Anti-beta-amyloid antibodies for treating alzheimer's disease

Abstract

To provide an anti-beta-amyloid antibody for treating Alzheimer's disease.SOLUTION: Provided are methods of treating Alzheimer's disease in a human subject in need thereof, comprising administering to the human subject multiple doses of an anti-beta-amyloid antibody (e.g., aducanumab). In one aspect, the disclosure features a method of treating Alzheimer's disease in a human subject in need thereof. In some embodiments, the Alzheimer's disease is mild Alzheimer's disease, early stage Alzheimer's disease, prodromal Alzheimer's disease, mild Alzheimer's disease dementia, or mild cognitive impairment due to Alzheimer's disease.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 62 / 924,633, filed October 22, 2019, the contents of which are incorporated herein by reference in their entirety.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in ASCII format, which is incorporated herein by reference in its entirety. The ASCII copy, created on October 16, 2020, is named 13751-0323WO1_SL.txt and is 10,440 bytes in size.

[0003] The present disclosure relates generally to methods of treating Alzheimer's disease. [Background technology]

[0004] Alzheimer's disease (AD) is a progressive neurodegenerative disorder that clinically manifests as cognitive impairment, behavioral disturbances, psychiatric symptoms, and impairment in activities of daily living. These clinical symptoms constitute AD dementia.

[0005] AD International predicts that globally, the number of people with dementia will increase from the current 47 million to 131 million by 2050. AD, the most common cause of dementia, accounts for 60-80% of dementia cases. In the United States, it is estimated that 5.2 million Americans have dementia due to AD, and that the number of cases will double or triple by 2050 unless effective treatments are found.

[0006] Clinical research criteria for AD dementia have recently been updated to conform to the latest concepts of the disease, and a diagnostic framework has been developed to encompass pre-dementia stages of AD (e.g., prodromal AD). The primary neuropathological features of the disease are (i) extracellular senile (neuritic) plaques containing aggregated β-amyloid (Aβ) peptides and (ii) intraneuronal neurofibrillary tangles (NFTs) composed of abnormal hyperphosphorylated tau protein. The "amyloid cascade" hypothesis proposes that the driving force behind the disease process is the accumulation of Aβ due to an imbalance between Aβ production and Aβ clearance in the brain.

[0007] Aβ is a peptide derived from the metabolism of amyloid precursor protein. Several Aβ peptide alloforms exist (e.g., Aβ40, Aβ42). These monomeric peptides have a variable tendency to aggregate into higher-order dimers and oligomers. Through the process of fibril formation, soluble oligomers can transition to insoluble deposits with a β-pleated sheet structure. These deposits, also known as amyloid plaques, are primarily composed of fibrillar amyloid. Both soluble and fibrillar forms of Aβ appear to contribute to the disease process.

[0008] Biomarker, clinicopathological, and cohort studies suggest that the disease course begins 10 to 20 years before the clinical onset of symptoms, and some of the early pathological findings include neocortical neuritic plaque deposits and mesial temporal NFTs, followed several years later by neocortical NFTs.

[0009] Therefore, there is a need for methods of treating patients with Alzheimer's disease. Summary of the Invention

[0010] The present disclosure fills the need for methods of treating patients with Alzheimer's disease (AD).

[0011] In one aspect, the disclosure features a method of treating Alzheimer's disease in a human subject in need thereof. The method includes administering multiple doses of an anti-beta-amyloid antibody to the human subject, wherein the multiple doses are administered as follows: (a) administering the anti-beta-amyloid antibody to the subject in an amount of 1 mg / kg of the subject's body weight; (b) 4 weeks after step (a), administering the antibody to the subject in an amount of 1 mg / kg of the subject's body weight; (c) 4 weeks after step (b), administering the antibody to the subject in an amount of 3 mg / kg of the subject's body weight; and (d) (e) four weeks after step (d), the antibody is administered to the subject in an amount of 6 mg / kg of the subject's body weight; (f) four weeks after step (e), the antibody is administered to the subject in an amount of 6 mg / kg of the subject's body weight; and (g) after step (f), in consecutive four week intervals, the antibody is administered at least 15 times in an amount of 10 mg / kg of the subject's body weight. Here, the anti-beta-amyloid antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises a complementarity determining region (VHCDR1) having the amino acid sequence of SEQ ID NO: 3, a VHCDR2 having the amino acid sequence of SEQ ID NO: 4, and a VHCDR3 having the amino acid sequence of SEQ ID NO: 5, and the VL comprises a VLCDR1 having the amino acid sequence of SEQ ID NO: 6, a VLCDR2 having the amino acid sequence of SEQ ID NO: 7, and a VLCDR3 having the amino acid sequence of SEQ ID NO: 8.

[0012] In some embodiments, step (g) comprises administering the antibody at least 16, at least 17, at least 18, at least 19, or at least 20 times, consecutively at 4-week intervals, each in an amount of 10 mg / kg of body weight of the subject.

[0013] In some embodiments of any of the foregoing methods, all administrations specified in steps (a) through (g) are administered without interruption, even if the human subject develops amyloid-related imaging abnormalities (ARIA) during the course of treatment.

[0014] In some embodiments of any of the foregoing methods, the human subject develops ARIA during the course of treatment, and all administrations specified in steps (a) through (g) are administered without interruption.

[0015] In some embodiments of any of the aforementioned methods, the Alzheimer's disease is mild Alzheimer's disease, early Alzheimer's disease, prodromal Alzheimer's disease, mild Alzheimer's dementia, or mild cognitive impairment due to Alzheimer's disease.

[0016] In some embodiments of any of the aforementioned methods, each administration is administered intravenously.

[0017] In some embodiments of any of the foregoing methods, the human subject is confirmed to have cerebral amyloid beta pathology before initiation of treatment. In some embodiments, the cerebral amyloid beta pathology is identified by positron emission tomography (PET) imaging. In some embodiments, the cerebral amyloid beta pathology is identified by Congo red staining and birefringence under polarized light microscopy. In some embodiments, the cerebral amyloid beta pathology is identified by immunohistochemistry. In some embodiments, the cerebral amyloid beta pathology is identified by electron microscopy or mass spectrometry. In some embodiments, the cerebral amyloid beta pathology is identified by CSF analysis. In some embodiments, the cerebral amyloid beta pathology is identified by blood analysis.

[0018] In another aspect, the disclosure features a method of treating mild Alzheimer's disease, early Alzheimer's disease, prodromal Alzheimer's disease, mild Alzheimer's dementia, or mild cognitive impairment due to Alzheimer's disease in a human subject in need of such treatment, the method comprising administering multiple doses of an anti-beta-amyloid antibody to the human subject, the method comprising administering at least six doses of the antibody at consecutive four-week intervals, each dose being administered in an amount of 10 mg / kg of the subject's body weight, the anti-beta-amyloid antibody comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises a complementarity-determining region (VHCDR1) having the amino acid sequence of SEQ ID NO:3, a VHCDR2 having the amino acid sequence of SEQ ID NO:4, and a VHCDR3 having the amino acid sequence of SEQ ID NO:5, and the VL comprises a VLCDR1 having the amino acid sequence of SEQ ID NO:6, a VLCDR2 having the amino acid sequence of SEQ ID NO:7, and a VLCDR3 having the amino acid sequence of SEQ ID NO:8.

[0019] In some embodiments, the methods comprise administering the antibody at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 times in consecutive 4-week intervals, wherein each administration is given in an amount of 10 mg / kg of body weight of the subject.

[0020] In some embodiments of any of the foregoing methods, all of the prescribed doses are administered without interruption, even if the human subject develops ARIA during the course of treatment.

[0021] In some embodiments of any of the foregoing methods, the human subject develops ARIA during the course of treatment, and all of the prescribed doses are administered without interruption.

[0022] In some embodiments of any of the aforementioned methods, each administration is administered intravenously.

[0023] In some embodiments of any of the foregoing methods, the human subject is identified as having cerebral amyloid beta pathology prior to initiation of treatment. In some embodiments, the cerebral amyloid beta pathology is identified by PET imaging.

[0024] In another aspect, the disclosure features a method of treating Alzheimer's disease in a human subject in need thereof. The method includes administering multiple doses of an anti-beta-amyloid antibody to the human subject, wherein the multiple doses are administered as follows: (a) administering the anti-beta-amyloid antibody to the subject in an amount of 1 mg / kg of the subject's body weight, (b) 4 weeks after step (a), administering the antibody to the subject in an amount of 1 mg / kg of the subject's body weight, (c) 4 weeks after step (b), administering the antibody to the subject in an amount of 3 mg / kg of the subject's body weight, and (d (e) four weeks after step (d), the antibody is administered to the subject in an amount of 6 mg / kg of the subject's body weight; (f) four weeks after step (e), the antibody is administered to the subject in an amount of 6 mg / kg of the subject's body weight; and (g) in consecutive four week intervals after step (f), the antibody is administered to the subject in an amount of 10 mg / kg of the subject's body weight. wherein the anti-beta-amyloid antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises a complementarity determining region (VHCDR1) having the amino acid sequence of SEQ ID NO: 3, a VHCDR2 having the amino acid sequence of SEQ ID NO: 4, and a VHCDR3 having the amino acid sequence of SEQ ID NO: 5, and the VL comprises a VLCDR1 having the amino acid sequence of SEQ ID NO: 6, a VLCDR2 having the amino acid sequence of SEQ ID NO: 7, and a VLCDR3 having the amino acid sequence of SEQ ID NO: 8, and all of the specified administrations are administered without interruption even if the human subject develops ARIA during the course of treatment.

[0025] In some embodiments, the human subject develops ARIA during the course of treatment and all of the prescribed doses are administered without interruption.

[0026] In some embodiments of any of the aforementioned methods, step (g) comprises administering the antibody at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 times in consecutive 4-week intervals, each time in an amount of 10 mg / kg of body weight of the subject.

[0027] In some embodiments of any of the aforementioned methods, the Alzheimer's disease is mild Alzheimer's disease, early Alzheimer's disease, prodromal Alzheimer's disease, mild Alzheimer's dementia, or mild cognitive impairment due to Alzheimer's disease.

[0028] In some embodiments of any of the aforementioned methods, each administration is administered intravenously.

[0029] In some embodiments of any of the foregoing methods, the human subject is identified as having cerebral amyloid beta pathology prior to initiation of treatment. In some embodiments, the cerebral amyloid beta pathology is identified by PET imaging.

[0030] In another aspect, the disclosure features a method of treating Alzheimer's disease in a human subject in need thereof. The method includes administering multiple doses of an anti-beta-amyloid antibody to the human subject, wherein the multiple doses are administered as follows: (a) intravenously administering the anti-beta-amyloid antibody to the subject in an amount of 1 mg / kg of the subject's body weight, (b) 4 weeks after step (a), intravenously administering the antibody to the subject in an amount of 1 mg / kg of the subject's body weight, (c) 4 weeks after step (b), intravenously administering the antibody to the subject in an amount of 3 mg / kg of the subject's body weight, and (d) (e) four weeks after step (d), the antibody is administered intravenously to the subject in an amount of 6 mg / kg of the subject's body weight; (f) four weeks after step (e), the antibody is administered intravenously to the subject in an amount of 6 mg / kg of the subject's body weight; and (g) after step (f), at consecutive four week intervals, the antibody is administered intravenously to the subject at least six times in an amount of 10 mg / kg of the subject's body weight. Here, the anti-beta-amyloid antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises a complementarity determining region (VHCDR1) having the amino acid sequence of SEQ ID NO: 3, a VHCDR2 having the amino acid sequence of SEQ ID NO: 4, and a VHCDR3 having the amino acid sequence of SEQ ID NO: 5, and the VL comprises a VLCDR1 having the amino acid sequence of SEQ ID NO: 6, a VLCDR2 having the amino acid sequence of SEQ ID NO: 7, and a VLCDR3 having the amino acid sequence of SEQ ID NO: 8.

[0031] In some embodiments, step (g) comprises intravenously administering the antibody at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 times, each in an amount of 10 mg / kg of body weight of the subject, at consecutive 4-week intervals.

[0032] In some embodiments of any of the foregoing methods, all administrations specified in steps (a) through (g) are administered without interruption, even if the human subject develops ARIA during the course of treatment.

[0033] In some embodiments of any of the foregoing methods, the human subject develops ARIA during the course of treatment, and all administrations specified in steps (a) through (g) are administered without interruption.

[0034] In some embodiments of any of the aforementioned methods, the Alzheimer's disease is mild Alzheimer's disease, early Alzheimer's disease, prodromal Alzheimer's disease, mild Alzheimer's dementia, or mild cognitive impairment due to Alzheimer's disease.

[0035] In some embodiments of any of the foregoing methods, the human subject is identified as having cerebral amyloid beta pathology prior to initiation of treatment. In some embodiments, the cerebral amyloid beta pathology is identified by PET imaging.

[0036] In some embodiments of any of the methods described herein, the VH of the anti-beta-amyloid antibody comprises the amino acid sequence of SEQ ID NO:1 and the VL of the anti-beta-amyloid antibody comprises the amino acid sequence of SEQ ID NO:2.

[0037] In some embodiments of any of the methods described herein, the anti-beta-amyloid antibody comprises a human IgG1 constant region.

[0038] In some embodiments of any of the methods described herein, the anti-beta-amyloid antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 10 and the light chain comprises the amino acid sequence of SEQ ID NO: 11.

[0039] In another aspect, the disclosure features a method for reducing Abeta (Aβ), particularly Aβ plaques and tau, in a human subject in need thereof. The method includes administering multiple doses of an anti-beta-amyloid antibody to the human subject, the anti-beta-amyloid antibody comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises a complementarity-determining region (VHCDR1) having the amino acid sequence of SEQ ID NO: 3, a VHCDR2 having the amino acid sequence of SEQ ID NO: 4, and a VHCDR3 having the amino acid sequence of SEQ ID NO: 5, and the VL comprises a VLCDR1 having the amino acid sequence of SEQ ID NO: 6, a VLCDR2 having the amino acid sequence of SEQ ID NO: 7, and a VLCDR3 having the amino acid sequence of SEQ ID NO: 8. In a particularly preferred embodiment, the antibody is BIIB037, also known as aducanumab. See below.

[0040] In this aspect, the invention is based, inter alia, on the observation of amyloid clearance by aducanumab and the previously unrecognized pleiotropic activity of aducanumab against pathological tau variants in human patients.

[0041] As shown in Example 14, in human patients from the PRIME trial (LTE patients) who subsequently received 30 doses of 6 mg / kg aducanumab, and who further demonstrated amyloid clearance and unusual "worm-eaten" amyloid plaque structure (FIGS. 11D and 12B) as evidenced by PET data (FIGS. 10B and 10C), and microglial plaque association (FIGS. 12C and 12D), surprisingly, there was also a neuropathological reduction in p-tau, as evidenced by lower neocortical p-tau densities in the LTE patients compared to the range of untreated advanced AD cases (FIG. 13).

