alzheimer's disease.

Remeneta can be used substantially as described herein to prevent or delay the onset or progression of Alzheimer's disease. According to some embodiments, such patients may be at risk for AD. For example, the patient may have a family history of AD and/or be at risk as identified by biomarkers of AD pathology. Additionally, Remeneta can be used substantially as described herein to prevent or delay the onset or progression of Alzheimer's disease in patients who are homozygous or heterozygous for APOE ε4 and/or in patients with a dominantly inherited (also known as autosomal dominant) AD genetic profile. Additionally, remenergic can be used as maintenance therapy to prevent or delay the progression of AD after treatment with Aβ-lowering/Aβ-eliminating disease-modifying therapies, such as donetumor, remenergic, Leqembi® (ramcanezumab), or Aduhelm® (aducanemab). For example, in embodiments, for patients with dominantly inherited AD, patients with a family history of AD, or other at-risk populations with identified biomarkers of AD pathology, after treatment with any Aβ-lowering/Aβ-clearing disease-modifying therapy, and/or patients who have previously been treated with an Aβ-lowering/Aβ-clearing disease-modifying therapy and have cleared Aβ plaques below a specific level (e.g., 24% myoblastoid starch value), Remenita may be administered as follows: About 200 mg or about 400 mg subcutaneously every 12 weeks for long-term administration (e.g., up to 72 weeks or 76 weeks); About 200 mg or about 400 mg subcutaneously every 12 weeks for 5 consecutive doses, followed by about 400 mg subcutaneously every 8 weeks. mg, long-term administration (e.g., up to 72 or 76 weeks); About 200 mg or about 400 mg by subcutaneous injection for 5 consecutive doses every 12 weeks, followed by about 400 mg and/or about 800 mg by subcutaneous injection every 8 or 12 weeks for long-term administration (e.g., up to 72 or 76 weeks).

Additional embodiments may include use primarily for the prevention of AD in at-risk populations with known homozygous or heterozygous APOE ε4 genetic profiles and/or other biomarkers of AD pathology, wherein Remenita may be administered as follows: About 200 mg subcutaneously every 26 weeks for long-term administration (e.g., up to 72 weeks or 76 weeks); About 200 mg subcutaneously every 52 weeks for long-term administration (e.g., up to 72 weeks or 76 weeks); About 400 mg subcutaneously every 26 weeks for long-term administration (e.g., up to 72 weeks or 76 weeks); About 400 mg subcutaneously every 52 weeks for long-term administration (e.g., up to 72 weeks or 76 weeks); About 600 mg subcutaneously every 26 weeks for long-term administration (e.g., up to 72 or 76 weeks); or About 600 mg subcutaneously every 52 weeks for long-term administration (e.g., up to 72 or 76 weeks).

