Methods for treating alzheimer's disease

Abstract

To provide methods for reducing the incidence of ARIA in Alzheimer's disease patients during AD treatment protocols.SOLUTION: This invention aids in fulfilling these needs in the art by providing a method for treating a human patient for Alzheimer's disease (AD). The method comprises sequential administration of multiple doses of a recombinant, fully human, anti-amyloid β monoclonal antibody to a patient. In a preferred embodiment, the antibody is administered to the patient in increasing amounts over a certain period of time. In a preferred embodiment, the method decreases cerebral amyloid accumulation. In a more preferred embodiment, the method reduces the susceptibility of the patient to ARIA.SELECTED DRAWING: None

Description

[Background technology]

[0001] Alzheimer's disease (AD) is a progressive neurodegenerative disorder clinically characterized by cognitive impairment, behavioral disturbances, psychiatric symptoms, and physical impairment in activities of daily living. These clinical symptoms constitute AD dementia.

[0002] Alzheimer's Disease International predicts that the number of people living with dementia worldwide will increase from the current 35.6 million to 115.4 million by 2050 (Alzheimer's Disease International). Alzheimer's disease, the most common cause of dementia, accounts for 60 to 80% of dementia cases. In the United States, it is estimated that 5.3 million Americans have dementia due to Alzheimer's disease, and the prevalence will double or triple by 2050 unless an effective treatment is found (Alzheimer's Association 2010).

[0003] Clinical research criteria for dementia due to AD have recently been updated, and a diagnostic framework has been developed to incorporate pre-dementia stages of AD (e.g., prodromal AD) in line with current concepts of the disease [Dubois 2010, Sperling 2011]. The primary psychopathological features of this disease are (i) extracellular senile (neuritic) plaques containing aggregated amyloid-β peptide (Aβ) and (ii) intraneuronal neurofibrillary tangles (NFTs) composed of abnormal hyperphosphorylated tau protein. While the development of these plaques and tangles and their contribution to the clinical pathology remain to be fully elucidated, the leading hypothesis, the "amyloid cascade hypothesis," proposes that the driving force behind the disease process is the accumulation of Aβ resulting from an imbalance between Aβ production and Aβ clearance in the brain [Hardy and Selkoe 2002].

[0004] Aβ is generated from the metabolism of amyloid precursor protein. Multiple Aβ peptide alloforms exist (e.g., Aβ40, Aβ42). These monomeric peptides have variable propensity to aggregate into higher dimers and oligomers. Through the process of fibril formation, soluble oligomers can transition to insoluble deposits with pleated sheet structures. These deposits are also called amyloid plaques and are therefore composed predominantly of fibrillar amyloid [Hampel et al. 2010, Gregory and Halliday 2005]. Both soluble and fibrillar forms of Aβ appear to contribute to the disease process [Meyer-Luehmann 2009, Hock 2003, Selkoe 2011].

[0005] Biomarker [Jack 2010], clinicopathological [Delacourte 2002], and demographic [Amieva 2008] studies suggest that the disease process begins 10–20 years before the clinical onset of symptoms, and some of the earliest pathological findings include neocortical senile plaque deposition and mesial temporal lobe NFTs, followed several years later by neocortical NFTs [Nelson et al. 2009].

[0006] Currently, there are no treatments that modify the progression of Alzheimer's disease. Currently approved treatments provide only minor symptomatic benefits and do not attenuate the course of the disease [Birks 2006, McShane 2006]. Several potential disease-modifying drug candidates are currently being investigated. These candidates include small molecules and immunotherapies (active and passive) that aim to provide therapeutic benefit by targeting the Aβ pathway in the brain or cerebrospinal fluid (CSF) and reducing either soluble or insoluble forms of Aβ.

[0007] In response to guidance issued by the US Food and Drug Administration (FDA) to various stakeholders involved in conducting clinical trials of amyloid-modifying drugs for the treatment of Alzheimer's disease, the Alzheimer's Association Research Roundtable convened a working group in July 2010. This working group was composed of academic and industry representatives based on their expertise and interest in this field. Its purpose was to provide expert advice regarding FDA concerns related to MRI abnormalities, including signal changes thought to represent vasogenic edema (VE) and microhemorrhages (mH). MRI signal changes were first observed in trials of monoclonal antibodies against amyloid beta [Black 2010, Salloway 2009, Sperling 2009] and have since been associated with other amyloid-modifying therapies.

[0008] Although the exact pathophysiological mechanisms of these MRI abnormalities remain unclear, VE and mH are typically detected on different MRI sequences. They appear to represent a diverse set of imaging abnormalities that may share a common underlying pathophysiological mechanism for both the natural history of AD and amyloid-modifying therapeutic approaches. The working group proposed to refer to this set of abnormalities as amyloid-related imaging abnormalities (ARIA).