[0042] Surprisingly, the therapeutic effect did not reverse the specific appearance order of tau pathology according to the "reverse Braak pattern," but reduced the intensity of tau staining in all Braak V-VI regions. This pattern of reduced tau staining intensity in all Braak V-VI regions can only be explained by a reduction in the amount of pathological tau in all Braak regions that previously established tau pathology according to the known specific progression of the disease. In other words, treatment directed at tau as a therapeutic target is expected to reduce tau pathology in all affected Braak regions, but will not "reverse" the Braak stage pattern, for example, from an earlier stage, e.g., from stage VI to stage II.

[0043] Aducanumab treatment demonstrated exactly this pattern, reducing the amount of pathological tau staining in all previously affected Braak regions. This mechanism is surprising because the oft-cited "amyloid cascade hypothesis" views amyloid as the trigger for tau pathology. Following this logic, amyloid clearance by aducanumab halts or reduces the formation of "new" tau pathology.

[0044] Taking into account the data and possible theories, the Phase 3 studies, Study 1 and Study 2, were evaluated for the impact of aducanumab treatment on tau pathology and clinical benefit in patients. Thus, as shown in Example 12 and Figure 9, PET and CSF biomarker studies showed that aducanumab reduced Aβ tau pathology and neurodegeneration in subjects with early Alzheimer's disease.

[0045] However, the observed effects not only indicate the clearance of "new" tau pathology, but more importantly, the reduction of pre-existing tau pathology via a novel therapeutic mechanism that is not subject to the logic of the amyloid cascade hypothesis. Without intending to be bound by theory, this novel mechanism may involve proteasome-mediated degradation of intracellular pathological tau within affected neurons and / or phagocytosis-mediated clearance of extracellular species of pathological tau by microglial cells or macrophages, potentially explaining the reduction in CSF levels of pathological phospho-tau observed in aducanumab-treated patients.

[0046] If pathological tau is subject to natural turnover, blocking its production may also result in the reduced staining intensity observed in aducanumab-treated patients. This reduction in pathology formation may be explained by aducanumab's neutralization and removal of neurotoxic oligomeric amyloid beta species from presynaptic axon terminals, protecting axons from amyloid-induced damage and allowing unphosphorylated, microtubule-bound tau to remain in its physiological axonal location, thereby preventing the abnormal relocalization of tau from axons to the somatodendritic compartment in amyloid-affected neurons, where tau becomes abnormally phosphorylated and prone to aggregation. Natural mechanisms of tau turnover include ubiquitination followed by proteasomal degradation, microglial phagocytosis, and perivascular drainage into the CSF and blood.

[0047] An even more surprising and unexpected possibility is the pleiotropy of aducanumab's function as a stimulator of microglial phagocytosis. Such pleiotropic effects can be explained by aducanumab's previously unknown activity of targeting pathological tau aggregate species for microglial phagocytosis and degradation. It may also involve the uptake and degradation of previously unknown coaggregates of amyloid beta oligomers and pathological tau aggregates. Such coaggregations of amyloid beta aggregates with other unrelated proteins are known. As an example, amyloid beta coaggregates with islet amyloid polypeptide IAPP (amylin), a self-aggregating polypeptide produced by insulin-secreting pancreatic beta cells.

[0048] In summary, data from clinical trials conducted in accordance with the present invention lead to the conclusion that amyloid clearance with aducanumab not only attenuates disease-associated tau gain, but also leads to a reduction in pathological forms of tau in the brains of Alzheimer's disease patients, and is associated with cognitive improvements in treated patients.

[0049] This is a completely unexpected finding given the prior knowledge that aducanumab binds to amyloid but not tau.

[0050] Indeed, until now, when targeting Aβ in immunotherapy for Alzheimer's disease, tau has only been considered as a cerebrospinal fluid (CSF) biomarker in positron emission tomography (PET) imaging for AD diagnosis, to monitor clinical stage and classify the type of cognitive decline. For reviews, see, e.g., Gabelli, J. Lab. Precis. Med. 15 (2020) | http: / / dx.doi.org / 10.21037 / jlpm.2019.12.04 and Nguyen et al., Diagnostics 2020, 10, 326; doi:10.3390 / diagnostics10050326.

[0051] Accordingly, in one embodiment, the invention features a method of treating Alzheimer's disease in a human subject in need thereof, the method comprising administering to the human subject a therapeutically effective amount of an anti-beta-amyloid antibody comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises a VH complementarity-determining region 1 (VHCDR1) having the amino acid sequence of SEQ ID NO: 3, a VHCDR2 having the amino acid sequence of SEQ ID NO: 4, and a VHCDR3 having the amino acid sequence of SEQ ID NO: 5, and the VL comprises a VLCDR1 having the amino acid sequence of SEQ ID NO: 6, a VLCDR2 having the amino acid sequence of SEQ ID NO: 7, and a VLCDR3 having the amino acid sequence of SEQ ID NO: 8, wherein the human subject has p-tau tangles, p-tau threads, and / or p-tau senile plaques. Optionally, the human subject has neocortical p-tau tangles, neocortical p-tau threads, and / or neocortical p-tau senile plaques.

[0052] In some embodiments, administration of the anti-beta-amyloid antibody reduces p-tau tangles, p-tau threads, and / or p-tau neuritic plaques in the brain of the human subject, or reduces the amount of phosphorylated tau (p-tau) and / or total tau (t-tau) in the cerebrospinal fluid (CSF) of the human subject. In certain examples, prior to administration of the anti-beta-amyloid antibody, p-tau tangles, p-tau threads, and / or p-tau neuritic plaques are detected by positron emission tomography (PET) scan of the human subject's brain or by analyzing the amount of p-tau and / or t-tau in the human subject's CSF.

[0053] In some cases, the method further includes monitoring p-tau tangles, p-tau threads, and / or p-tau plaques over the course of treatment by PET scan of the human subject's brain or analysis of the amount of p-tau and / or t-tau in the human subject's CSF.

[0054] In certain instances, the dosage of the anti-beta-amyloid antibody and / or the frequency of administration of the anti-beta-amyloid antibody is adjusted over the course of treatment by monitoring p-tau tangles, p-tau threads, and / or p-tau plaques in the brain of the human subject using a PET scan or by analysis of the amount of p-tau and / or t-tau in the CSF of the human subject.

[0055] In some cases, the treatment results in (i) a decrease in the SUVR, density, and / or distribution of p-tau tangles, p-tau threads, and / or p-tau plaques compared to a previous PET scan, or (ii) a decrease in the amount of p-tau and / or t-tau in a CSF analysis compared to a previous CSF analysis.

[0056] In another aspect, the disclosure features a method for reducing tau in a human subject in need thereof. The method includes administering to the human subject an effective amount of an anti-beta-amyloid antibody comprising a VH and a VL, wherein the VH comprises a VHCDR1 having the amino acid sequence of SEQ ID NO: 3, a VHCDR2 having the amino acid sequence of SEQ ID NO: 4, and a VHCDR3 having the amino acid sequence of SEQ ID NO: 5, and the VL comprises a VLCDR1 having the amino acid sequence of SEQ ID NO: 6, a VLCDR2 having the amino acid sequence of SEQ ID NO: 7, and a VLCDR3 having the amino acid sequence of SEQ ID NO: 8. Optionally, the human subject has Alzheimer's disease.

[0057] In yet another aspect, the disclosure features a method for reducing beta amyloid and tau in a human subject in need thereof. The method includes administering to the human subject an effective amount of an anti-beta amyloid antibody comprising a VH and a VL, wherein the VH comprises a VHCDR1 having the amino acid sequence of SEQ ID NO: 3, a VHCDR2 having the amino acid sequence of SEQ ID NO: 4, and a VHCDR3 having the amino acid sequence of SEQ ID NO: 5, and the VL comprises a VLCDR1 having the amino acid sequence of SEQ ID NO: 6, a VLCDR2 having the amino acid sequence of SEQ ID NO: 7, and a VLCDR3 having the amino acid sequence of SEQ ID NO: 8. Optionally, the human subject has Alzheimer's disease.

[0058] In another aspect, the disclosure provides a method for treating Alzheimer's disease by reducing the amount of tau in a human subject in need thereof, the method comprising administering to the human subject an effective amount of an anti-beta-amyloid antibody comprising a VH and a VL, wherein the VH comprises a VHCDR1 having the amino acid sequence of SEQ ID NO: 3, a VHCDR2 having the amino acid sequence of SEQ ID NO: 4, and a VHCDR3 having the amino acid sequence of SEQ ID NO: 5, and the VL comprises a VLCDR1 having the amino acid sequence of SEQ ID NO: 6, a VLCDR2 having the amino acid sequence of SEQ ID NO: 7, and a VLCDR3 having the amino acid sequence of SEQ ID NO: 8.

[0059] In some cases, the human subject has been diagnosed with or has previously been diagnosed with p-tau tangles, p-tau threads, and / or p-tau neuritic plaques in the brain, and / or has been diagnosed with or has previously been diagnosed with increased amounts of p-tau and / or t-tau in the CSF of the human subject compared to human subjects who do not have Alzheimer's disease.

[0060] In some cases, the amount of tau in the brain and / or CSF of the human subject is reduced. In certain cases, the amount of p-tau and / or t-tau in the human subject is reduced.

[0061] In certain cases, the human subject has elevated levels of tau measured in the CSF or in the brain by PET scan before administration of the anti-beta-amyloid antibody. Tau levels are elevated in AD (see, e.g., Blennow and Zetterberg, J. Int. Med 2018, Biomarkers for Alzheimer's disease: current status and prospects for the future). P-tau and t-tau levels can be measured in CSF (e.g., obtained by lumbar puncture) or by blood tests.

[0062] In some cases, the Alzheimer's disease is mild Alzheimer's disease, early Alzheimer's disease, prodromal Alzheimer's disease, mild Alzheimer's dementia, mild cognitive impairment due to Alzheimer's disease, intermediate Alzheimer's disease, or late Alzheimer's disease, where optionally intermediate Alzheimer's disease is characterized by a Mini-Mental State Examination (MMSE) score of about 10-20 or an equivalent score on another scale, and late Alzheimer's disease is characterized by an MMSE score of 9 or less or an equivalent score on another scale. In some cases, the Alzheimer's disease is mild cognitive impairment due to Alzheimer's disease. In certain cases, the Alzheimer's disease is mild Alzheimer's dementia.

[0063] In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 1 and the VL comprises the amino acid sequence of SEQ ID NO: 2. In certain examples, the anti-beta-amyloid antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 10 and a light chain comprising the amino acid sequence of SEQ ID NO: 11.

[0064] Optionally, the anti-beta-amyloid antibody is administered intravenously.

[0065] In certain embodiments, the method comprises administering the anti-beta-amyloid antibody in an amount of 3 mg antibody / kg body weight of the human subject. In certain embodiments, the method comprises administering the anti-beta-amyloid antibody in an amount of 6 mg antibody / kg body weight of the human subject. In other embodiments, the method comprises administering the anti-beta-amyloid antibody in an amount of 10 mg antibody / kg body weight of the human subject.

[0066] In certain embodiments, the method comprises administering the anti-beta-amyloid antibody multiple times as follows: (a) administering the anti-beta-amyloid antibody to the human subject in an amount of 1 mg antibody / kg body weight of the human subject; (b) 4 weeks after step (a), administering the antibody to the human subject in an amount of 1 mg antibody / kg of body weight of the human subject; (c) 4 weeks after step (b), administering the antibody to the human subject in an amount of 3 mg antibody / kg of body weight of the human subject; (d) 4 weeks after step (c), administering the antibody to the human subject in an amount of 3 mg antibody / kg of body weight of the human subject; (e) 4 weeks after step (d), administering the antibody to the human subject in an amount of 6 mg antibody / kg of body weight of the human subject; (f) 4 weeks after step (e), administering the antibody to the human subject in an amount of 6 mg antibody / kg of body weight of the human subject; (g) In successive four week intervals following step (f), the antibody is administered to the human subject in an amount of 10 mg antibody / kg of body weight of the human subject.

[0067] In some embodiments, the method comprises administering the antibody at a cumulative dose of at least 150 mg antibody / kg body weight of the human subject, hi certain embodiments, the method comprises administering the antibody at a cumulative dose of at least 200 mg antibody / kg body weight of the human subject.

[0068] In certain embodiments, the method comprises administering the antibody in an amount of 10 mg antibody / kg of body weight of the human subject every 4 weeks for at least 52 weeks, hi other embodiments, the method comprises administering the antibody in an amount of 6 mg antibody / kg of body weight of the human subject every 4 weeks for at least 112 weeks.

[0069] In some embodiments, the method comprises administering the antibody to the human subject multiple times, wherein the multiple administrations include: (a) administering at least two doses every four weeks at 3 mg antibody / kg body weight of the human subject; and (b) at least 30 doses every 4 weeks at 6 mg antibody / kg body weight of the human subject.

[0070] In certain embodiments, the human subject is an ApoE3 carrier.

[0071] In some embodiments, the human subject does not develop amyloid-related imaging abnormalities (ARIA) during the course of treatment that require discontinuation of treatment.

[0072] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, exemplary methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present application, including definitions, will control. The materials, methods, and examples are illustrative only and are not intended to be limiting.

[0073] Other features and advantages of the invention will become apparent from the following detailed description and claims.