Additional embodiments may include use as a maintenance therapy following treatment with Aβ-lowering/Aβ-clearing disease-modifying therapy to prevent progression of Aβ pathology. According to such embodiments, Remeneta may be administered according to the dosing regimen described in Example 14 provided herein. References ( each of which is incorporated herein by reference in its entirety ) : Arrighi H, Barakos J, Barkhof F, et al. Amyloid-related imaging abnormalities-haemosiderin (ARIA-H) in patients with Alzheimer's disease treated with bapineuzumab: a historical, prospective secondary analysis. J Neurol Neurosurg Psychiatry 2016;8 7:106-112 Bretz F, Maurer W, Brannath W, Posch M. A graphical approach to sequentially rejective multiple test procedures. Stat Med . 2009;28(4):586-604 Bretz F, Posch M, Glimm E, et al. Graphical approaches for multiple comparison procedures using weighted Bonferroni, Simes, or parametric tests. Biom J . 2011;53(6):894-913 Carlson, C, Siemers, E, Hake, A et al. Amyloid-related imaging abnormalities from trials of solanezumab for Alzheimer's disease. Alzheimer 's & Dementia 2016; 2(2): 75-85 Clark CM, Schneider JA, Bedell BJ, et al. Use of florbetapir-PET for imaging beta-amyloid pathology. JAMA . Incidence of cerebral microbleeds: a longitudinal study in a memory clinic population. Neurology 2010;74: 1954-60 Hayato S, Reyderman L, Zhang Y, et al. OC14: BAN2401 and ARIA-E in early Alzheimer's disease: pharmacokinetic / pharmacodynamic time-to-event analysis from the phase 2 study in early Alzheimer's disease. J. Prev. Alzheimer's Dis. 2020;7(Suppl 1): 2-54 Klunk WE, Koeppe RA, Price JC, et al. The Centiloid Project: standardizing quantitative amyloid plaque estimation by PET. Alzheimer's Dement . 2015 Jan;11(1):1-15.e1-4 Fleisher, A., Pontecorvo, M., Devous, M et al., “Positron Emission Tomography Imaging With [18F]flortaucipir and Postmortem Assessment of Alzheimer Disease Neuropathologic Changes,” JAMA Neurol . 2020; 77(7):829-839 [FDA] United States Food and Drug Administration. Estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers. July 2005. Accessed 01, July 2022. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/estimating-maximum-safe-starting-dose-initial-clinical-trials-therapeutics-adult-healthy-volunteers. Mintun MA, Lo AC, Evans CD, et al. Donanemab in early Alzheimer's disease. N Eng J Med. 2021;384(18):1691-1704 Navitsky M, Joshi AD., Kennedy I. Standardization of amyloid quantitation with florbetapir standardized uptake value Incidence of cerebral microbleeds in the general population : the Rotterdam Scan Study Stroke 2011 42(3): 656-61 Salloway S, Chalkias S, Barkhof F, et al. Amyloid-related imaging abnormalities in 2 phase 3 studies evaluating aducanumab in patients with early Alzheimer disease. JAMA Neurol. 2022;79(1):13-21 Sperling R, Salloway, S, Broos, D et al. Amyloid-related imaging abnormalities in patients with Alzheimer's disease treated with bapineuzumab: a retrospective analysis. Lancet Neurol 2012;11: 241-9 A Study of LY3372993 in Participants With Alzheimer's Disease (AD) and Healthy Participants (Clinical Trial No.: NCT04451408) https://clinicaltrials.gov/ct2/show/NCT04451408?term=LY3372993&draw=2&rank=1 in Healthy Participants and Participants With Alzheimer's Disease (AD) (Clinical Trial No.: NCT03720548) https://clinicaltrials.gov/ct2/show/NCT04451408?term=LY3372993&draw=2&rank=1 A Study of Remternetug (LY3372993) in Participants With Alzheimer's Disease (TRAILRUNNER-ALZ 1) (Clinical Trial No.: NCT05463731) https://clinicaltrials.gov/ct2/show/NCT05463731?term=LY3372993&draw=2&rank=3 US Patent No. 8,679,498 US Patent No. 8,961,972 US Patent No. 11,312,763 US Patent No. 10,647,759 US Patent No. 11,078,261 US Patent Application No. 17/711,099 International Patent Application No. PCT/US2022/011894 US Patent Application No. 17/391,821 Exemplary Embodiment 1. A method for treating or preventing amyloid beta in the brain of a human subject in need thereof A method for treating a disease characterized by accumulation of Aβ plaques, comprising: administering to the subject one or more intravenous (IV) doses of about 20 mg to about 3000 mg of an anti-N3pGlu Aβ antibody at a frequency of: i) about every twelve weeks (Q12W); ii) about every eight weeks (Q8W); or iii) about every four weeks (Q4W); wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 8 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 7. 2. The method of embodiment 1, wherein the antibody is administered to the subject in one or more doses for a duration sufficient to treat or prevent the disease. 3. The method of embodiment 1 or 2, wherein the antibody is administered until the Aβ plaques in the brain of the human subject are cleared. 4. The method of embodiment 1, wherein the antibody is administered until at least one of the following occurs: i) the Aβ plaques in the brain of the human subject are 24.1% amyloid count or less as measured by two consecutive amyloid PET imaging scans, wherein the two consecutive amyloid PET imaging scans are at least 6 months apart; or ii) the Aβ plaques in the brain of the human subject are 11% amyloid count or less as measured by a single amyloid PET imaging scan. 5. The method of embodiment 1 or 2, wherein the antibody is administered until the subject is amyloid negative. 6. The method of embodiment 1 or 2, wherein the antibody is administered until an Aβ plaque level of ≤24.1 percentile amyloid value is achieved as measured by amyloid PET imaging scan. 7. The method of embodiment 1, wherein the antibody is administered to the subject in a dose of about one to about 20 doses or a dose of about one to about 10 doses. 8. The method of embodiment 1, wherein the antibody is administered to the subject in a dose of about three to about seven doses. 9. The method of embodiment 1, wherein the antibody is administered to the subject in a dose of about 250 mg to about 2800 mg. 10. The method of Example 1, wherein at least two sub-doses of about 2300 mg of the antibody are administered to the subject at a frequency of about once every twelve weeks (Q12W). 11. The method of Example 10, wherein two sub-doses of about 2300 mg of the antibody are administered to the subject at a frequency of about once every twelve weeks. 12. The method of Example 11, wherein the subject has preclinical AD. 13. The method of Example 11, wherein three doses of about 2300 mg of the antibody are administered to the subject at a frequency of about once every twelve weeks. 14. The method of Example 13, wherein the subject has early symptomatic AD. 15. The method of Example 1, wherein the subject is administered at least two doses of about 1500 mg of the antibody at a frequency of about once every twelve weeks (Q12W). 16. The method of Example 15, wherein the subject is administered three doses of about 1500 mg of the antibody at a frequency of about once every twelve weeks. 17. The method of Example 16, wherein the subject has preclinical AD. 18. The method of Example 15, wherein the subject is administered four doses of about 1500 mg of the antibody at a frequency of about once every twelve weeks. 19. The method of Example 18, wherein the subject has early symptomatic AD. 20. The method of embodiment 1, wherein at least two doses of about 800 mg of the antibody are administered to the subject at a frequency of about once every 8 weeks (Q8W). 21. The method of embodiment 20, wherein about 5 to about 7 doses of about 800 mg of the antibody are administered to the subject at a frequency of about once every 8 weeks. 22. The method of embodiment 21, wherein about 5 doses, about 6 doses, or about 7 doses of the antibody are administered to the subject. 23. The method of embodiment 1, wherein at least two doses of about 800 mg of the antibody are administered to the subject at a frequency of about once every 4 weeks (Q4W). 24. The method of embodiment 23, wherein about 800 mg of the antibody is administered to the subject in about 5 to about 7 doses at a frequency of about once every 4 weeks. 25. The method of embodiment 24, wherein about 5 doses, about 6 doses, or about 7 doses are administered to the subject. 26. The method of any one of embodiments 1 to 25, wherein the disease characterized by Aβ plaques 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 syndrome, clinical amyloid vasculopathy, and preclinical amyloid vasculopathy. 27. The method of embodiment 1, wherein the disease is preclinical AD. 28. The method of embodiment 1, wherein the disease is early symptomatic AD, prodromal AD, or mild dementia caused by AD. 29. The method of any of the above embodiments, wherein treating or preventing the disease results in i) a reduction in Aβ plaques in the brain of the human subject; ii) a slowing of cognitive decline in the human subject; or iii) a slowing of functional decline in the human subject. 30. The method of embodiment 29, wherein the reduction in Aβ plaques in the brain of the human subject is determined by amyloid positron emission tomography (PET) brain imaging or diagnostics that detect Aβ or an Aβ biomarker. 31. The method of any of the above embodiments, wherein administration of the antibody does not cause an amyloid-associated imaging abnormality (ARIA) event in the individual. 32. The method of any of the above embodiments, wherein administration of the antibody does not cause a symptomatic ARIA event in the individual. 33. The method of embodiment 1, further comprising the steps of evaluating a magnetic resonance imaging (MRI) scan of the individual's brain to determine ARIA after administration of at least one dose of the antibody, and modifying the administration step until the ARIA has resolved. 34. The method of embodiment 33, wherein administration of the antibody is temporarily withheld or interrupted if symptoms consistent with ARIA develop. 35. The method of embodiment 33, wherein administration of the antibody is temporarily withheld if symptoms consistent with mild to moderate ARIA develop. 36. The method of embodiment 33, wherein administration of the anti-N3pGlu Aβ antibody is discontinued if symptoms consistent with severe or symptomatic ARIA develop. 37. The method of any of the above embodiments, wherein the anti-N3pGlu Aβ antibody comprises a LC and a HC, wherein the LC comprises the amino acid sequence of SEQ ID NO: 10 and the HC comprises the amino acid sequence of SEQ ID NO: 9. 38. The method of any of the above embodiments, wherein the anti-N3pGlu Aβ antibody comprises two light chains and two heavy chains, wherein the LC comprises the amino acid sequence of SEQ ID NO: 10 and the HC comprises the amino acid sequence of SEQ ID NO: 9. 39. The method of embodiment 1, wherein prior to administration of the antibody, the individual's brain tau level is less than 1.46 normalized take-up value ratio (SUVr), wherein the brain tau level is measured by a tau PET imaging scan. 40. The method of embodiment 1, wherein prior to administration of the antibody, the individual's brain tau level is greater than 1.10 SUVr and less than 1.46 SUVr, wherein the brain tau level is measured by a tau PET imaging scan. 41. The method of embodiment 39 or embodiment 40, wherein brain tau level is measured by ¹⁸ F-fluroxipyr PET imaging. 42. The method of embodiment 1, wherein the individual has at least one APOE4 allele. 43. The method of any of the preceding embodiments, wherein the antibody is administered to the human subject in an amount until the Aβ plaques in the brain of the human subject are reduced by i) an average of about 25 percentile starch value to about 100 percentile starch value, ii) an average of about 50 percentile starch value to about 100 percentile starch value, or iii) about 100 percentile starch value, or iv) about 84 percentile starch value. 44. The method of any one of the preceding embodiments, wherein the antibody is administered to the human subject in an amount until the Aβ plaques in the brain of the human subject are reduced by i) about 25 percentile starch value to about 100 percentile starch value, or ii) about 50 percentile starch value to about 100 percentile starch value. 45. A method for treating or preventing a disease characterized by deposition of amyloid beta plaques in the brain of a human individual in need thereof, comprising: administering to the individual one or more subcutaneous doses of about 20 mg to about 1000 mg of an anti-N3pG Aβ antibody at the following frequencies: i) about once a week (Q1W); ii) about once every two weeks (Q2W); or iii) about once every four weeks (Q4W); wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 8 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 7. 46. The method of embodiment 45, wherein one or more doses of the antibody are administered to the subject for a duration sufficient to treat or prevent the disease. 47. The method of embodiment 45 or 46, wherein the antibody is administered until the Aβ plaques in the brain of the human subject are cleared. 48. The method of embodiment 45, wherein the antibody is administered until at least one of the following occurs: i) the Aβ plaques in the brain of the human subject are at an Aβ percentage of 24.1% or less as measured by two consecutive Aβ PET scans, wherein the two consecutive Aβ PET scans are at least 6 months apart, or ii) the Aβ plaques in the brain of the human subject are at an Aβ percentage of 11% or less as measured by a single Aβ PET scan. 49. The method of embodiment 45 or 46, wherein the antibody is administered until the subject is negative for Aβ. 50. The method of embodiment 45 or 46, wherein the antibody is administered until an Aβ plaque level of ≤24.1 percentile amyloid value is achieved as measured by amyloid PET imaging scan. 51. The method of embodiment 45, wherein the antibody is administered to the subject in a range of about one dose to about 100 doses. 52. The method of embodiment 45, wherein 24 doses are administered to the subject. 53. The method of embodiment 45, wherein 36 doses are administered to the subject. 54. The method of embodiment 45, wherein 52 doses are administered to the subject. 55. The method of embodiment 45, wherein 76 doses are administered to the subject. 56. The method of embodiment 45, wherein the antibody is administered to the subject in an amount of about 250 mg to about 500 mg. 57. The method of embodiment 45, wherein 400 mg of the antibody is administered to the subject about once a week (Q1W) for 24 weeks or once a week for 36 weeks. 58. The method of embodiment 45, wherein 400 mg of the antibody is administered to the subject about once every two weeks (Q2W) for 36 weeks, 52 weeks, or 76 weeks. 59. The method of any one of Examples 45 to 58, wherein the disease characterized by Aβ plaques in the brain of the human subject is selected from preclinical AD, clinical AD, prodromal AD, mild AD, moderate AD, severe AD, Down syndrome, clinical amyloid vasculopathy, and preclinical amyloid vasculopathy. 60. The method of Example 45, wherein the disease is preclinical AD. 61. The method of Example 60, wherein the antibody is administered to the subject in an amount of about 1 to about 24 doses of 400 mg once weekly. 62. The method of embodiment 60, wherein the subject is administered about one to about 26 doses of 400 mg of the antibody once every two weeks. 63. The method of embodiment 62, wherein the subject is administered 18 or 26 doses of the antibody. 