[0074] To avoid any misunderstanding, expressions such as "in some embodiments," "in certain embodiments," "in certain examples," "optionally," "in a further embodiment," "in one embodiment," and "in a further embodiment" are used, and it is emphasized that such expressions mean that any of the embodiments described herein should be read in the context of combining each of the features of those embodiments, and that the present disclosure should be treated in the same way as if the combination of features of those embodiments were described in detail in one embodiment. The same applies to any combination of embodiments and features of the appended claims and features exemplified in the examples, which are also intended to be combined with features from the corresponding embodiments disclosed in the description. Only for the sake of consistency and conciseness, the embodiments are characterized by a dependency relationship; in fact, each embodiment and combination of features that may be interpreted by a (multiple) dependency relationship must be considered as literally disclosed, and not as a selection among different alternatives. In this regard, those skilled in the art will understand that the features disclosed in the embodiments and examples are intended to be generalized to equivalents having the same function as those exemplified therein. [Brief explanation of the drawings]

[0075] [Figure 1] A schematic diagram of the study design, including aducanumab doses, is shown. [Figure 2] Change from baseline in AβPET composite SUVR (reference region = cerebellum) by MMRM - 18F-florbetapir AβPET analysis population - Study 2. [Figure 3] Change from baseline in AβPET composite SUVR (reference region = cerebellum) by MMRM - 18F-florbetapir AβPET analysis population - Study 1. [Figure 4] CSF p-tau change at 18 months in studies 1 and 2 is shown using ANCOVA. CSF corrected analysis population. [Figure 5]CSF t-tau change at 18 months in studies 1 and 2 is shown using ANCOVA. CSF corrected analysis population. [Figure 6] Temporal profiles of mean AβPET composite SUVR are shown for patients receiving 10 or more doses of 10 mg / kg at steady state. [Figure 7] 1 shows the time profiles of the mean CDR-SB for patients from Studies 1 and 2 belonging to the 10 mg / kg ≧6 SS dosing interval group, the 10 mg / kg ≧8 SS dosing interval group, and the 10 mg / kg ≧10 SS dosing interval group. [Figure 8A] Included are scatter plots showing the correlation between cerebrospinal fluid (CSF) p-tau levels and cumulative aducanumab dose through week 78 in Study 2 and Study 1. Squares represent low-dose aducanumab. Triangles represent high-dose aducanumab (see Figure 1). [Figure 8B] Included are scatter plots showing the correlation between CSF total tau levels and cumulative aducanumab dose through week 78 in Study 2 and Study 1. Squares represent low-dose aducanumab. Triangles represent high-dose aducanumab (see Figure 1). [Figure 9A] Figures 9A and B show tau deposition in the mesial temporal complex of the brain in subjects. (A) Graph showing the adjusted mean change from baseline in tau positron emission tomography (PET) mean standardized uptake value ratio (SUVR), assessed by 18F-MK-6240, in a tau PET study. Values ​​are based on an analysis of covariance (ANCOVA) model at week 78, fitting change from baseline as the dependent variable and categorical treatment, baseline tau PET value, and laboratory APOE ε4 status (carrier vs. noncarrier) as independent variables. P value: ***P<0.001 compared with placebo (nominal). Due to the early termination of these studies, all post-baseline tau PET assessments were performed within 9–20 months post-baseline during the placebo-controlled period. (B) Scatterplot of change from baseline in mesial temporal complex SUVR in correlation with cumulative dose through week 78. SE, standard error. [Figure 9B]Figures 9A and B show tau deposition in the mesial temporal complex of the brain in subjects. (A) Graph showing the adjusted mean change from baseline in tau positron emission tomography (PET) mean standardized uptake value ratio (SUVR), assessed by 18F-MK-6240, in a tau PET study. Values ​​are based on an analysis of covariance (ANCOVA) model at week 78, fitting change from baseline as the dependent variable and categorical treatment, baseline tau PET value, and laboratory APOE ε4 status (carrier vs. noncarrier) as independent variables. P value: ***P<0.001 compared with placebo (nominal). Due to the early termination of these studies, all post-baseline tau PET assessments were performed within 9–20 months post-baseline during the placebo-controlled period. (B) Scatterplot of change from baseline in mesial temporal complex SUVR in correlation with cumulative dose through week 78. SE, standard error. [Figure 10]A, B, and C show cognitive progression and amyloid PET biomarker data from one AD patient (subject 218-110) treated with placebo during a Phase 1b study (Study 221-AD-103) and aducanumab in the long-term extension (LTE). A is a graphical representation of the progression of CDR-SB (black line) and MMSE (gray line) data from initial patient screening to Phase 1b (placebo) and LTE (aducanumab). Screening data are shown to the left of the y-axis. The cognitive data point highlighted in red is the measurement immediately prior to aducanumab administration, consistent with mild-to-moderate dementia prior to enrollment in the LTE. (B) Axial-slice amyloid PET (florbetapir) images are shown at baseline (top row), weeks 26 and 54 (second and third rows) in the placebo group of the Phase 1b study, and weeks 110 and 166 (fourth and fifth rows) in the LTE study. These images demonstrate a decrease in amyloid PET standardized uptake value ratio (SUVR), indicating a reduction in Aβ plaques after aducanumab administration. (C) Graphical representation of composite and regional SUVR values. Taking the week 0 graph as an example, the lowest graph is the striatum, followed by composite, then frontal, and highest is the occipital SUVR. These indicate a reduction in amyloid plaques in the frontal cortex, occipital cortex, and striatum. [Figure 11]A–F show immunohistochemical staining for Aβ (6E10 antibody) demonstrating sparse residual Aβ plaques composed primarily of dense cores after aducanumab treatment. A–D show low- and high-magnification images of the frontal neocortex from an untreated, high-AD neuropathology case in the Yale ADRC study cohort, demonstrating frequent cortical Aβ plaques and amyloid angiopathy (A, C). Images from an LTE subject show sparse cortical Aβ plaques composed primarily of dense cores surrounded by reactive microglia (B, D). Dense cores surrounded by a moth-eaten peripheral halo of less dense Aβ were most prevalent in the occipital neocortex (inset 11D). Amyloid angiopathy was also observed. (E) Heatmaps generated from 6E10 immunostained sections of the midfrontal cortex (left column), medial temporal cortex (center column), and peristriate cortex (right column) show reduced Aβ plaque immunoreactivity in our PRIME LTE subjects (bottom row) compared with untreated AD-rich neuropathology controls (top row). (F) Graphical comparison of very low density of temporal neocortical Aβ plaques in PRIME LTE subjects to extensive temporal neocortical Aβ plaque density in a group of nine untreated AD-rich controls. [Figure 12] A–D show microglia surrounding residual dense-core Aβ plaques and displaying amoeboid reactive morphology. A and B show low-magnification images of sections from an untreated, high-AD case-control (A) and an LTE patient (B) stained with a dual IBA1 / 6E10 immunohistochemical staining protocol. Highly reactive, amoeboid microglial morphology is observed surrounding residual plaques in the LTE patient. C shows a graph quantification of IBA1 immunoreactive processes within 5 microns of Aβ plaques, demonstrating increased microglial binding to plaques in the LTE patient compared with the untreated, high-AD case-control cohort. D shows microglia (IBA1) surrounding residual dense-core Aβ plaques displaying reactive amoeboid morphology and cytoplasmic staining consistent with Aβ phagocytosis. [Figure 13]A–E: Immunohistochemistry of phosphorylated tau (p-tau, 40E8) shows sparse neocortical senile plaques (NPs) in LTE patients. A shows sections of midfrontal neocortex from untreated high-AD neuropathology controls from the Yale ADRC research cohort (top row), untreated high-AD neuropathology controls from the Netherlands Brain Bank (NBB, middle row), and LTE subjects (bottom row). Left column: Low-magnification images (original magnification 2.5x) show dense p-tau immunohistochemical reactivity in high-AD sections from Yale and NBB compared with LTE subjects. Middle column: Medium-magnification images of the region identified by the box in the left column, showing frequent NPs (arrows) in high-AD sections from Yale and NBB, but not in sections from LTE subjects. Right column: High-magnification images showing NPs (arrows), frequent NFTs, and dense NTs in high-AD sections from Yale and NBB. Sections from LTE patients show relatively few NFTs and NTs. B shows sections of the medial temporal lobe, including the hippocampus, parahippocampal gyrus, and occipitotemporal gyrus, from a high-AD neuropathology case from Yale (top row) and a PRIME LTE subject (bottom row). Left column: Low-magnification images (original magnification 2.5x) show dense p-tau immunohistochemical reactivity in the occipitotemporal neocortex of a high-AD case from Yale compared with an LTE subject. Parahippocampal gyrus reactivity is comparable in these two cases. Center column: Medium-magnification images of the occipitotemporal neocortical region identified by the box in the left column, showing frequent NPs (arrows) in the high-AD sections from Yale but no NPs in the sections from the LTE subject. Right column: High-magnification images showing NPs (arrows), frequent NFTs, and dense NTs in high-AD sections from Yale and NBB. Sections from LTE patients show relatively few NFTs and NTs. C shows a graphical comparison of very low density temporal neocortical p-tau neuropathology in a PRIME LTE subject versus extensive temporal neocortical p-tau neuropathology in a group of nine untreated high-AD controls. D shows representative images of dual Aβ / p-tau immunoreactivity in NP. Top panel: NP from a high-AD patient shows normal p-tau immunoreactive dystrophic neurites (NP-tau).Lower panel: sparse p-tau immunoreactive dystrophic neurites surrounding residual dense-core amyloid plaques in a PRIME LTE subject. E shows a graphical comparison of the very sparse NP-tau neuropathology in a PRIME LTE subject to the extensive temporal neocortical NP-tau neuropathology in a group of nine untreated high-AD controls. [Figure 14A] The mean change from baseline in CDR-SB score over 78 weeks is shown. Longitudinal changes from baseline in clinical measures for the ITT population are presented here. The mean change from baseline in CDR-SB score is shown. Scores range from 0 to 18, with higher scores indicating greater impairment. Values ​​at each time point are based on an MMRM model, in which the change from baseline in CDR-SB score is the dependent variable, and the fixed effects are treatment group, category visit, treatment × visit interaction, baseline measure, baseline measure × visit interaction, baseline MMSE score (same as baseline score in the MMSE model), baseline Alzheimer's disease symptomatic medication use, region, and ApoE ε4 status by test. P values: †P<0.1 and ≥0.05, *P<0.05, **P<0.01, ***P<0.001. Error bars indicate standard error. adu, aducanumab; ApoE, apolipoprotein E; CDR-SB; Clinical Dementia Scale-Global. MMRM, mixed model for repeated measures; SE, standard error. [Figure 14B]The mean change from baseline in MMSE score over 78 weeks is shown. Longitudinal changes from baseline in clinical measures for the ITT population are shown here. The mean change from baseline in MMSE score is shown. Scores range from 0 to 30, with lower scores indicating greater impairment. Values ​​at each time point are based on the MMRM model, where change from baseline in MMSE score is the dependent variable, and the fixed effects are treatment group, category visit, treatment × visit interaction, baseline measure, baseline measure × visit interaction, baseline MMSE score (same as baseline score in the MMSE model), baseline Alzheimer's disease symptomatic medication use, region, and ApoE ε4 status by test. P values: †P<0.1 and ≥0.05, *P<0.05, **P<0.01, ***P<0.001. Error bars indicate standard error. adu, aducanumab; ApoE, apolipoprotein E; MMRM, mixed models for repeated measures; MMSE, Mini-Mental State Examination; SE, standard error. [Figure 14C] The mean change from baseline in ADAS-Cog13 scores over 78 weeks is shown. Longitudinal changes from baseline in clinical measures for the ITT population are shown here. The mean change from baseline in ADAS-Cog13 scores is shown. Scores range from 0 to 85, with higher scores indicating greater impairment. Values ​​at each time point are based on an MMRM model, in which the change from baseline in ADAS-Cog13 score is the dependent variable, and the fixed effects are treatment group, category visit, treatment × visit interaction, baseline measure, baseline measure × visit interaction, baseline MMSE score (same as baseline score in the MMSE model), baseline Alzheimer's disease symptomatic medication use, region, and ApoE ε4 status by test. P values: †P<0.1 and ≥0.05, *P<0.05, **P<0.01, ***P<0.001. Error bars indicate standard error. ADAS-Cog13, Alzheimer's Disease Assessment Scale, 13 items; adu, aducanumab; ApoE, apolipoprotein E; MMRM, mixed models for repeated measures; SE, standard error. [Figure 14D]The mean change from baseline in ADCS-ADL-MCI scores over 78 weeks is shown. Longitudinal changes from baseline in clinical measures for the ITT population are presented here. The mean change from baseline in ADCS-ADL-MCI scores is shown. Scores range from 0 to 53, with lower scores indicating greater impairment. Values ​​at each time point are based on an MMRM model, in which the change from baseline in ADCS-ADL-MCI scores is the dependent variable, and the fixed effects are treatment group, category visit, treatment × visit interaction, baseline measure, baseline measure × visit interaction, baseline MMSE score (same as baseline score in the MMSE model), baseline Alzheimer's disease symptomatic medication use, region, and ApoE ε4 status by test. P values: †P<0.1 and ≥0.05, *P<0.05, **P<0.01, ***P<0.001. Error bars indicate standard error. ADCS-ADL-MCI, Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory, Mild Cognitive Impairment Version; adu, aducanumab; ApoE, apolipoprotein E; MMRM, mixed models for repeated measures; SE, standard error. [Figure 15]Figure 1 shows longitudinal change from baseline in amyloid PET mean standardized uptake value ratio (SUVR) assessed by 18F-florbetapir in the amyloid PET substudy. Composite SUVR was calculated from the frontal, parietal, temporal, and sensorimotor cortices, anterior cingulate cortex, and posterior cingulate cortex and normalized using the cerebellum as the reference region. Change from baseline in amyloid PET SUVR was analyzed using an MMRM model with fixed effects of treatment, categorical visit, treatment × visit interaction, baseline SUVR, baseline SUVR × visit interaction, baseline MMSE, ApoE ε4 status by test (carrier vs. noncarrier), and baseline age. Placebo (diamond) values ​​represent adjusted mean change from baseline at week 78. Low-dose (square) and high-dose (triangle) aducanumab values ​​represent difference from placebo at week 78. ***P<0.001. Error bars represent SE. adu, aducanumab; ApoE, apolipoprotein E; MMRM, mixed models for repeated measures; MMSE, Mini-Mental State Examination; PET, positron emission tomography; SE, standard error. [Figure 16] CSF Aβ1-42 at Week 78. These figures show the adjusted mean change from baseline in CSF Aβ1-42 levels in the CSF substudy. Values ​​are based on an ANCOVA model at Week 78, fitting change from baseline as the dependent variable and treatment, baseline CSF Aβ1-42 levels, baseline age, and laboratory ApoE ε4 status (carriers and noncarriers) as independent variables. P value: ***P<0.001. ANCOVA, analysis of covariance; ApoE, apolipoprotein E; CSF, cerebrospinal fluid; SE, standard error. [Figure 17]CSF p-tau and t-tau at week 78 are shown. Adjusted mean change from baseline in CSF levels of p-tau and t-tau in the CSF subtest. Values ​​are based on an ANCOVA model at week 78, fitting change from baseline as the dependent variable and treatment, baseline biomarker value, baseline age, and laboratory ApoE ε4 status (carrier and non-carrier) as independent variables. P values: *P<0.05, **P<0.01, and ***P<0.001. ANCOVA, analysis of covariance; ApoE, apolipoprotein E; CSF; cerebrospinal fluid; p-tau, phosphorylated tau-181; SE, standard error; t-tau, total tau. [Figure 18] Figure 1. Tau deposition in the medial temporal complex. Adjusted mean change from baseline in tau PET mean SUVR assessed by 18F-MK-6240 in the tau PET substudy. Values ​​based on an ANCOVA model at week 78, with change from baseline as the dependent variable and categorical treatment, baseline tau PET value, and laboratory ApoE ε4 status (carrier and non-carrier) as independent variables. P values: *P<0.05, **P<0.01, and ***P<0.001. ANCOVA, analysis of covariance; PET, positron emission tomography; SE, standard error; SUVR, standard uptake value ratio. DETAILED DESCRIPTION OF THE INVENTION

[0076] Alzheimer's disease Alzheimer's disease, abbreviated herein as AD, is a dementia that is primarily identified by clinical diagnosis and established by markers of the disease.