64. The method of embodiment 45, wherein the disease is early symptomatic AD, prodromal AD, or mild dementia due to AD. 65. The method of embodiment 45, wherein the disease is early symptomatic AD. 66. The method of embodiment 65, wherein the subject is administered about one to about 36 doses of 400 mg of the antibody once per week. 67. The method of embodiment 65, wherein the subject is administered about one dose to about 38 doses of 400 mg of the antibody at a frequency of once every two weeks. 68. The method of embodiment 67, wherein the subject is administered 26 doses or 38 doses of the antibody. 69. The method of any of the above embodiments, wherein administration of the antibody does not cause an amyloid-associated imaging abnormality (ARIA) event in the subject. 70. The method of any of the above embodiments, wherein administration of the antibody does not cause a symptomatic ARIA event in the subject. 71. The method of embodiment 45, further comprising the step of evaluating the individual's brain for ARIA by magnetic resonance imaging (MRI) scan after administration of at least one dose of the antibody, and modifying the administration step until the ARIA has resolved. 72. The method of embodiment 71, wherein administration of the antibody is temporarily withheld or interrupted if symptoms consistent with ARIA develop. 73. The method of embodiment 72, wherein administration of the antibody is temporarily withheld if symptoms consistent with mild to moderate ARIA develop. 74. The method of embodiment 72, wherein administration of the anti-N3pGlu Aβ antibody is interrupted if symptoms consistent with severe or symptomatic ARIA develop. 75. The method of any of the above embodiments, wherein the anti-N3pGlu Aβ antibody comprises a LC and a HC, wherein the LC comprises the amino acid sequence of SEQ ID NO: 10 and the HC comprises the amino acid sequence of SEQ ID NO: 9. 76. The method of any of the above embodiments, wherein the anti-N3pGlu Aβ antibody comprises two light chains and two heavy chains, wherein the LC comprises the amino acid sequence of SEQ ID NO: 10 and the HC comprises the amino acid sequence of SEQ ID NO: 9. 77. The method of any of the above embodiments, wherein treating or preventing the disease results in i) a reduction in Aβ plaques in the brain of the human individual; ii) a slowing of cognitive decline in the human individual; or iii) a slowing of functional decline in the human individual. 78. The method of embodiment 77, wherein the reduction of Aβ plaques in the brain of the human subject is determined by amyloid PET brain imaging or diagnostics that detect Aβ or a biomarker of Aβ. 79. The method of embodiment 45, wherein prior to administration of the antibody, the subject's brain tau level is less than 1.46 standardized uptake value ratio (SUVr), wherein the brain tau level is measured by a tau PET imaging scan. 80. The method of embodiment 45, wherein prior to administration of the antibody, the subject's brain tau level is greater than 1.10 SUVr and less than 1.46 SUVr, wherein the brain tau level is measured by a tau PET imaging scan. 81. The method of embodiment 79 or embodiment 80, wherein brain tau levels are measured by ¹⁸ F-fluroxipyr PET imaging. 82. The method of embodiment 45, wherein the individual has at least one APOE4 allele. 83. The method of any of the above embodiments, wherein the antibody is administered to the human individual at a dose until the Aβ plaques in the brain of the human individual are reduced by i) an average of about 25 percentile starch value to about 100 percentile starch value, ii) an average of about 50 percentile starch value to about 100 percentile starch value, or iii) about 100 percentile starch value, or iv) about 84 percentile starch value. 84. The method of any one of the preceding embodiments, wherein the antibody is administered to the human subject in an amount until the Aβ plaques in the brain of the human subject are reduced by i) about 25 percentile starch value to about 100 percentile starch value, or ii) about 50 percentile starch value to about 100 percentile starch value. 85. A method for reducing amyloid beta plaques in the brain of a human subject in need thereof, comprising: administering to the subject one or more intravenous doses of about 20 mg to about 3000 mg of an anti-N3pG Aβ antibody at the following frequencies: i) about once every twelve weeks; ii) about once every eight weeks; or iii) about once every four weeks; wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 8 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 7. 86. A method for reducing amyloid beta in the brain of a human individual in need thereof, comprising: administering to the individual one or more subcutaneous doses of about 20 mg to about 1000 mg of an anti-N3pG Aβ antibody at the following frequencies: i) about once a week; ii) about once every two weeks; or iii) about once every four weeks; wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 8 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 7. 87. A method for slowing the progression of Alzheimer's disease (AD) in a human subject in need thereof, comprising: administering to the subject one or more intravenous doses of about 20 mg to about 3000 mg of an anti-N3pG Aβ antibody at the following frequencies: i) about once every twelve weeks; ii) about once every eight weeks; or iii) about once every four weeks; wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 8 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 7. 88. A method for slowing the progression of Alzheimer's disease (AD) in a human subject in need thereof, comprising: administering to the subject one or more subcutaneous doses of about 20 mg to about 1000 mg of an anti-N3pG Aβ antibody at the following frequencies: i) about once a week; ii) about once every two weeks; or iii) about once every four weeks; wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 8 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 7. 89. An improved method for reducing amyloid beta in the brain of a human subject in need thereof, comprising: i) administering to the subject one to three IV doses of 2300 mg of an anti-N3pGlu Aβ antibody once every 12 weeks (Q12W); ii) administering to the subject one to four IV doses of 1500 mg of the anti-N3pGlu Aβ antibody once every 12 weeks (Q12W); or iii) administering to the subject one to seven IV doses of 800 mg of the anti-N3pGlu Aβ antibody once every 8 weeks (Q8W); wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR is represented by SEQ ID NO: The HCVR consists of the amino acid sequence of SEQ ID NO: 7. 90. An improved method for reducing amyloid beta in the brain of a human AD subject in need thereof, comprising: i) administering to the subject one to 36 SC doses of 400 mg of an anti-N3pGlu Aβ antibody once weekly (Q1W); ii) administering to the subject one to 26 SC doses of 400 mg of the anti-N3pGlu Aβ antibody once every 2 weeks (Q2W); or iii) administering to the subject one to 38 SC doses of 400 mg of the anti-N3pGlu Aβ antibody once every 2 weeks (Q2W); wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR is represented by SEQ ID NO: XX and the HCVR consists of the amino acid sequence of SEQ ID NO: XX. 91. The method of any one of embodiments 85 to 90, further comprising the step of evaluating a magnetic resonance imaging (MRI) scan of the individual's brain for amyloid-associated imaging abnormality (ARIA) after administration of a dose of the anti-N3pGlu Aβ antibody, wherein further administration of the dose is temporarily discontinued if symptoms consistent with ARIA appear. 92. The method of embodiment 91, wherein administration of the additional dose is resumed after resolution of ARIA symptoms or stabilization of radiographic findings on MRI. 93. The method of embodiment 91, wherein the additional dose is discontinued and a corticosteroid is administered to the individual. 94. The method of any one of embodiments 85 to 90, further comprising the step of evaluating a magnetic resonance imaging (MRI) scan of the subject's brain after administration of the dose to determine amyloid-associated imaging abnormality (ARIA), wherein further administration of the dose is interrupted if symptoms consistent with severe or symptomatic ARIA develop. 95. The method of embodiment 94, wherein administration of the additional dose is resumed after resolution of ARIA symptoms or stabilization of radiographic findings on MRI. 96. The method of embodiment 94, wherein the additional dose is discontinued and, optionally, a corticosteroid is administered to the subject. 97. The method of embodiment 94, wherein further administration of the dose is interrupted and, optionally, a corticosteroid is administered to the subject. 98. A method of treating Alzheimer's disease in a subject in need thereof until symptoms consistent with ARIA-E develop, comprising: i) administering to the subject one or more intravenous doses of about 20 mg to about 3000 mg of an anti-N3pG Aβ antibody about once every twelve weeks, about once every eight weeks, or about once every four weeks; or ii) administering to the subject one or more subcutaneous doses of about 20 mg to about 1000 mg of an anti-N3pG Aβ antibody about once every week, about once every two weeks, or about once every four weeks; wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 8 and a nucleotide sequence comprising SEQ ID NO: 99. The method of embodiment 98, wherein the symptoms of ARIA are detected or manifested in the individual by MRI. 100. A method of treating a patient with Remeneta, wherein the patient suffers from Alzheimer's disease, comprising the steps of: a) administering to the subject [or having administered] i) one or more intravenous doses of about 20 mg to about 3000 mg of an anti-N3pG Aβ antibody at a frequency of about once every twelve weeks, about once every eight weeks, or about once every four weeks; or ii) one or more subcutaneous doses of about 20 mg to about 1000 mg of an anti-N3pG Aβ antibody at a frequency of about once every week, about once every two weeks, or about once every four weeks; b) i) determining whether the patient has symptoms of ARIA-E by performing or having performed an MRI after administration of the antibody, or ii) if clinical symptoms consistent with ARIA-E develop; and c) temporarily interrupting treatment with Remeneta if the patient has moderate symptoms of ARIA-E; and d) if the patient does not have symptomatic ARIA-E, administering Remeneta to the patient until brain amyloid is cleared, the patient is negative for amyloid, or has a degraded amyloid value of <24.1%. 101. An improved method of treating a patient with Remeneta, wherein the patient suffers from Alzheimer's disease, wherein the improvement comprises: a) administering [or having administered] to the subject i) one or more intravenous doses of about 20 mg to about 3000 mg of an anti-N3pG Aβ antibody at a frequency of about once every twelve weeks, about once every eight weeks, or about once every four weeks; or ii) one or more subcutaneous doses of about 20 mg to about 1000 mg of an anti-N3pG Aβ antibody at a frequency of about once every week, about once every two weeks, or about once every four weeks; b) i) determining whether the patient has symptoms of ARIA-E by performing or having performed an MRI after administration of the antibody, or ii) if clinical symptoms consistent with ARIA-E develop; and c) temporarily interrupting treatment with Remeneta if the patient has moderate symptoms of ARIA-E; and d) if the patient does not have symptomatic ARIA-E, administering Remeneta to the patient until brain amyloid is cleared, the patient is negative for amyloid, or has a degraded amyloid value of <24.1%. 102. A method of treating a patient with Remeneta, wherein the patient suffers from Alzheimer's disease, comprising the steps of: a) administering [or having administered] to the subject i) one or more intravenous doses of about 20 mg to about 3000 mg of an anti-N3pG Aβ antibody about once every twelve weeks, about once every eight weeks, or about once every four weeks; or ii) one or more subcutaneous doses of about 20 mg to about 1000 mg of an anti-N3pG Aβ antibody about once every week, about once every two weeks, or about once every four weeks; b) interrupting treatment if the patient has symptoms of moderate ARIA-E; and c) Once ARIA-E resolves, treatment is continued by administering Remeneta to the patient until brain amyloid is cleared, becomes negative, <24.1 CL, or ARIA-E symptoms reappear. 103. The method of embodiment 102, wherein the symptoms or ARIA-E are confirmed or determined by MRI scan. 104. A method of treating a patient with Remeneta, wherein the patient suffers from Alzheimer's disease, the method comprising the steps of: a) administering [or having administered] to the subject i) one or more intravenous doses of about 20 mg to about 3000 mg of an anti-N3pG Aβ antibody at a frequency of about once every twelve weeks, about once every eight weeks, or about once every four weeks; or ii) one or more subcutaneous doses of about 20 mg to about 1000 mg of an anti-N3pG Aβ antibody at a frequency of about once every week, about once every two weeks, or about once every four weeks; b) continuing treatment with Remeneta until brain amyloid is cleared, negative, or <24.1 CL, as long as the patient does not have symptomatic ARIA-E. 105. The method of embodiment 104, wherein the symptoms or ARIA-E are confirmed or determined by MRI scanning. 106. A method for treating or preventing early symptomatic Alzheimer's disease in a human subject in need thereof, comprising: a. administering to the subject three doses of 2300 mg of an anti-N3pGlu Aβ antibody once every 12 weeks (Q12W); b. administering to the subject four doses of 1500 mg of the antibody once every 12 weeks (Q12W); c. administering to the subject seven doses of 800 mg of the antibody once every 8 weeks (Q8W); d. administering to the subject three doses of 400 mg of the antibody once every 4 weeks (Q4W); mg of the antibody, followed by five doses of 800 mg of the antibody administered to the subject at a frequency of once every 8 weeks (Q8W); or e. thirteen doses of 400 mg of the antibody administered to the subject at a frequency of once every 8 weeks (Q8W); wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 8 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 7, and each dose is administered intravenously. 107. A method for treating or preventing early symptomatic Alzheimer's disease in a human subject in need thereof, comprising: a. administering to the subject thirty-six doses of 400 mg of an anti-N3pGlu Aβ antibody at a frequency of once per week (Q1W); b. administering to the subject thirteen doses of 800 mg of the antibody at a frequency of once every four weeks (Q4W); or c. administering to the subject three doses of 400 mg of the antibody at a frequency of once every four weeks (Q4W), followed by ten doses of 800 mg of the antibody at a frequency of once every four weeks (Q4W); wherein the anti-N3pGlu Aβ antibody comprises SEQ ID NO: 8 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 7, and each dose was administered subcutaneously. 