[0077] AD is a continuum with specific operationally defined stages of disease progression. AD pathology begins before the onset of clinical symptoms. For example, amyloid plaques, one marker of AD pathology, form 10 to 20 years before the onset of AD dementia. Currently recognized stages of AD include pre-clinical, prodromal, mild, moderate, and severe. These stages can be further subdivided based on the severity of symptoms and measures of AD progression.

[0078] Because AD does not occur in discrete stages, those skilled in the art will recognize that differences between patient groups may not be distinguishable in certain clinical settings. Nevertheless, the clinical stages can be characterized by measurements and changes in these measurements over time, such as Aβ accumulation (CSF / PET), synaptic dysfunction (FDG-PET / fMRI), tau-mediated neuronal damage (CSF), brain structure (volumetric MRI), cognition, and clinical function. (Jack CR, et al. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade.Lancet Neurol.,2010;9(1):119-28).

[0079] The current core clinical criteria, referred to as the NINCDS-ADRDA criteria for all dementias (McKhann GM, V. Diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimer's & Dementia, 7 (2011) 263-269), are known in the art and can be used in the practice of the present invention. They include cognitive or behavioral impairments, including impaired ability to acquire and remember new information, impaired reasoning and processing of complex tasks, impaired visuospatial ability, impaired language function (speaking, reading, writing), and changes in personality, behavior, or attitude. Alzheimer's disease is currently diagnosed using these core criteria and is typically characterized by symptoms that develop gradually over months to years (insidious onset) rather than suddenly over hours or days. Subjects with Alzheimer's disease typically have a history of clear cognitive deterioration, either reported or observed.

[0080] As new information about AD becomes available, other diagnostic classification systems have evolved. These systems include the International Working Group (IWG) New Research Criteria for Diagnosis of AD (Dubois B et al., Lancet Neurol., 2007;6(8):734-736), the IWG Research Criteria (Dubois et al., Lancet Neurol., 2010;9(11):1118-27), the NIA / AA Criteria (Jack CR et al. Alzheimer's Dement., 2011;7(3):257-62), and the DSM-5 Criteria (American Psychiatric Association, DSM-5, 2013). These classification systems can also be used to diagnose AD subjects for treatment according to the methods of the present disclosure.

[0081] patient The term "patient" is intended to include any human subject for whom diagnosis, prediction, prevention, or treatment of Alzheimer's disease is desired, including a human subject in need of treatment. Human subjects in need of treatment include those already with AD, those prone to having AD, or those in whom symptoms of AD should be prevented. A typical patient is a male or female between the ages of 40 and 90 (e.g., 45-90, 50-90, 55-90, or 60-90). In one embodiment, the present disclosure provides methods for treating AD patients (including, but not limited to, pre-clinical, prodromal, mild, moderate, or severe AD patients). In certain examples, the present disclosure provides methods for treating patients with prodromal Alzheimer's disease. In some cases, the present disclosure provides methods for treating patients with early Alzheimer's disease. In some cases, the present disclosure provides methods for treating patients to reduce clinical deterioration of Alzheimer's disease. In some cases, the present disclosure provides methods for treating patients with mild cognitive impairment due to Alzheimer's disease. In another example, the present disclosure provides a method of treating a patient with mild Alzheimer's disease dementia. In a further embodiment, the patient has amyloid pathology confirmed, for example, by positron emission tomography (PET) imaging. In some cases, the amyloid beta pathology is 18 In some cases, amyloid-β pathology can be confirmed by [F]-florbetapir PET imaging. 18 In some cases, amyloid-β pathology can be confirmed by [F]-flutemetomol PET imaging. 18 Optionally, the amyloid-beta pathology is confirmed by [F]-florbetaben PET imaging. Optionally, the amyloid-beta pathology is confirmed by amyloid-beta analysis of CSF. Optionally, the amyloid-beta pathology is confirmed by amyloid-beta analysis of blood. Optionally, the amyloid-beta pathology is confirmed by Congo red staining and birefringence under polarized light microscopy. Optionally, the amyloid-beta pathology is confirmed by immunohistochemistry (IHC), electron microscopy, or mass spectrometry. Optionally, the amyloid-beta pathology is confirmed by any method assessing amyloid-beta levels.

[0082] In certain examples, the patient to be treated has an MMSE score of 24 to 30 (inclusive). Optionally, the patient to be treated has a CDR global score of 0.5. Optionally, the patient to be treated has an RBANS score of 85 or less (based on the Delayed Memory Index score). Optionally, the patient to be treated has at least 6 years of employment experience. Optionally, the patient to be treated has an MMSE score of 24 to 30 (inclusive), a CDR global score of 0.5, and an RBANS score of 85 or less (based on the Delayed Memory Index score). In certain examples, the patient is an ApoE4 carrier (ApoE4 positive). In certain examples, the patient is an ApoE4 non-carrier (ApoE4 negative).

[0083] AD patients in need of treatment range from subjects with amyloid pathology and early neurodegeneration, to subjects with widespread neurodegeneration and irreversible neuronal loss with progressive cognitive and functional impairment, towards dementia.

[0084] Preclinical AD patients can be identified by an asymptomatic phase with or without memory symptoms and new episodic memory and executive dysfunction, which is typically characterized by the appearance of in vivo molecular biomarkers of AD and the absence of clinical symptoms.

[0085] Prodromal AD patients are primarily in the pre-dementia stage, characterized by cognitive impairment and new functional deficits associated with disease progression. Patients with prodromal AD typically have a Mini-Mental State Examination (MMSE) score of 24–30 (inclusive), spontaneous memory symptoms, objective memory impairment defined as a free recall score of less than 27 on the Cued and Uncued Selective Recall Test (FCSRT), a global Clinical Dementia Scale (CDR) score of 0.5, no significant levels of impairment in other cognitive domains, essentially preserved activities of daily living, and no dementia.

[0086] Patients with mild AD typically have an MMSE score of 20–26 (inclusive), a global CDR of 0.5 or 1.0, and meet the National Institute on Aging-Alzheimer's Association core clinical criteria for probable AD (see section 22).

[0087] When AD is diagnosed based on clinical symptoms, patients with mild AD exhibit noticeable behavior at work, forgetfulness, mood swings, and attention disorders. Patients with moderate AD exhibit cognitive impairment, limitations in daily activities, disorientation, apraxia, agnosia, aphasia, and behavioral abnormalities. Patients with severe AD are characterized by loss of independence, disruption of memory and speech, and incontinence.

[0088] In certain embodiments, the treatment comprises 18 In certain embodiments, the treatment is for patients with early stage amyloid-positive disease as assessed by [F]-florbetapir PET scan. 18 The treatment is for early-stage patients who are amyloid-positive as assessed by [18F]-flutemetomol PET scan. In certain embodiments, the treatment is for early-stage patients who are amyloid-positive as assessed by [18F]-florbetaben PET scan. In certain examples, the human subject is confirmed to have cerebral amyloid beta pathology before the start of treatment. The patient may be asymptomatic or only show transient symptoms such as headache, confusion, difficulty walking, or visual impairment. The patient may or may not be an ApoE4 carrier as identified by ApoE genotyping.

[0089] In other embodiments, treatment is of patients with any medical or neurological condition (other than AD) that may be causing cognitive impairment in the subject, such as stroke or other cerebrovascular condition, other neurodegenerative disease, a history of clinically significant psychiatric illness, acute or subacute micro- or macrobleeds, previous macrobleeds, or superficial cerebral hemosiderosis. These patients may be treated after screening and selection by a qualified clinician.

[0090] Anti-beta amyloid antibodies The antibody BIIB037, also known as aducanumab, is a biological treatment for Alzheimer's disease. It is an anti-Aβ antibody that recognizes aggregated forms of Aβ, including plaques. BIIB037 contains a human kappa light chain. BIIB037 consists of two heavy chains and two human kappa light chains linked by interchain disulfide bonds. "BIIB037" or "aducanumab" refers to an anti-Aβ antibody comprising the amino acid sequences set forth in SEQ ID NOs: 10 and 11.

[0091] In vitro characterization studies confirmed that antibody BIIB037 recognizes a conformational epitope present in Aβ aggregates, the accumulation of which is thought to underlie the onset and progression of AD.

[0092] In vivo pharmacological studies have shown that a mouse IgG2a chimeric form of an antibody with similar properties (ch 12F6A) significantly reduces amyloid plaque burden in the brains of aged Tg2576 mice, a mouse model of AD. This has been reported for certain anti-Aβ antibodies (Wilcock OM, Colton CA. Immunotherapy, vascular pathology, and microhemorrhages in transgenic mice. CNS & Neurological Disorders Drug Targets, 2009 Mar;8(1):50-64), the reduction in parenchymal amyloid was not accompanied by changes in vascular amyloid.

[0093] The VH and VL of antibody BIIB037 have amino acid sequences identical to those of the VH and VL of antibody NI-101.12F6A described in U.S. Patent No. 8,906,367 (see Tables 2-4, incorporated herein by reference in its entirety). Specifically, antibody BIIB037 has an antigen-binding domain comprising the VH and VL variable regions shown in Table A (VH) and Table B (VL), corresponding complementarity-determining regions (CDRs) shown in Table C, and heavy and light chains shown in Table D(H) and Table E(L). [Table A] [Table B] [Table C]

[0094] The amino acid sequence of the mature heavy chain of BIIB037 is shown in Table D below. [Table D]

[0095] The amino acid sequence of the mature light chain of BIIB037 is shown in Table E below. [Table E]

[0096] In addition to antibody BIIB037, the present disclosure contemplates the use of other anti-beta-amyloid antibodies, such as antibodies comprising either a VH region comprising or consisting of SEQ ID NO: 1 or a VL region comprising or consisting of SEQ ID NO: 2, or antibodies comprising a VH region comprising or consisting of SEQ ID NO: 1 and a VL region comprising or consisting of SEQ ID NO: 2, wherein the VH and / or VL regions have one or more substitutions, deletions, and / or insertions. In some embodiments, these VH and VL regions can have up to 25, up to 20, up to 15, up to 10, up to 5, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid substitutions and still be capable of binding to beta-amyloid. In certain embodiments, these amino acid substitutions occur only in the framework regions. In some embodiments, the amino acid substitution(s) are conservative amino acid substitutions. In certain embodiments, the VH and VL regions can contain deletions and / or additions of 1 to 5 (1, 2, 3, 4, 5) amino acids and still be capable of binding to beta-amyloid. In certain embodiments, these deletions and / or additions are made at the N-terminus and / or C-terminus of the VH and / or VL regions. In one embodiment, one amino acid is deleted and / or added at the N-terminus and / or C-terminus of the VH region. In one embodiment, one amino acid is deleted and / or added at the N-terminus and / or C-terminus of the VL region.

[0097] Other antibodies contemplated for use in the present disclosure include antibodies comprising the variable heavy chain (VH) CDRs and variable light chain (VL) CDRs of Table C. Thus, the anti-beta amyloid antibodies comprise CDRs comprising or consisting of the amino acid sequences of SEQ ID NOS: 3-8. In one embodiment, the anti-beta amyloid antibodies comprise CDRs comprising or consisting of the amino acid sequences of SEQ ID NOS: 4-8, and include an amino acid sequence comprising or consisting of GFAFSSYGMH (SEQ ID NOS: 9) as the VH CDR1. In some cases, the present disclosure encompasses anti-beta amyloid antibodies comprising the VH and VL CDRs of BIIB037 based on any CDR definition (e.g., Kabat, Chothia, modified Chothia, AbM, or contact definition). See, for example, http: / / www.bioinf.org.uk / abs / index.html. In one embodiment, the present disclosure encompasses anti-beta amyloid antibodies comprising the VH and VL CDRs of BIIB037 based on the Chothia definition. In one embodiment, the disclosure encompasses anti-beta-amyloid antibodies comprising the VH and VL CDRs of BIIB037 according to the modified Chothia definition. In another embodiment, the disclosure encompasses anti-beta-amyloid antibodies comprising the VH and VL CDRs of BIIB037 according to the AbM definition. In yet another embodiment, the disclosure encompasses anti-beta-amyloid antibodies comprising the VH and VL CDRs of BIIB037 according to the contact definition.

[0098] Antibody BIIB037 and other antibodies used in the present invention can be prepared using known methods. In some embodiments, the antibody is expressed in a Chinese hamster ovary (CHO) cell line.

[0099] The maximum tolerated dose of the anti-Aβ antibody is an amount consistent with the safety of the antibody that produces a clinically significant response in the treatment of Alzheimer's disease. A major safety concern when treating patients according to the methods of the invention is the occurrence of ARIA, particularly ARIA-E or ARIA-H. The methods of the invention allow for the use of higher doses of antibody BIIB037 for the treatment of patients with AD than was feasible using previously known protocols.

[0100] It will be understood that dose adjustments can be made during treatment protocols. For example, for safety or efficacy reasons, the dose may be increased to enhance the effect of anti-Aβ antibody on AD, or may be decreased to reduce the rate and severity of ARIA. If a dose is missed, the patient should preferably receive the missed dose and then resume dosing by continuing according to the described regimen.

[0101] In certain embodiments, the anti-Aβ antibody is administered to a patient by intravenous infusion after dilution with saline. Using this method of administration, each infusion step in the titration regime of the present invention typically takes about 1 hour.

[0102] The dose ranges and other numerical values ​​herein include amounts having the same effect as the numerically expressed amount as shown by treating Alzheimer's disease in a patient, and reducing the incidence and susceptibility of the patient to ARIA compared to individuals not treated with the methods of the invention. At the very least, each numerical parameter should be construed in light of the number of significant digits, applying ordinary rounding techniques. Moreover, any numerical value inherently contains certain errors from the standard deviation of its measurement, and such values ​​are within the scope of the invention.

[0103] treatment As used herein, the term "treating" or "treatment" generally refers to obtaining a desired pharmacological and / or physiological effect in a subject receiving the anti-beta amyloid antibody. Thus, as used herein, the term "treatment" includes (a) suppressing AD, e.g., halting its onset, (b) alleviating AD, e.g., causing regression of AD, or (c) prolonging survival compared to expected survival if not receiving treatment.

[0104] In one embodiment, the treatment is therapeutic. In another embodiment, the treatment has a disease-modifying effect. This means that the treatment slows or delays the underlying pathological or pathophysiological course of the disease, and there is an improvement in the clinical signs and symptoms of AD compared to placebo.

[0105] In further embodiments, treatment results in symptomatic improvement, which may consist of enhanced cognition, increased autonomy, and / or improvement in neuropsychiatric and behavioral dysfunction, even if only for a limited period of time.

[0106] In another embodiment, the present disclosure relates to a method for delaying clinical deterioration or progression of a disease or for symptomatic relief. Delaying clinical deterioration or disease progression directly impacts patients and caregivers, thereby delaying disability, maintaining independence, and allowing patients to lead normal lives for a longer period of time. Relieving symptoms as much as possible can result in gradual improvements in cognition, function, behavioral symptoms, and mood.