108. A method for treating or preventing preclinical Alzheimer's disease in a human subject in need thereof, comprising: a. administering to the subject two doses of 2300 mg of an anti-N3pGlu Aβ antibody once every 12 weeks (Q12W); b. administering to the subject three doses of 1500 mg of the antibody once every 12 weeks (Q12W); c. administering to the subject five doses of 800 mg of the antibody once every 8 weeks (Q8W); d. administering to the subject three doses of 400 mg of the antibody once every 4 weeks (Q4W); mg of the antibody, followed by three doses of 800 mg of the antibody at a frequency of once every 8 weeks (Q8W); e. three doses of 400 mg of the antibody at a frequency of once every 4 weeks (Q4W), followed by four doses of 800 mg of the antibody at a frequency of once every 8 weeks (Q8W); or f. ten doses of 400 mg of the antibody at a frequency of once every 8 weeks (Q8W); wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 8 and a CRISPR-Cas9 antibody comprising SEQ ID NO: 7 amino acid sequence in a heavy chain variable region (HCVR), and wherein each dose is administered intravenously. 109. A method for treating or preventing preclinical Alzheimer's disease in a human subject in need thereof, comprising: a. administering to the subject twenty-five doses of 400 mg of an anti-N3pGlu Aβ antibody at a frequency of once per week (Q1W); b. administering to the subject ten doses of 800 mg of the antibody at a frequency of once every four weeks (Q4W); or c. administering to the subject three doses of 400 mg of the antibody at a frequency of once every four weeks (Q4W), followed by eight doses of 800 mg of the antibody at a frequency of once every four weeks (Q4W); wherein the anti-N3pGlu Aβ antibody comprises SEQ ID NO: 8 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 7, and each dose was administered subcutaneously. 110. The method of any one of embodiments 106 to 109, wherein after administration is completed, at least one of the following occurs: a. the Aβ plaques in the brain of the human individual are at a 24.1 percent amyloid value or less as measured by two consecutive amyloid PET imaging scans, wherein the two consecutive amyloid PET imaging scans are at least 6 months apart; b. the individual is amyloid negative; c. the Aβ plaques in the brain of the human individual are at a 11 percent amyloid value or less as measured by a single amyloid PET imaging scan. 111. The method of any one of embodiments 106 to 110, wherein treating or preventing the disease results in i) a reduction in Aβ plaques in the brain of the human individual; ii) a slowing of cognitive decline in the human individual; or iii) a slowing of functional decline in the human individual. 112. The method of embodiment 111, wherein the reduction in Aβ plaques in the brain of the human individual is determined by amyloid PET brain imaging or diagnostics that detect Aβ or a biomarker of Aβ. 113. The method of any one of embodiments 106 to 112, wherein administration of the antibody does not cause an amyloid-associated imaging abnormality (ARIA) event in the individual. 114. The method of any one of embodiments 106 to 113, wherein administration of the antibody does not cause a symptomatic ARIA event in the individual. 115. The method of any one of embodiments 106 to 109, further comprising the step of evaluating a magnetic resonance imaging (MRI) scan of the individual's brain to determine ARIA after administration of at least one dose of the antibody, and modifying the administration step until ARIA has resolved. 116. The method of embodiment 115, wherein administration of the antibody is temporarily withheld or interrupted if symptoms consistent with ARIA develop. 117. The method of embodiment 115, wherein administration of the antibody is temporarily withheld if symptoms consistent with mild to moderate ARIA develop. 118. The method of embodiment 115, wherein administration of the anti-N3pGlu Aβ antibody is discontinued if symptoms consistent with severe or symptomatic ARIA develop. 119. The method of any one of embodiments 106 to 118, wherein the anti-N3pGlu Aβ antibody comprises a LC and a HC, wherein the LC comprises the amino acid sequence of SEQ ID NO: 10 and the HC comprises the amino acid sequence of SEQ ID NO: 9. 120. The method of any one of embodiments 106 to 119, wherein the anti-N3pGlu Aβ antibody comprises two light chains and two heavy chains, wherein the LC comprises the amino acid sequence of SEQ ID NO: 10 and the HC comprises the amino acid sequence of SEQ ID NO: 9. 121. The method of any one of embodiments 106 to 109, wherein prior to administration of the antibody, the individual's brain tau level is less than 1.46 normalized take-up value ratio (SUVr), wherein the brain tau level is measured by a tau PET imaging scan. 122. The method of any one of embodiments 106 to 109, wherein prior to administration of the antibody, the individual's brain tau level is greater than 1.10 SUVr and less than 1.46 SUVr, wherein the brain tau level is measured by a tau PET imaging scan. 123. The method of embodiment 121 or embodiment 122, wherein brain tau level is measured by ¹⁸ F-fluroxipyr PET imaging. 124. The method of any one of embodiments 106 to 109, wherein the individual has at least one APOE4 allele. 125. The method of any one of embodiments 106 to 124, wherein the patient does not have baseline superficial siderosis. Sequence Antibody 1 ( Remeneta ) , HCDR1 (SEQ ID NO: 1) AASGFTFSSYPMS Antibody 1 , HCDR2 (SEQ ID NO: 2) AISGSGGSTYYADSVKG Antibody 1 , HCDR3 (SEQ ID NO: 3) AREGGSGSYYNGFDY Antibody 1 , LCDR1 (SEQ ID NO: 4) RASQSLGNWLA Antibody 1 , LCDR2 (SEQ ID NO : 5) YQASTLES Antibody 1 , LCDR3 (SEQ ID NO: 6) QHYKGSFWT Antibody 1 , HCVR (SEQ ID NO: 7) EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYPMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREGGSGSYYNGFDYWGQGTLVTVSS Antibody 1 , LCVR (SEQ ID NO: 8) DIQMTQSPSTLSASSVGDRVTITCRASQSLGNWLAWYQQKPGKAPKLLIYQASTLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQHYKGSFWTFGQGTKVEIK Antibody 1 , heavy chain (SEQ ID NO: 9) EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYPMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREGGSGSYYNGFDYWG QGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG Antibody 1 , light chain (SEQ ID NO: 10) DIQMTQSPSTLSASVGDRVTITCRASQSLGNWLAWYQQKPGKAPKLLIYQASTLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQHYKGSFWTFGQGTKVEIKRTVAAPS VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECExemplary DNA expressing the heavy chain of antibody 1 (SEQ ID NO: 11) gaggtgcagctgttggagtctgggggaggcttggtacagcctggggggtccctgagactctcctgtgcagcctctggattcacctttagcagctatcctatgagctgggtccgccaggctccagggaaggggctggagtgggtctca gctattagtggtagtggtggtagcacatactacgcagactccgtgaagggccggttcaccatctccagagacaattccaagaacacgctgtatctgcaaatgaacagcctgagagccgaggacacggccgtatattactgtgcgaga gaggggggctcaggggagttattataacggctttgattattggggccagggaaccctggtcaccgtctcctcagcctccaccaagggcccatcggtcttcccgctagcaccctcctccaagagcacctctgggggcacagcggccctg ggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagc agcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggac ccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaag acaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtg caaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggacgagctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtggggagagcaatgggca gccggagaacaactacaagaccacgccccccgtgctggactccgacggctccttcttcctctatagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtExemplary DNA expressing the light chain of Antibody 1 (SEQ ID NO: 12) gacatccagatgacccagtctccttccaccctgtctgcatctgtaggagacagagtcaccatcacttgccgggccagtcagagtcttggtaactggttggcctggtatcagcagaaaccagggaaagcccctaaactcctgatctatcaggcgtctactt tagaatctggggtcccatcaagattcagcggcagtggatctgggacagagttcactctcaccatcagcagcctgcagcctgatgattttgcaacttattactgccaacattataaaggttctttttggacgttcggccaagggaccaaggtggaaatcaaa cggaccgtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccagg agagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacagggagagtgc N3pGlu Aβ (SEQ ID NO: 13) [pE]FRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIA

Figure 1 is a graph showing the least square mean change in brain amyloid plaque from baseline to day 169 by drug group, where LY = LY3372993/remenetate; MMRM = mixed model with repeated measures; Q4W = once every 4 weeks; QW = once weekly; SC = subcutaneous; SD = single dose; TRT = treatment.

FIG2 is a PET scan of amyloid protein from a LAKB participant in Cohort 12 who received a single dose of 2800 mg of remenitabine, showing representative amyloid protein reduction through day 85, with the X-axis representing the standardized uptake value (SUV); this shows a reduction of 144 CL of amyloid protein on day 85; brain regions are labeled "A" for anterior, "P" for posterior, "L" for left, and "R" for right.

Figure 3 provides a graphical representation of the study summary of Appendix 1 of LAKC as described in Example 5, where IV = intravenous; Q12W = every 12 weeks; V = visit; and V1 occurs up to 49 days before V2 (denoted as "a").

Figure 4 provides a graphical representation of the study summary of Appendix 3 of LAKC as described in Example 5, where IV = intravenous; Q4W = every 4 weeks; Q8W = every 8 weeks; V = visit; and V1 occurs up to 49 days before the start of the V2 study intervention (denoted as "a").

Figure 5 provides a graphical representation of the study summary of Appendix 4 of LAKC as described in Example 5, where SC = subcutaneous; QW = weekly; Q4W = every 4 weeks; V1 occurs up to 49 days before V2 (indicated as "a").

Figure 6 provides a graphical representation of the study summary of Appendix 4 of LAKC as described in Example 5, where SC = subcutaneous; Visit 1 occurred up to 49 days before the start of the study intervention at Visit 2 (denoted as "a"); Visit 801 occurred 20 weeks after the last dose (denoted as "b").

Figure 7 provides a graphical overview of the study for the primary regimen of Study LAKC, as described in Example 5, in which V601 occurred up to 30 days before V1 (denoted as "a"); V1 occurred up to 49 days before V2 (denoted as "a"); and participants in the 400 mg QW SC group were dose-titrated to 800 mg SC Q4W or placebo after a minimum of 4 weeks of treatment suspension (denoted as "b").

Figure 8 provides a graphical representation of the study summary of Study LAKD as described in Example 6, where SC = subcutaneous; V601 occurs up to 30 days before V1 (denoted as "a"); and V1 occurs up to 63 days before V2 (denoted as "a").

FIG9 provides a graphical representation of the study summary of Study LAKE as described in Example 7.