[0107] The present disclosure features titration regimens (sequential administration of increasing doses of an anti-beta amyloid antibody) for treating Alzheimer's disease, optionally mild Alzheimer's disease, early Alzheimer's disease, prodromal Alzheimer's disease, mild Alzheimer's dementia, or mild cognitive impairment due to Alzheimer's disease.

[0108] In one method of treating Alzheimer's disease, the anti-beta amyloid antibody is administered to a human patient in increasing amounts over a period of time. This procedure of continuously administering the antibody to the patient is referred to herein as "titration" because it involves administering carefully measured amounts of a standardized drug of known concentration until the procedure is completed.

[0109] One advantage of the titration regime of the present invention is that it allows AD patients to be administered a higher dose of monoclonal antibody without incurring the same degree of ARIA as observed with standard dosage regimens.In certain embodiments, this higher dose comprises 10mg / kg of the anti-Aβ antibody dose(s) per subject's body weight.Without intending to be limited to any particular mechanism, it is believed that titration reduces amyloid clearance at the beginning and slows down clearance over the course of the entire treatment.

[0110] The titration of anti-Aβ antibody (e.g., BIIB037) is carried out by multiple administrations.For example, two administrations of antibody can be administered to the patient at an amount less than the minimum therapeutic dose per administration, and then four administrations of the antibody can be administered at an amount approximately equal to the minimum therapeutic dose per administration.Then, after this regime, multiple administrations can be administered at an amount greater than the minimum therapeutic dose per administration but less than the maximum tolerated dose until the patient's AD shows acceptable changes.For example, administration can be administered at intervals of about 4 weeks for about 52 weeks (a total of 14 times).Progress can be monitored by regular evaluation.

[0111] In some cases, the disclosure features a method of reducing tau or reducing Abeta and / or tau to treat Alzheimer's disease in a human patient in need thereof, the method including sequentially administering to the human patient multiple increasing amounts of an anti-Aβ antibody (e.g., BIIB037) over a period of time, where the human patient is administered multiple doses of 1 mg antibody / kg of body weight of the human patient about four weeks apart; the human patient is administered multiple doses of 3 mg antibody / kg of body weight of the human patient about four weeks apart; the human patient is administered multiple doses of 6 mg antibody / kg of body weight of the human patient about four weeks apart; and the human patient is administered multiple doses of 10 mg antibody / kg of body weight of the human patient about four weeks apart. By multiple administrations is meant at least two (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 123, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30) administrations.

[0112] One protocol according to the present disclosure, referred to as Protocol A, includes the following: (A) administering the anti-beta amyloid antibody to the patient in an amount of 1 mg / kg of body weight of the patient; (B) 4 weeks after step (A), administering the anti-beta amyloid antibody to the patient in an amount of 1 mg / kg of body weight of the patient; (C) 4 weeks after step (B), administering the anti-beta amyloid antibody to the patient in an amount of 3 mg / kg of body weight of the patient; (D) 4 weeks after step (C), administering the anti-beta amyloid antibody to the patient in an amount of 3 mg / kg of body weight of the patient; (E) 4 weeks after step (D), administering the anti-beta amyloid antibody to the patient in an amount of 6 mg / kg of body weight of the patient; (F) 4 weeks after step (E), administering the anti-beta amyloid antibody to the patient in an amount of 6 mg / kg of body weight of the patient; (G) At successive four week intervals following step (F), the anti-beta amyloid antibody is administered to the patient in an amount of 10 mg / kg of the patient's body weight.

[0113] In other words, Protocol A involves administering to the patient a first dose of an anti-beta amyloid antibody in an amount of 1 mg / kg of the patient's body weight, followed by a second dose four weeks after the first dose in an amount of 1 mg / kg of body weight. Four weeks after the second dose, the patient is administered a third and fourth dose of the antibody in an amount of 3 mg / kg of body weight. Four weeks after the fourth dose, the patient is administered a fifth and sixth dose of the antibody in an amount of 6 mg / kg of body weight. Then, four weeks after the sixth dose, the patient is administered a seventh dose of the antibody in an amount of 10 mg / kg of body weight.

[0114] In some cases, after the seventh administration of Protocol A, 5, 6, 7, 8, 9, or 10 doses of the anti-beta amyloid antibody are administered to the patient in an amount of 10 mg / kg of body weight.In certain examples, at least 10, at least 11, at least 12, at least 13, or at least 14 doses of the anti-beta amyloid antibody are administered to the patient in an amount of 10 mg / kg of body weight of the subject.In certain examples, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 doses of the anti-beta amyloid antibody are administered to the patient in an amount of 10 mg / kg of body weight of the subject. In certain examples, 15-16, 15-17, 15-18, 15-19, 15-20, 15-21, 15-22, 15-23, 15-24, or 15-25 doses of the anti-beta amyloid antibody are administered to the patient in an amount of 10 mg / kg of subject body weight. In certain examples, the doses are administered at consecutive 4-week intervals. In certain examples, the doses are administered intravenously to the patient.

[0115] In some cases, after the seventh administration of Protocol A, the patient is administered at least 10 doses of the anti-beta amyloid antibody (e.g., intravenously) at uninterrupted four-week intervals in an amount of 10 mg / kg of subject body weight.

[0116] Another protocol according to the present disclosure, referred to as Protocol B, includes the following: (a) administering the anti-beta-amyloid antibody to the subject in an amount of 1 mg / kg of body weight of the subject; (b) 4 weeks after step (a), administering the anti-beta-amyloid antibody to the subject in an amount of 3 mg / kg of body weight of the subject; (c) 4 weeks after step (b), administering the anti-beta-amyloid antibody to the subject in an amount of 6 mg / kg of body weight of the subject; (d) after step (c), at successive intervals of four weeks, at least ten administrations of the anti-beta-amyloid antibody are administered in an amount of 10 mg / kg of body weight of the subject.

[0117] In some cases, after step (d) of protocol B, additional administration of the anti-beta amyloid antibody is administered to the patient in an amount of 10 mg / kg of body weight.In certain examples, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 administrations of the anti-beta amyloid antibody are administered to the patient in an amount of 10 mg / kg of subject body weight.In certain examples, at least 21, at least 22, at least 23, at least 24, at least 24, or at least 25 administrations of the anti-beta amyloid antibody are administered to the patient in an amount of 10 mg / kg of subject body weight. In certain examples, 11-12, 11-13, 11-14, 11-15, 11-16, 11-17, 11-18, 11-19, 11-20, or 11-25 doses of the anti-beta amyloid antibody are administered to the patient in an amount of 10 mg / kg of subject body weight. In certain examples, the additional doses are administered at consecutive 4-week intervals. In certain examples, the doses are administered intravenously to the patient.

[0118] In certain instances, if a patient develops amyloid-related imaging abnormalities (ARIA), such as ARIA-E, during treatment, the treatment will be discontinued until the ARIA resolves.In some cases, the treatment will be discontinued for 1 to 15 (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15) weeks to allow the ARIA to resolve, and then resume.In certain instances, if the subject develops ARIA-E and / or ARIA-H accompanied by severe clinical symptoms, or if the subject develops ARIA-H accompanied by 10 or more microhemorrhages and / or 2 or more superficial hemosiderosis lesion areas, or if any new concomitant macrohemorrhages occur, the treatment will be permanently discontinued.

[0119] In certain instances, if the patient develops an amyloid-related imaging abnormality (ARIA) during treatment with Protocol A or B, the patient will continue to receive the above doses without dose reduction. In some cases, the dose may be administered after the ARIA has resolved.

[0120] If treatment is interrupted for any reason (for example, if a doctor's appointment is missed, or if a doctor recommends due to ARIA or other side effects), the patient should continue with the same or a higher dose after treatment is resumed.For example, if the patient has already received 3 mg / kg of the anti-beta amyloid antibody twice before interruption, the patient should receive 6 mg / kg after treatment is resumed.If the patient has already received 6 mg / kg of the anti-beta amyloid antibody twice before interruption, the patient should receive 10 mg / kg after treatment is resumed.If the patient has already received 10 mg / kg of the anti-beta amyloid antibody twice before interruption, the patient should receive 10 mg / kg after treatment is resumed, and should continue to receive 10 mg / kg for as long as possible.

[0121] The present disclosure also features a method for treating mild Alzheimer's disease, early Alzheimer's disease, prodromal Alzheimer's disease, mild Alzheimer's dementia, or mild cognitive impairment due to Alzheimer's disease in a human subject in need of such treatment.The method comprises administering an anti-beta-amyloid antibody to the human subject multiple times, the method comprising administering the antibody at least six times at consecutive four-week intervals, each administration being administered in an amount of 10 mg / kg of the subject's body weight.In some cases, the method comprises administering the antibody at least seven times at consecutive four-week intervals, each administration being administered in an amount of 10 mg / kg of the subject's body weight.In some cases, the method comprises administering the antibody at least eight times at consecutive four-week intervals, each administration being administered in an amount of 10 mg / kg of the subject's body weight. In some cases, the method comprises administering the antibody at least 9 times at consecutive 4-week intervals, each administration being administered in an amount of 10 mg / kg of the subject's body weight. In some cases, the method comprises administering the antibody at least 10 times at consecutive 4-week intervals, each administration being administered in an amount of 10 mg / kg of the subject's body weight. In some cases, the method comprises administering the antibody at least 11 times at consecutive 4-week intervals, each administration being administered in an amount of 10 mg / kg of the subject's body weight. In some cases, the method comprises administering the antibody at least 12 times at consecutive 4-week intervals, each administration being administered in an amount of 10 mg / kg of the subject's body weight. In some cases, the method comprises administering the antibody at least 13 times at consecutive 4-week intervals, each administration being administered in an amount of 10 mg / kg of the subject's body weight. In some cases, the method includes administering the antibody at least 14 times at consecutive 4-week intervals, each administration being administered in an amount of 10 mg / kg of the subject's body weight. In some cases, the method includes administering the antibody at least 15 times at consecutive 4-week intervals, each administration being administered in an amount of 10 mg / kg of the subject's body weight. In certain examples, all of the specified administrations are administered without interruption, even if the human subject develops ARIA during the course of treatment.In certain instances, if administration is interrupted due to ARIA or other side effects, the treatment continues at the same or a higher dose of the antibody. If the patient is on the highest dose of Protocol A (10 mg / kg), the patient will continue to receive 10 mg / kg of the antibody when treatment is resumed after an interruption.

[0122] In some cases, the anti-beta amyloid antibody of the above protocols and methods comprises a VH and VL comprising the six CDRs of BIIB037. In certain examples, the anti-beta amyloid antibody comprises a VH and VL of BIIB037. In other examples, the anti-beta amyloid antibody comprises a heavy chain and a light chain of BIIB037. In some cases, the anti-beta amyloid antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises a complementarity determining region (VHCDR1) having the amino acid sequence of SEQ ID NO:3, a VHCDR2 having the amino acid sequence of SEQ ID NO:4, and a VHCDR3 having the amino acid sequence of SEQ ID NO:5, and the VL comprises a VLCDR1 having the amino acid sequence of SEQ ID NO:6, a VLCDR2 having the amino acid sequence of SEQ ID NO:7, and a VLCDR3 having the amino acid sequence of SEQ ID NO:8. In some cases, the anti-beta amyloid antibody comprises a VH comprising or consisting of SEQ ID NO:1, and a VL comprising or consisting of SEQ ID NO:2. Optionally, the anti-beta amyloid antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises or consists of SEQ ID NO:10 and the light chain comprises or consists of SEQ ID NO:11. [Example]

[0123] Example 1: Overview of Phase 3 Study The efficacy and safety of aducanumab in subjects with mild cognitive impairment (MCI) due to Alzheimer's disease or mild Alzheimer's disease dementia were evaluated in two similarly designed phase 3 studies, Study 1 and Study 2. These studies were designed based on an understanding of the mechanism of action of aducanumab, the results of previous studies, and current understanding of the disease course and underlying pathology. Table 1 provides an overview of the study design. [Table 1]

[0124] These phase 3 trials recruited early-stage patients who were Aβ positive (visually read) on AβPET scans and met clinical criteria for mild cognitive impairment (MCI) due to Alzheimer's disease or mild Alzheimer's disease dementia (as defined by the NIA-AA criteria). Enrollment was monitored to ensure that approximately 80% of this phase 3 study population included subjects with a baseline clinical stage of MCI due to Alzheimer's disease (as assessed by the investigator's clinical assessment). Subjects were also required to have a CDR global score of 0.5, a RBANS score ≤ 85 (based on the Delayed Memory Index score), and an MMSE score of 24–30 (inclusive), and to have at least 6 years of education or work experience. Subjects were required to be 50–85 years of age at screening. Subjects with medical or neurological conditions other than Alzheimer's disease that may have contributed to their cognitive impairment were excluded. Subjects were required to be healthy except for Alzheimer's disease.

[0125] Notably, this phase 3 protocol also required subjects to undergo ApoE genotyping, given that the ε4 allele is a major risk factor for Alzheimer's disease. Both ApoE ε4 carriers and noncarriers were enrolled in both phase 3 studies, but dosing discrimination based on carrier status was limited to the aducanumab "low" dose only. See Figure 1.

[0126] Example 2: Primary Efficacy Endpoint of Study 2 The primary endpoint results for modified intent to treat (mITT) and opportunity to complete (OTC) subjects who had the opportunity to complete the 78-week visit are summarized in Table 2. In the high-dose group, the significance of the mean change in CDR-SB for aducanumab versus placebo was -0.40 (23% less worsening, nominal p=0.0101). The low-dose group also had less decline in CDR-SB than placebo, but the difference was smaller than that of the high-dose group and did not achieve statistical significance. [Table 2]

[0127] Example 3: Secondary Endpoints of Study 2 The results of the secondary efficacy endpoints for the mITT and OTC datasets are summarized in Table 3.

[0128] The high-dose group demonstrated statistically significant differences from placebo (nominal p-values ​​<0.05) for all secondary endpoints in both data sets, except for MMSE in the mITT data set. The low-dose group did not demonstrate statistical significance for any of these three secondary endpoints in either the mITT or OTC data sets. However, a small numerical advantage over placebo was observed for the low dose for all endpoints except for MMSE. [Table 3]

[0129] Example 4: Tertiary Endpoint of Study 2—Brain Aβ Measured by PET and Quantified as Standardized Uptake Value Ratio (SUVR) Serial assessment of brain Aβ plaque levels, measured by AβPET and quantified as SUVR, was performed in a subset of subjects who participated in the longitudinal AβPET substudy. PET scans in this longitudinal substudy were: 18 F-florbetapir Aβ PET tracer was used (except for a small number of subjects who used a different tracer). 18 Results for subjects undergoing F-florbetapir PET scans are summarized here.

[0130] To analyze the effect of aducanumab on brain Aβ plaque levels measured by PET, standardized uptake value ratios (SUVRs, the ratio of radiotracer uptake in areas expected to harbor Aβ pathology to a reference region with minimal or no Aβ pathology) were calculated for the entire cerebellum as a reference region, along with a composite region of interest including major cortical regions of the brain (frontal, parietal, temporal, sensorimotor, anterior cingulate, and posterior cingulate cortices) [Ostrowitzki et al., Alzheimers Res. Ther. 8;9(1):95(2017); Chiao et al., J Nucl Med. 60(1):100-106(2019); Sevigny, Nature 537(7618):50-6(2016)]. SUVRs for this composite region were used as the primary endpoint for Aβ PET analysis. A negative change from baseline in this composite SUVR indicates a reduction in Aβ plaque levels, and a negative treatment difference (aducanumab minus placebo) favors aducanumab.

[0131] Figure 2 shows the time- and dose-dependent decrease in brain Aβ levels. At week 26, which coincided with the end of the titration phase, the adjusted mean change from baseline in AβPET composite SUVR was -0.070 and -0.076 for the low- and high-dose groups, respectively, compared with 0.007 for the placebo group. Separation between the low- and high-dose groups was not expected due to similar dosing during the titration phase. At week 78, the adjusted mean change from baseline in AβPET composite SUVR was -0.165 and -0.272 for the low- and high-dose groups, respectively, compared with 0.019 for the placebo group.

[0132] Example 5: Primary Efficacy Endpoint of Study 1 The results of the mITT and OTC analyses of this primary endpoint indicate that the high dose of aducanumab did not reduce exacerbations compared with placebo (Table 4). The low dose group did not achieve nominal statistical significance for this primary endpoint. However, a small numerical advantage over placebo was observed for the low dose. This difference was similar in magnitude to the difference between the low dose and placebo in Example 1. [Table 4]

[0133] Example 6: Secondary Efficacy Endpoints of Study 1 The results of the mITT and OTC analyses of this secondary endpoint show no statistically significant differences compared with placebo for declines in MMSE, ADAS-Cog13, or ADCS-ADL-MCI (Table 5). However, a small numerical advantage over placebo was observed for the low dose for these endpoints. The results for the high-dose group were similar to those for the low-dose group for ADAS-Cog13 or ADCS-ADL-MCI. [Table 5]

[0134] Example 7: Tertiary Endpoint of Study 1—Brain Aβ Measured by PET and Quantified as Standardized Uptake Value Ratio (SUVR) As in the test in Example 3, 18 A longitudinal AβPET substudy was conducted using the F-florbetapir AβPET tracer.

[0135] As can be seen in Figure 3, aducanumab produced time- and dose-dependent reductions in brain Aβ levels. At week 26, which coincided with the end of the titration phase, the adjusted mean change from baseline in AβPET composite SUVR was -0.066 for both the low- and high-dose aducanumab groups, compared with -0.002 for the placebo group. Separation between the low- and high-dose groups was not expected due to similar dosing during the titration phase. At week 78, the adjusted mean change from baseline in AβPET composite SUVR was -0.168 and -0.238 for the low- and high-dose aducanumab groups, respectively, compared with -0.005 for the placebo group.

[0136] Example 8: CSF levels of p-tau in studies 1 and 2 Cerebrospinal fluid (CSF) was collected in a subset of subjects at selected study sites at baseline and week 78. p-tau 181P CSF levels of tau and total tau were measured using the Lumipulse® G immunoassay (Fujirebio, Malvern, PA, USA).

[0137] CSF levels of p-tau have been correlated with neocortical neurofibrillary tangles [Buerger, Brain, 129(Pt 11):3035-41(2006)] and PET imaging of tau [Gordon, Brain, 139(Pt 8):2249-60(2016)]. Elevated CSF levels of p-tau have been reported to be specific for Alzheimer's disease [Olsson, Lancer Neurol., 15(7):673-684(2016)]. Analysis of published Alzheimer's Disease Neuroimaging Initiative (ADNI) data indicates an expected annual increase in CSF p-tau of approximately 2%.

[0138] Consistent with the effect of aducanumab on tau PET, a statistically significant reduction in CSF p-tau levels was observed in Studies 1 and 2, with a dose-proportional response in Study 2 (see Figures 4 and 8A).

[0139] Example 9: t-tau levels in studies 1 and 2 In contrast to p-tau, elevated CSF t-tau levels have been reported in multiple neurodegenerative diseases as well as traumatic brain injury and stroke [Jack et al., Alzheimer's Dement, 14(4):535-562(2018)] and are thought to reflect nonspecific neurodegeneration and axonal degeneration in the brain [Blennow et al., Nat. Rev. Neurol., 6(3):131-44(2010)]. As can be seen in Figures 5 and 8B, aducanumab produced a numerical reduction in CSF t-tau levels in Study 1 and Study 2, with a dose-proportional response in Study 2.

[0140] Example 10: Time Profile of Mean AβPET Complex SUVR in Patients Receiving 10 or More Doses of 10 mg / kg at Steady State Figure 6 shows the mean brain AβPET composite SUVR-time profiles for Study 1 and 2 subjects in the groups receiving 10 mg / kg doses over 10 steady-state dosing intervals, as well as the AβPET composite SUVR profiles for the respective placebo groups. The mean AβPET composite SUVR profiles for the two groups of interest in Study 1 and 2 had very similar shapes, with equal means at Week 78.

[0141] Example 11: Mean CDR-SB time profiles of subjects in studies 1 and 2 Figure 7 shows the mean CDR-SB time profiles for patients in Studies 1 and 2 who received 10 mg / kg for 6 or more steady-state dosing intervals (sample size Study 1: n=241 and Study 2: n=257), 10 mg / kg for 8 or more steady-state dosing intervals (sample size Study 1: n=186 and Study 2: n=194), and 10 mg / kg for 10 or more steady-state dosing intervals (sample size Study 1: n=116 and Study 2: n=147). CDR-SB profiles for the respective placebo groups are also shown.

[0142] In Study 2, the various dose groups had similar CDR-SB responses. In Study 1, the difference from placebo increased with increasing number of uninterrupted 10 mg / kg doses, implying that much of the difference between studies may be attributable to subjects receiving fewer than 10 uninterrupted suboptimal doses of 10 mg / kg.

[0143] Example 12: Tau PET study 18 Tau PET imaging using F-MK-6240 ligand was performed in a subset of subjects at selected centers at screening and week 78. Composite standardized uptake value ratios (SUVRs) for the medial temporal, temporal, and frontal regions were calculated using the cerebellar cortex as the reference region. Due to small sample sizes, all analyses were performed using pooled data from both studies.

[0144] This tau PET study pooled data from both studies (n=37) 18 Tau deposition was analyzed using F-MK-6240 as a tau ligand. Subjects treated with aducanumab demonstrated a statistically significant, dose-dependent reduction in tau SUVR levels in the medial temporal complex brain region compared to placebo (P = 0.0012 for the low dose and P = 0.0005 for the high dose) (Figure 9A). Changes from baseline in tau PET medial temporal complex SUVR correlated with cumulative dose through week 78 (Figure 9B). 18 F-MK-6240 has been shown to be a suitable PET tau tracer for in vivo imaging, as well as for characterization and quantification of tau neurofibrillary tangles and aggregates in Alzheimer's disease. See, e.g., Pascoal et al. Alzheimer's Research & Therapy (2018) 10:74 and Betthauser et al., J. Nucl. Res. Med. 60 (2019), 93-99. Thus, the results of this tau PET study, along with the findings from the PRIME trial presented in Example 14 below, demonstrate that aducanumab, particularly at high doses and the dosing regimes disclosed herein, can reduce the number of tau tangles in the brains of patients with Alzheimer's disease.

[0145] In summary, PET and CSF biomarker studies showed that aducanumab reduced Aβ, as well as tau pathology and neurodegeneration, in subjects with early Alzheimer's disease. This was the first evidence in a Phase 3 trial that correction of underlying disease pathology was associated with a statistically significant slowing of clinical deterioration. Thus, the results of Studies 1 and 2 provide important evidence that Aβ clearance can translate into clinical benefit.

[0146] Example 13: Safety The incidence of adverse events occurring during the placebo-controlled study period was comparable between the placebo and aducanumab groups across both studies. In Study 2, 93.1% of subjects in the high-dose group, 89.5% in the low-dose group, and 87.4% in the placebo group had an adverse event; in Study 1, 90.1% of subjects in the high-dose group, 90.0% in the low-dose group, and 86.5% in the placebo group had an adverse event. With the exception of amyloid-related imaging abnormalities (ARIA), the incidence and nature of adverse events were consistent with the Alzheimer's disease diagnosis and expected comorbidities for the age of the study population (median age: 70.7 years in Study 2 and 70.1 years in Study 1). There were 16 fatal events during the placebo-controlled period between the two studies, 11 in aducanumab-treated subjects and 5 in placebo-treated subjects. The reported causes of death were consistent with Alzheimer's disease or underlying comorbidities, such as cardiovascular disease.

[0147] As shown in Table 6, the most common adverse events with an incidence greater than 10% in either treatment group were ARIA-edema (ARIA-E), cerebral microhemorrhage (referred to in this study as ARIA-H microhemorrhage), headache, nasopharyngitis, falls, focal superficial hemosiderosis (referred to in this study as ARIA-H superficial hemosiderosis), and dizziness. ARIA-E was the most common adverse event in aducanumab-treated subjects. Compared with placebo, aducanumab-treated subjects experienced an increased incidence of cerebral microhemorrhage and focal superficial hemosiderosis. In these subjects, microhemorrhage and focal superficial hemosiderosis often occurred simultaneously with ARIA-E. In the absence of ARIA-E, the incidence of cerebral microhemorrhage and focal superficial hemosiderosis was similar between the aducanumab and placebo groups. [Table 6]

[0148] The majority of subjects with ARIA remained symptom-free during the course of the ARIA (Study 2: 80.3% high-dose, 78.7% low-dose, 96.4% placebo; Study 1: 71.2% high-dose, 83.6% low-dose, 94.5% placebo). Symptoms reported in the setting of ARIA were transient and included headache, confusion, and dizziness. The majority of ARIA-E episodes resolved within 12 weeks, and the majority of subjects with ARIA continued treatment without interruption or resumed treatment after a temporary interruption. Specifically, a total of 65 subjects in Study 2 (7.0% high-dose, 4.8% low-dose, 0.2% placebo) and 73 subjects in Study 1 (7.2% high-dose, 5.1% low-dose, 0.9% placebo) permanently discontinued study treatment due to ARIA.

[0149] Permanent discontinuation of treatment for a subject with ARIA may be necessary if the subject develops any of the following: o "Other medically significant events" * ARIA-E with severe clinical symptoms, excluding o "Other medically significant events" * Symptomatic ARIA-H (microhemorrhage) with severe clinical symptoms, excluding o "Other medically significant events" * Symptomatic ARIA-H (superficial cerebral hemosiderosis) with severe clinical symptoms, excluding o ARIA-H with ≥10 microhemorrhages and / or ≥2 focal areas of superficial hemosiderosis. Any new concomitant macrobleeds (T2 * defined as diameter >1 cm in the sequence). The subject becomes pregnant. Study treatment must be immediately discontinued and the pregnancy must be reported. o The subject withdraws consent to continue study treatment. o The subject experiences a medical emergency requiring permanent discontinuation of study treatment or unblinding of the subject's treatment assignment. o The subject experiences an AE that does not resolve or requires ongoing treatment that meets the exclusion criteria. o The subject experiences a severe infusion reaction. o Investigator discretion for medical reasons. Investigator or sponsor discretion for non-compliance.

[0150] Subjects who discontinue treatment will remain in the study and attend the FU visit 18 weeks after the last dose, and will immediately continue with protocol-required testing and assessments at a subset of clinic visits according to the schedule of events until the end of the study or until the subject withdraws consent.

[0151] * = "Other medically significant events" include those that are life-threatening (in the opinion of the investigator), require patient hospitalization or extension of existing hospitalization, and / or result in persistent or significant disability / incapacity or congenital anomaly / birth defect.

[0152] In summary, the most common adverse events were ARIA-E and headache. The majority of ARIA episodes were transient and asymptomatic.

[0153] Example 14: Alzheimer's Disease Neuropathology in Patients Treated with Aducanumab Case presentation The patient was an 84-year-old woman diagnosed with probable mild AD in 2013. Her APOE genotype was E3 / E3. Her medical history included coronary artery disease (prior to coronary stenting), hypertension, hyperlipidemia, and depression. Her medications included Exelon patches and Namenda. Cognitive screening for the study revealed a CDR-SB score of 3.5 and MMSE score of 23, corresponding to mild cognitive impairment (Figure 10A). Amyloid-PET (florbetapir) scans revealed Aβ plaques throughout the cerebral cortex and striatum (Figures 10B-C). This patient was randomized to the placebo arm of the Phase 1b PRIME trial, during which she received 14 IV infusions of placebo between May 1, 2013, and April 30, 2014. This patient showed rapid progression of cognitive impairment, with scores of 6 on the CDR-SB and 15 on the MMSE at week 54, corresponding to mild-moderate dementia (FIG. 10A).

[0154] This patient was subsequently enrolled in a long-term extension (LTE), during which he received two monthly 3 mg / kg IV infusions of aducanumab, followed by 30 monthly 6 mg / kg IV infusions from June 2, 2014, to November 10, 2016. During this time, all surveillance MRI scans were negative for amyloid-related imaging abnormalities (ARIA). Amyloid PET scans at weeks 110 and 166, 56 and 112 after initiation of aducanumab treatment, respectively, demonstrated robust standardized uptake value ratio (SUVR) declines in the frontal, temporal, and parietal cortices and striatum (Figure 10B-C). SUVR signal declined in the occipital cortex during aducanumab treatment but remained elevated compared to other regions. Despite robust Aβ plaque reduction, this patient continued to experience cognitive deterioration and moderate to severe dementia (CDR-SB11, MMSE5 / 30). The patient entered skilled nursing care in November 2016, at which time aducanumab was discontinued. The patient died 4 months later in March 2017. An autopsy of the brain donation was performed at Yale University 17 hours after death.

[0155] Neuropathological examination Whole-brain examination revealed a brain weight of 1,000 grams. Leptomeninges showed no hemorrhage or hemosiderin. There was symmetric cortical atrophy involving the frontal, temporal, and parietal lobes. Coronal sections showed hippocampal atrophy. The substantia nigra was normally pigmented. There were no new or previous infarcts or parenchymal hemorrhages. According to the NIA / AA consensus guidelines, histological sections examined at Yale confirmed the presence of Alzheimer's disease neuropathological changes. Aβ plaques were observed in the neocortex and hippocampus (Thal phase 2), NFTs were observed in association neocortical sections (Braak stage V), and sparse neocortical NPs were observed in modified Bielschowsky-stained sections (CERAD score 1). The composite NIA / AA ABC score was A1, B3, and C1, consistent with "low AD neuropathological changes." There was no significant glial tauopathy, no ballooning of neurons, and no other neuropathological signs of non-Alzheimer's tauopathies. The neuropathological examination was also negative for Lewy bodies and TDP-43 proteinopathy, hippocampal sclerosis (LATE), and microinfarcts.