Figure 10 provides a graphical representation of the study summary of Study LAKE as described in Example 8, where IV = intravenous; V601 occurs up to 30 days before V1 (denoted as "a"); and V1 occurs up to 63 days before V2 (denoted as "a").

FIG11 provides a schematic diagram of tau layering of LAKD and LAKF of Example 9.

TWI894689B_112144584_SEQL.xml

Claims (16)

A use of an anti-N3pG Aβ antibody for preparing a pharmaceutical for reducing amyloid beta (Aβ) plaques in the brain of a human subject in need thereof, wherein administration of the antibody comprises administering to the subject one or more subcutaneous doses of about 100 mg to about 1000 mg of the anti-N3pG Aβ antibody at a frequency of about once every four weeks (Q4W), about once every eight weeks (Q8W), about once every twelve weeks (Q12W), or a combination thereof, wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) having the amino acid sequence of SEQ ID NO: 8 and a heavy chain variable region (HCVR) having the amino acid sequence of SEQ ID NO: 7. A use of an anti-N3pG Aβ antibody for preparing a pharmaceutical for treating a disease characterized by Aβ plaque deposition in the brain of a human subject in need thereof, wherein administration of the antibody comprises administering to the subject one or more subcutaneous doses of about 100 mg to about 1000 mg of the anti-N3pG Aβ antibody at a frequency of about once every four weeks (Q4W), about once every eight weeks (Q8W), about once every twelve weeks (Q12W), or a combination thereof, wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) having the amino acid sequence of SEQ ID NO: 8 and a heavy chain variable region (HCVR) having the amino acid sequence of SEQ ID NO: 7. A use of an anti-N3pG Aβ antibody for the preparation of a pharmaceutical for preventing a disease characterized by brain Aβ plaque deposition in a human subject in need thereof, wherein administration of the antibody comprises administering to the subject one or more subcutaneous doses of about 100 mg to about 1000 mg of the anti-N3pG Aβ antibody at a frequency of about once every four weeks (Q4W), about once every eight weeks (Q8W), about once every twelve weeks (Q12W), or a combination thereof, wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) having the amino acid sequence of SEQ ID NO: 8 and a heavy chain variable region (HCVR) having the amino acid sequence of SEQ ID NO: 7. The use of any one of claims 1 to 3, wherein the one or more subcutaneous doses are selected from one of the following: about 100 mg; about 200 mg; about 400 mg; about 800 mg; or about 1000 mg. The use of any one of claims 1 to 3, wherein the human individual suffers from one of MCI, preclinical AD, or early symptomatic Alzheimer's disease. The use of any one of claims 1 to 3, wherein the antibody is administered until the Aβ plaques in the brain of the human subject are 24.1 percent amyloid or less as measured by amyloid PET imaging scan. The use of any one of claims 1 to 3, wherein the administration results in at least one of the following: (i.) a reduction in Aβ plaques in the brain as measured by amyloid PET imaging scan; (ii.) a slowing of cognitive decline; or (iii.) a slowing of functional decline. The use of any one of claims 1 to 3, wherein the individual has at least one APOE4 allele. A use of an anti-N3pG Aβ antibody for preparing a pharmaceutical for preventing the progression of AD in a human subject in need thereof, wherein administration of the antibody comprises administering to the subject a subcutaneous dose of about 100 mg to about 800 mg of the anti-N3pG Aβ antibody at a frequency of about once every eight weeks (Q8W), about once every twelve weeks (Q12W), about once every twenty-six weeks (Q26W), or about once every fifty-two weeks (Q52W), wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) having the amino acid sequence of SEQ ID NO: 8 and a heavy chain variable region (HCVR) having the amino acid sequence of SEQ ID NO: 7. A use of an anti-N3pG Aβ antibody for preparing a pharmaceutical for delaying the onset of AD in a human subject in need thereof, wherein administration of the antibody comprises administering to the subject a subcutaneous dose of about 100 mg to about 800 mg of the anti-N3pG Aβ antibody at a frequency of about once every eight weeks (Q8W), about once every twelve weeks (Q12W), about once every twenty-six weeks (Q26W), or about once every fifty-two weeks (Q52W), wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) having the amino acid sequence of SEQ ID NO: 8 and a heavy chain variable region (HCVR) having the amino acid sequence of SEQ ID NO: 7. A use of an anti-N3pG Aβ antibody for the preparation of a pharmaceutical for preventing the progression of Aβ pathology in a human subject in need thereof, wherein administration of the antibody comprises administering to the subject a subcutaneous dose of about 100 mg to about 800 mg of the anti-N3pG Aβ antibody at a frequency of about once every eight weeks (Q8W), about once every twelve weeks (Q12W), about once every twenty-six weeks (Q26W), or about once every fifty-two weeks (Q52W), wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) having the amino acid sequence of SEQ ID NO: 8 and a heavy chain variable region (HCVR) having the amino acid sequence of SEQ ID NO: 7. The use of any one of claims 9 to 11, wherein the human individual has a family history of AD; has biomarkers of AD pathology; has an APOe4 allele; is homozygous for APOe4; has a dominantly inherited AD genotype; or has previously been treated for AD with an anti-N3pG Aβ antibody. The use of any one of claims 1 to 3 and 9 to 11, wherein the anti-N3pGlu Aβ antibody comprises a light chain (LC) having the amino acid sequence of SEQ ID NO: 10 and a heavy chain (HC) having the amino acid sequence of SEQ ID NO: 9. The use of any one of claims 1 to 3 and 9 to 11, wherein the administration does not cause symptomatic amyloid-associated imaging abnormality (ARIA) in the human subject. The use of any one of claims 1 to 3 and 9 to 11, wherein the human subject experiences symptoms consistent with mild to moderate ARIA after administration of one or more doses of the anti-N3pGlu Aβ antibody. For the use in claim 15, the pharmaceutical product is used in combination with a corticosteroid.