[0156] Immunohistochemical staining for Aβ (antibody 6E10) showed frequent Aβ plaques in sections from the untreated, high-AD case (Figures 11A and 11C). In contrast, cortical sections from this LTE patient (Figures 11B and 11D) showed sparse Aβ plaques. The remaining plaques in sections from this LTE patient consisted primarily of dense cores lacking a surrounding halo of less dense Aβ (Figure 11D). Where a surrounding halo of less dense Aβ persisted, particularly in sections of the peri-striate cortex, they displayed a moth-eaten appearance, evident by reactive microglia (Figure 11D, inset). Visiopharm-generated cortical Aβ plaque whole-slide image (WSI) heatmaps showed clearance of Aβ plaques across sections of the frontal, temporal, and occipital cortex in this LTE patient, compared with the high plaque density in sections from the untreated, high-AD case (Figure 11E). The highest levels of residual Aβ plaque immunoreactivity were present in the peristriate cortex of the occipital lobe (Figure 11E, right panel), consistent with the amyloid-PET SUVR data. Sections from the basal ganglia and midbrain were devoid of Aβ plaques. Comparison of temporal neocortical Aβ plaque density between this LTE patient and a cohort of high-AD patients who did not receive aducanumab (Figure 11F) revealed significantly fewer Aβ plaques in the LTE patients. Taken together, these ex vivo neuropathological findings confirm the robust Aβ plaque clearance in LTE patients demonstrated by florbetapir-PET.

[0157] We examined microglial reactivity to residual Aβ plaques using a dual 6E10 / IBA1 immunohistochemistry assay. Compared with sections from untreated high-AD cases (Figure 12A), residual and worm-eaten plaques from this LTE patient appeared to show greater association of microglia with highly reactive amoeboid morphology (Figure 12B). A WSI analysis algorithm designed to segment microglial IBA1 immunoreactivity within a 5 μm radius from the edge of Aβ plaques revealed higher microglial plaque association in this LTE patient compared to a cohort of untreated high-AD patients (Figure 12C). Higher magnification views of Aβ plaques from this LTE patient showed Aβ plaques surrounded by microglial processes and Aβ within the plasma membrane boundaries of amoeboid microglia (Figure 12D).

[0158] Phosphorylated TAU was measured in sections from this patient with LTE. Ser202,Thr205 Immunohistochemical staining (p-tau, 40E8) (Figure 13) revealed neurofibrillary tangles indicative of Braak stage V / VI (NIA / AA stage B3) neurofibrillary tangles in sections of the association neocortex. However, compared with sections from untreated high-grade AD cases, sections of the frontal and occipitotemporal neocortex from this LTE patient had significantly lower densities of p-tau immunoreactivity (Figures 13A and 13B). Whole-slide imaging analysis algorithms designed to segment and quantify p-tau immunoreactivity in somatic and neuropil threads demonstrated lower neocortical p-tau density in this LTE patient compared with the range of untreated high-grade AD cases (Figure 13C). A dual Aβ, p-tau (40E8) immunohistochemistry assay used to segment p-tau immunoreactive dystrophic neurites around senile plaque p-tau (NP-tau), i.e., Aβ plaques that propagate proteopathic tau seeds in AD, showed abundant NP-tau in sections from an untreated high-AD patient (Figure 13D, upper panel), but residual NP-tau-free plaques in this LTE patient (Figure 13D, lower panel). The mean density of NP-tau in this LTE patient was lower than the range of NP-tau densities in control high-AD specimens (Figure 13E).

[0159] In summary, these are the first neuropathological data from AD patients treated with aducanumab. The neuropathological findings support the florbetapir-PET data showing Aβ plaque clearance, demonstrate microglial binding and phagocytosis of Aβ plaques, and provide evidence of neuropathological reduction of p-tau, consistent with the tau-PET and CSF p-tau biomarker assay data from Studies 1 and 2.

[0160] Example 15: Final Analysis of the Placebo-Controlled Periods of Study 1 and Study 2 The primary endpoint was met in Study 2. High-dose aducanumab versus placebo demonstrated a mean difference in change from baseline in CDR-SB scores at week 78 of -0.39 (95% confidence interval, -0.69 to -0.09, P=0.012), a 22% reduction (Table 7, Figure 14A-D). High-dose aducanumab also demonstrated a slower rate of deterioration compared with placebo in MMSE (-18%), ADAS-Cog13 (-27%), and ADCS-ADL-MCI (-40%) scores (P<0.05). No statistically significant differences were observed in the low-dose aducanumab group compared with placebo.

[0161] The primary endpoint was not met in Study 1. For high-dose aducanumab vs. placebo, the mean difference in change from baseline in CDR-SB scores at week 78 was 0.03 (95% confidence interval, -0.26 to 0.33; P = 0.833), a 2% increase (Table 7, Figure 14A-D). The change in MMSE score (3%), change in ADAS-Cog score (-11%), and change in ADCS-ADL-MCI score (-18%) relative to placebo were not statistically significant. The results for this low-dose group were consistent with those of Study 2. [Table 7]

[0162] In the amyloid PET substudy, dose- and time-dependent declines in amyloid PET SUVR were observed at week 78. The difference in adjusted mean change from baseline between high-dose aducanumab and placebo was −0.28 (95% confidence interval, −0.31 to −0.25, P<0.001) in Study 2 and −0.23 (95% confidence interval, −0.26 to −0.21, P<0.001) in Study 1 (Figure 15).

[0163] In a CSF substudy, patients receiving high-dose aducanumab showed lower Aβ levels, a measure of target binding, compared with patients receiving placebo. 1-42 CSF levels of Aβ increased in a dose-dependent manner (Figure 16). 1-42The differences from placebo in adjusted mean changes from baseline in CSF levels of Aβ were 318.88 (95% CI, 247.18 to 390.58, P<0.001) and 198.73 (95% CI, 91.02 to 306.43, P<0.001) in Study 2 and Study 1, respectively. As expected, CSF Aβ levels were significantly higher in the placebo group than in the control group. 1-40 There were no significant differences between treatment groups (data not shown). In Study 2, there was a dose-dependent and significant decrease in CSF levels of p-tau, a disease biomarker, and t-tau, a nonspecific marker of neurodegeneration (Figure 17). In Study 1, there were numerical decreases in CSF levels of p-tau and t-tau that did not reach statistical significance.

[0164] The tau PET substudy included patients pooled across both studies. Patients treated with aducanumab demonstrated statistically significant dose-dependent reductions in tau PET SUVR in the medial temporal, temporal, and frontal lobes compared with placebo-treated patients (Figure 18). Results for the parietal, cingulate, and occipital lobes were not statistically significant (data not shown).

[0165] An analysis plan was developed that included multiple lines of investigation to assess why the results differed between Study 2 and Study 1. The two main factors contributing to the discrepancy in results between Study 1 and the high-dose arms of Study 2 were rapid progressors (defined as patients with a change from baseline in CDR-SB score of >8 at week 78) and the effect of underdosing.

[0166] We analyzed a subgroup of patients referred to as the post-PV4 subgroup who consented to PV4 (or a later protocol version) at or before week 16. Patients in this subgroup randomized to receive high-dose aducanumab had the opportunity to receive all 14 doses of 10 mg / kg aducanumab. Protocol management of ARIA in this subgroup also provided for fewer dose interruptions and the possibility of initiating titration after dose interruptions. Thus, the mean cumulative dose in the high-dose group in the pre-PV4 subgroup of Study 1 was lower than that in the post-PV4 subgroup (Table 8). Furthermore, 15 of the 18 rapid progressors in Study 1 belonged to the pre-PV4 subgroup.

[0167] Thus, analysis of the post-PV4 subgroup of Study 1 demonstrates results that are not influenced by lower dosing and rapidly progressing patients. The difference from placebo in the adjusted mean change from baseline in CDR-SB score at week 78 was −0.49 (95% confidence interval, −1.02 to 0.04) for patients in the post-PV4 group of Study 1 who received high-dose aducanumab, representing a 27% reduction (Table 8). [Table 8]

[0168] conclusion Analyses from the final data set in Study 2 demonstrated a statistically significant benefit of high-dose aducanumab versus placebo in the pre-specified primary endpoint, CDR-SB, at week 78. Statistically significant slowing of clinical deterioration was detected across three secondary endpoints, and consistent clinical superiority of aducanumab versus placebo was demonstrated using outcome measures assessing both cognitive and functional change in patients with early-stage AD.

[0169] The primary endpoint was not met in Study 1. A post-hoc analysis of a subset of patients with aducanumab at a target dose of 10 mg / kg (post-PV4 subgroup) suggested that the results of Study 1 were due to a cluster of patients with inadequate dosing and rapid disease progression.

[0170] Results from sub-studies of proximal pharmacodynamic biomarkers (Aβ CSF and PET) and Alzheimer's disease-specific downstream biomarkers (tau PET and CSF p-tau) and neurodegeneration (CSF t-tau) further supported the clinical findings. This was the first evidence in a phase 3 trial that modification of biomarkers of underlying disease pathology is associated with a statistically significant slowing of clinical deterioration. It is important to consider the small number of patients in the tau PET and CSF sub-studies. However, consistent with the lower cumulative dose in Study 1, the effects on biomarkers in the high-dose group in Study 1 were smaller compared with Study 2.

[0171] The most common adverse event associated with aducanumab was ARIA-E, an imaging abnormality detected via brain MRI in both studies. As observed in other studies of anti-amyloid monoclonal antibodies, ARIA was largely asymptomatic, and most patients with ARIA were able to continue treatment. Overall, the safety and tolerability profile of aducanumab in Study 2 and Study 1 was consistent with previous studies. In summary, Study 2 demonstrated the clinical significance of aducanumab versus placebo, reflecting a benefit over the current standard of care for patients with early-stage Alzheimer's disease. Results from a subgroup of patients in Study 1 exposed to high-dose aducanumab support these findings.

[0172] Other embodiments While the present invention has been described in conjunction with a detailed description thereof, the foregoing description is intended to be illustrative, but not limiting, of the scope of the invention, which is defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims. In certain embodiments, for example, the following are provided: (Item 1) 1. A method of treating Alzheimer's disease in a human subject in need thereof, comprising administering to said human subject multiple doses of an anti-beta-amyloid antibody, said multiple doses comprising: (a) administering the anti-beta-amyloid antibody to the subject in an amount of 1 mg / kg of body weight of the subject; (b) 4 weeks after step (a), administering the antibody to the subject in an amount of 1 mg / kg of body weight of the subject; (c) 4 weeks after step (b), administering the antibody to the subject in an amount of 3 mg / kg of body weight of the subject; (d) 4 weeks after step (c), administering the antibody to the subject in an amount of 3 mg / kg of body weight of the subject; (e) 4 weeks after step (d), administering the antibody to the subject in an amount of 6 mg / kg of body weight of the subject; (f) 4 weeks after step (e), administering the antibody to the subject in an amount of 6 mg / kg of body weight of the subject; (g) after step (f), administering the antibody at least 15 times in an amount of 10 mg / kg of body weight of the subject at consecutive 4-week intervals; the anti-beta-amyloid antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL); The VH comprises a complementarity determining region (VHCDR1) having the amino acid sequence of SEQ ID NO: 3, a VHCDR2 having the amino acid sequence of SEQ ID NO: 4, and a VHCDR3 having the amino acid sequence of SEQ ID NO: 5; The method, wherein the VL comprises a VLCDR1 having the amino acid sequence of SEQ ID NO: 6, a VLCDR2 having the amino acid sequence of SEQ ID NO: 7, and a VLCDR3 having the amino acid sequence of SEQ ID NO: 8. (Item 2) 10. The method of claim 1, wherein step (g) comprises administering the antibody at least 18 times at consecutive 4-week intervals, each time in an amount of 10 mg / kg of body weight of the subject. (Item 3) 10. The method of claim 1, wherein step (g) comprises administering the antibody at least 20 times at consecutive 4-week intervals, each time in an amount of 10 mg / kg of body weight of the subject. (Item 4) 4. The method according to any one of items 1 to 3, wherein all administrations specified in steps (a) to (g) are administered without interruption, even if the human subject develops amyloid-related imaging abnormalities (ARIA) during the course of the treatment. (Item 5) 4. The method of any one of items 1 to 3, wherein the human subject develops ARIA during the course of the treatment, and all doses specified in steps (a) to (g) are administered without interruption. (Item 6) 6. The method according to any one of items 1 to 5, wherein the Alzheimer's disease is mild Alzheimer's disease, early Alzheimer's disease, prodromal Alzheimer's disease, mild Alzheimer's disease dementia, or mild cognitive impairment due to Alzheimer's disease. (Item 7) 1. A method of treating mild Alzheimer's disease, early Alzheimer's disease, prodromal Alzheimer's disease, mild Alzheimer's dementia, or mild cognitive impairment due to Alzheimer's disease in a human subject in need thereof, comprising administering to the human subject multiple doses of an anti-beta-amyloid antibody, the method comprising at least six administrations of the antibody, spaced apart by four consecutive weeks, each administration in an amount of 10 mg / kg of body weight of the subject; the anti-beta-amyloid antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL); The VH comprises a complementarity determining region (VHCDR1) having the amino acid sequence of SEQ ID NO: 3, a VHCDR2 having the amino acid sequence of SEQ ID NO: 4, and a VHCDR3 having the amino acid sequence of SEQ ID NO: 5; The method, wherein the VL comprises a VLCDR1 having the amino acid sequence of SEQ ID NO: 6, a VLCDR2 having the amino acid sequence of SEQ ID NO: 7, and a VLCDR3 having the amino acid sequence of SEQ ID NO: 8. (Item 8) 8. The method of claim 7, comprising administering the antibody at least eight times at consecutive four-week intervals, wherein each administration is given in an amount of 10 mg / kg of body weight of the subject. (Item 9) 8. The method of claim 7, comprising administering the antibody at least 10 times at consecutive 4-week intervals, wherein each administration is given in an amount of 10 mg / kg of body weight of the subject. (Item 10) 8. The method of claim 7, comprising administering the antibody at least 15 times at consecutive 4-week intervals, wherein each administration is given in an amount of 10 mg / kg of body weight of the subject. (Item 11) 11. The method according to any one of items 7 to 10, wherein all of the prescribed doses are administered without interruption even if the human subject develops ARIA during the course of the treatment. (Item 12) 11. The method of any one of items 7 to 10, wherein the human subject develops ARIA during the course of the treatment and all of the specified doses are administered without interruption. (Item 13) 1. A method of treating Alzheimer's disease in a human subject in need thereof, comprising administering to said human subject multiple doses of an anti-beta-amyloid antibody, said multiple doses comprising: (a) administering the anti-beta-amyloid antibody to the subject in an amount of 1 mg / kg of body weight of the subject; (b) 4 weeks after step (a), administering the antibody to the subject in an amount of 1 mg / kg of body weight of the subject; (c) 4 weeks after step (b), administering the antibody to the subject in an amount of 3 mg / kg of body weight of the subject; (d) 4 weeks after step (c), administering the antibody to the subject in an amount of 3 mg / kg of body weight of the subject; (e) 4 weeks after step (d), administering the antibody to the subject in an amount of 6 mg / kg of body weight of the subject; (f) 4 weeks after step (e), administering the antibody to the subject in an amount of 6 mg / kg of body weight of the subject; (g) after step (f), in consecutive four week intervals, administering the antibody to the subject in an amount of 10 mg / kg of body weight of the subject; the anti-beta-amyloid antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL); The VH comprises a complementarity determining region (VHCDR1) having the amino acid sequence of SEQ ID NO: 3, a VHCDR2 having the amino acid sequence of SEQ ID NO: 4, and a VHCDR3 having the amino acid sequence of SEQ ID NO: 5; The method, wherein the VL comprises a VLCDR1 having the amino acid sequence of SEQ ID NO: 6, a VLCDR2 having the amino acid sequence of SEQ ID NO: 7, and a VLCDR3 having the amino acid sequence of SEQ ID NO: 8, and all of the specified administrations are administered without interruption even if the human subject develops ARIA during the course of the treatment. (Item 14) 14. The method of claim 13, wherein the human subject develops ARIA during the course of the treatment and all of the prescribed doses are administered without interruption. (Item 15) 15. The method of claim 13 or 14, wherein step (g) comprises administering the antibody at least six times, consecutively at intervals of four weeks, each time in an amount of 10 mg / kg of body weight of the subject. How to do it. (Item 16) 15. The method of claim 13 or 14, wherein step (g) comprises administering the antibody at least eight times, at consecutive four-week intervals, each time in an amount of 10 mg / kg of body weight of the subject. (Item 17) 15. The method of claim 13 or 14, wherein step (g) comprises administering the antibody at least 10 times at consecutive 4-week intervals, each time in an amount of 10 mg / kg of body weight of the subject. (Item 18) 18. The method according to any one of items 13 to 17, wherein the Alzheimer's disease is mild Alzheimer's disease, early Alzheimer's disease, prodromal Alzheimer's disease, mild Alzheimer's disease dementia, or mild cognitive impairment due to Alzheimer's disease. (Item 19) The method of any one of the preceding items, wherein each administration is administered intravenously. (Item 20) 1. A method of treating Alzheimer's disease in a human subject in need thereof, comprising administering to said human subject multiple doses of an anti-beta-amyloid antibody, said multiple doses comprising: (a) administering the anti-beta-amyloid antibody intravenously to the subject in an amount of 1 mg / kg of body weight of the subject; (b) 4 weeks after step (a), administering the antibody intravenously to the subject in an amount of 1 mg / kg of body weight of the subject; (c) 4 weeks after step (b), administering the antibody intravenously to the subject in an amount of 3 mg / kg of the subject's body weight; (d) 4 weeks after step (c), administering the antibody intravenously to the subject in an amount of 3 mg / kg of body weight of the subject; (e) 4 weeks after step (d), administering the antibody intravenously to the subject in an amount of 6 mg / kg of body weight of the subject; (f) 4 weeks after step (e), administering the antibody intravenously to the subject in an amount of 6 mg / kg of body weight of the subject; (g) after step (f), administering the antibody intravenously at least six times at consecutive four-week intervals in an amount of 10 mg / kg body weight to the subject; the anti-beta-amyloid antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL); The VH comprises a complementarity determining region (VHCDR1) having the amino acid sequence of SEQ ID NO: 3, a VHCDR2 having the amino acid sequence of SEQ ID NO: 4, and a VHCDR3 having the amino acid sequence of SEQ ID NO: 5; The method, wherein the VL comprises a VLCDR1 having the amino acid sequence of SEQ ID NO: 6, a VLCDR2 having the amino acid sequence of SEQ ID NO: 7, and a VLCDR3 having the amino acid sequence of SEQ ID NO: 8. (Item 21) 21. The method of claim 20, wherein step (g) comprises intravenously administering the antibody at least eight times at consecutive four-week intervals, each time in an amount of 10 mg / kg of body weight of the subject. (Item 22) 21. The method of claim 20, wherein step (g) comprises intravenously administering the antibody at least 10 times at consecutive 4-week intervals, each time in an amount of 10 mg / kg of body weight of the subject. (Item 23) 23. The method of any one of items 20 to 22, wherein all administrations specified in steps (a) to (g) are administered without interruption, even if the human subject develops ARIA during the course of the treatment. (Item 24) 23. The method of any one of items 20 to 22, wherein the human subject develops ARIA during the course of the treatment, and all doses specified in steps (a) to (g) are administered without interruption. (Item 25) 25. The method according to any one of Items 20 to 24, wherein the Alzheimer's disease is mild Alzheimer's disease, early Alzheimer's disease, prodromal Alzheimer's disease, mild Alzheimer's disease dementia, or mild cognitive impairment due to Alzheimer's disease. (Item 26) The method of any one of the preceding items, wherein the human subject is confirmed to have cerebral amyloid beta pathology prior to initiation of treatment. (Item 27) 27. The method of claim 26, wherein the cerebral amyloid beta pathology is identified by positron emission tomography (PET) imaging. (Item 28) The method according to any one of items 1 to 27, the VH comprises the amino acid sequence of SEQ ID NO: 1; The method, wherein the VL comprises the amino acid sequence of SEQ ID NO:2. (Item 29) 29. The method according to any one of items 1 to 28, wherein the antibody comprises a human IgG1 constant region. (Item 30) the anti-beta-amyloid antibody comprises a heavy chain and a light chain; the heavy chain comprises the amino acid sequence of SEQ ID NO: 10; 28. The method according to any one of items 1 to 27, wherein the light chain comprises the amino acid sequence of SEQ ID NO: 11. (Item 31) 1. A method for treating Alzheimer's disease in a human subject in need thereof, comprising administering to the human subject a therapeutically effective amount of an anti-beta-amyloid antibody comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises a VH complementarity determining region 1 (VHCDR1) having the amino acid sequence of SEQ ID NO: 3, a VHCDR2 having the amino acid sequence of SEQ ID NO: 4, and a VHCDR3 having the amino acid sequence of SEQ ID NO: 5, and the VL comprises a VLCDR1 having the amino acid sequence of SEQ ID NO: 6, a VLCDR2 having the amino acid sequence of SEQ ID NO: 7, and a VLCDR3 having the amino acid sequence of SEQ ID NO: 8, wherein the human subject has p-tau tangles, p-tau threads, and / or p-tau senile plaques, and optionally, the human subject has neocortical p-tau tangles, neocortical p-tau threads, and / or neocortical p-tau senile plaques. (Item 32) 32. The method of claim 31, wherein administration of the anti-beta-amyloid antibody reduces p-tau tangles, p-tau threads, and / or p-tau senile plaques in the brain of the human subject, or reduces the amount of phosphorylated tau (p-tau) and / or total tau (t-tau) in the cerebrospinal fluid (CSF) of the human subject. (Item 33) 33. The method of item 31 or 32, wherein prior to administration of the anti-beta-amyloid antibody, p-tau tangles, p-tau threads, and / or p-tau neuritic plaques are detected by a positron emission tomography (PET) scan of the human subject's brain or by analysis of the amount of p-tau and / or t-tau in the human subject's CSF. (Item 34) 34. The method of any one of items 31 to 33, further comprising monitoring p-tau tangles, p-tau threads, and / or p-tau neuritic plaques during the course of treatment by PET scan of the human subject's brain or analysis of the amount of p-tau and / or t-tau in the CSF of the human subject. (Item 35) 34. The method of any one of items 31 to 33, wherein the dosage of the anti-beta-amyloid antibody and / or the frequency of administration of the anti-beta-amyloid antibody is adjusted over the course of treatment by monitoring p-tau tangles, p-tau threads, and / or p-tau plaques in the brain of the human subject using a PET scan or by analysis of the amount of p-tau and / or t-tau in the CSF of the human subject. (Item 36) 36. The method of item 35, wherein the treatment results in (i) a decrease in SUVR, density, and / or distribution of p-tau tangles, p-tau threads, and / or p-tau plaques compared to a previous PET scan, or (ii) a decrease in the amount of p-tau and / or t-tau in a CSF analysis compared to a previous CSF analysis. (Item 37) A method for reducing tau in a human subject with Alzheimer's disease, comprising administering to the human subject an effective amount of an anti-beta-amyloid antibody comprising a VH and a VL, wherein the VH comprises a VHCDR1 having the amino acid sequence of SEQ ID NO: 3, a VHCDR2 having the amino acid sequence of SEQ ID NO: 4, and a VHCDR3 having the amino acid sequence of SEQ ID NO: 5, and the VL comprises a VLCDR1 having the amino acid sequence of SEQ ID NO: 6, a VLCDR2 having the amino acid sequence of SEQ ID NO: 7, and a VLCDR3 having the amino acid sequence of SEQ ID NO: 8. (Item 38) A method for treating Alzheimer's disease in a human subject in need thereof by reducing the amount of tau, the method comprising administering to the human subject an effective amount of an anti-beta-amyloid antibody comprising a VH and a VL, wherein the VH comprises a VHCDR1 having the amino acid sequence of SEQ ID NO: 3, a VHCDR2 having the amino acid sequence of SEQ ID NO: 4, and a VHCDR3 having the amino acid sequence of SEQ ID NO: 5, and the VL comprises a VLCDR1 having the amino acid sequence of SEQ ID NO: 6, a VLCDR2 having the amino acid sequence of SEQ ID NO: 7, and a VLCDR3 having the amino acid sequence of SEQ ID NO: 8. (Item 39) 39. The method of item 37 or 38, wherein the human subject has been diagnosed or has previously been diagnosed with p-tau tangles, p-tau threads, and / or p-tau neuritic plaques in the brain and / or has been diagnosed or has previously been diagnosed with increased amounts of p-tau and / or t-tau in the CSF of the human subject compared to a human subject without Alzheimer's disease. (Item 40) 40. The method of any one of items 37 to 39, wherein the amount of tau in the brain and / or CSF of the human subject is reduced. (Item 41) 41. The method according to any one of items 37 to 40, wherein the amount of p-tau and / or t-tau is reduced in the human subject. (Item 42) 42. The method of any one of items 37 to 41, wherein the human subject has elevated levels of tau measured in CSF or in the brain by PET scan prior to administration of the anti-beta-amyloid antibody. (Item 43) The Alzheimer's disease may be mild Alzheimer's disease, early Alzheimer's disease, prodromal Alzheimer's disease, or 43. The method of any one of items 31 to 42, wherein the diagnosis is Alzheimer's disease, mild Alzheimer's dementia, mild cognitive impairment due to Alzheimer's disease, intermediate-stage Alzheimer's disease, or late-stage Alzheimer's disease, optionally wherein intermediate-stage Alzheimer's disease is characterized by a Mini-Mental State Examination (MMSE) score of about 10 to 20 or an equivalent score on another scale, and wherein late-stage Alzheimer's disease is characterized by an MMSE score of about 9 or less or an equivalent score on another scale. (Item 44) 43. The method according to any one of items 31 to 42, wherein the Alzheimer's disease is mild cognitive impairment due to Alzheimer's disease. (Item 45) 43. The method according to any one of items 31 to 42, wherein the Alzheimer's disease is mild Alzheimer's disease dementia. (Item 46) 46. ​​The method according to any one of items 31 to 45, wherein the VH comprises the amino acid sequence of SEQ ID NO: 1 and the VL comprises the amino acid sequence of SEQ ID NO: 2. (Item 47) 46. ​​The method according to any one of items 31 to 45, wherein the anti-beta-amyloid antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 10 and a light chain comprising the amino acid sequence of SEQ ID NO: 11. (Item 48) 48. The method of any one of items 31 to 47, wherein the anti-beta-amyloid antibody is administered intravenously. (Item 49) 49. The method of any one of items 31 to 48, comprising administering the anti-beta-amyloid antibody in an amount of 3 mg antibody / kg body weight of the human subject. (Item 50) 49. The method of any one of items 31 to 48, comprising administering the anti-beta-amyloid antibody in an amount of 6 mg antibody / kg body weight of the human subject. (Item 51) 49. The method of any one of items 31 to 48, comprising administering the anti-beta-amyloid antibody in an amount of 10 mg antibody / kg body weight of the human subject. (Item 52) 49. The method of any one of items 31 to 48, comprising administering the anti-beta-amyloid antibody multiple times as follows: (a) administering the anti-beta-amyloid antibody to the human subject in an amount of 1 mg antibody / kg body weight of the human subject; (b) 4 weeks after step (a), administering the antibody to the human subject in an amount of 1 mg antibody / kg of body weight of the human subject; (c) 4 weeks after step (b), administering the antibody to the human subject in an amount of 3 mg antibody / kg of body weight of the human subject; (d) 4 weeks after step (c), administering the antibody to the human subject in an amount of 3 mg antibody / kg of body weight of the human subject; (e) 4 weeks after step (d), administering the antibody to the human subject in an amount of 6 mg antibody / kg of body weight of the human subject; (f) 4 weeks after step (e), administering the antibody to the human subject in an amount of 6 mg antibody / kg of body weight of the human subject; (g) At consecutive four week intervals following step (f), the antibody is administered to the human subject in an amount of 10 mg antibody / kg of body weight of the human subject. (Item 53) 49. The method of any one of items 31 to 48, comprising administering the antibody at a cumulative dose of at least 150 mg antibody / kg body weight of the human subject. (Item 54) 49. The method of any one of items 31 to 48, comprising administering the antibody at a cumulative dose of at least 200 mg antibody / kg body weight of the human subject. (Item 55) 49. The method of any one of items 31 to 48, comprising administering the antibody in an amount of 10 mg antibody / kg body weight of the human subject every 4 weeks for at least 52 weeks. (Item 56) 49. The method of any one of items 31 to 48, comprising administering the antibody in an amount of 6 mg antibody / kg body weight of the human subject every 4 weeks for at least 112 weeks. (Item 57) 49. The method of any one of items 31 to 48, comprising administering the antibody to the human subject multiple times, wherein the multiple administrations include: (a) administering at least two doses every four weeks at 3 mg antibody / kg body weight of the human subject; and (b) at least 30 doses every 4 weeks of 6 mg antibody / kg body weight of said human subject. (Item 58) 58. The method according to any one of items 31 to 57, wherein the human subject is an ApoE3 carrier. (Item 59) 59. The method of any one of items 31 to 58, wherein the human subject does not develop amyloid-related imaging abnormalities (ARIA) during the course of the treatment that require discontinuation of the treatment.

Claims

[Claim 1] The invention described in the specification.

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