[0009] Despite the possibility of a shared pathogenic mechanism, there may be instances where it is useful to describe specific phenomena. Therefore, this working group further refined the terminology. ARIA-E refers to MR signal changes that are representative of VE and thought to be related to vascular fluid phenomena. ARIA-H refers to MR signal changes attributable to mH and hemosiderosis.

[0010] ARIA-E commonly manifests as increased MR signal intensity on FLAIR or other T2-weighted sequences in the parenchyma and / or leptomeninges of the parietal, occipital, and frontal lobes, but has also been observed in the cerebellum and brainstem [Sperling 2009]. The presence of the ε4 allele of apolipoprotein E, ApoEε4, has been found to be a significant risk factor for the development of ARIA-E.

[0011] Currently, there are very limited published data on the clinical course associated with ARIA-E occurring in the setting of clinical trials of amyloid-modifying therapies. The working group reviewed data from clinical trials of bapineuzumab, but noted that it is unclear whether ARIA seen with other amyloid-modifying therapies follows a similar clinical course. In any event, the pathophysiological mechanisms underlying vasogenic edema remain unclear.

[0012] mH is generally due to one of two etiologies: small-vessel disease and cerebral amyloid angiopathy (CAA). The prevalence of mH is significantly increased in elderly individuals with cardiovascular risk factors and / or evidence of a previous cerebrovascular event [Goos 2010]. In AD, mH and superficial hemosiderosis result from blood leakage from CAA vessels [Nakata-Kudo 2006]. CAA weakens the vessel walls, increasing the risk of micro-leakage of blood into adjacent brain tissue, forming mH. Furthermore, published data on the incidence of mH in the setting of ARIA-E associated with amyloid-modifying therapy are very limited.

[0013] Preliminary reports of ARIA occurrence in therapeutic strategies aimed at reducing the production of specific A-beta peptides suggest that changes in the ratio of A-beta 1-42 or various A-beta species may alter the kinetics of amyloid production and clearance, leading to ARIA. Direct clearance of amyloid from the vessel wall would be associated with impaired vascular integrity. Alternatively, amyloid-associated endothelial cell dysfunction leading to increased vascular permeability could provide a similar explanation for increased permeability. As suggested by pathology reports from patients with CAA, there may also be a local inflammatory component that could lead to both ARIA-E and ARIA-H. Normal CSF has also been reported in inflammatory CAA, and local amyloid-associated vascular inflammation may contribute to some cases of ARIA. It also remains unclear whether various forms of immunotherapy or specific antibodies are more or less associated with ARIA [Siemers 2008]. The incidence of ARIA in patients being treated for Alzheimer's disease remains a persistent problem, and while there are multiple potential mechanisms of action, the answer to this question remains undiscovered. [Prior art documents] [Non-patent literature]

[0014] [Non-Patent Document 1] Alzheimer's Disease International. World Alzheimer Report 2010: The global economic impact of dementia. London: Alzheimer's Disease International 2010. [Non-patent document 2] Alzheimer's Association. 2010 Alzheimer's disease facts and figures. Alzheimers Dement. 2010 Mar;6(2):158-94. [Non-patent document 3] Dubois B, Feldman HH, Jacoba C, et al. Revising the definition of Alzheimer's disease: a new lexicon. Lancet Neurol. 2010;9(11):1118-27. [Non-patent document 4] Sperling RA, Jack Jr CR, Black SE, et al. Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: Recommendations from the Alzheimer's Association Research Roundtable Workgroup. Alzheimer's and Dementia. 2011;7(4):367-85. [Non-patent document 5] Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 2002 Jul 19;297(5580):353-6. [Non-patent document 6] Hampel H, Shen Y, Walsh DM et al. Biological markers of amyloid beta-related mechanisms in Alzheimer's disease. Exp Neurol2010 Jun;223(2):334-46. [Non-Patent Document 7] Gregory GC, Halliday GM. What is the dominant Abeta species in human brain tissue? A review. Neurotox Res. 2005;7(1-2):29~41. [Non-patent document 8] Meyer-Luehmann M, Mielke M, Spires-Jones TL et al. A reporter of local dendritic translocation shows plaque-related loss of neural system function in APP-transgenic mice. J Neurosci 2009 Oct 7;29(40):12636-40. [Non-Patent Document 9] Hock C, Konietzko U, Streffer JR, et al. Antibodies against beta-amyloid slow cognitive decline in Alzheimer's disease. Neuron. 2003;38(4):547~54. [Non-Patent Document 10] Selkoe DJ. Resolving controversies on the path to Alzheimer's therapeutics. Nat Med. 2011;17(9):1060-5. [Non-Patent Document 11] Jack CR, Knopman DS, Jagust WJ, et al. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol. 2010;9(1):119-28. [Non-Patent Document 12] Delacourte A, Sergeant N, Champain D, et al. Nonoverlapping but synergetic tau and APP pathologies in sporadic Alzheimer's disease. Neurology. 2002;59(3):398~407. [Non-Patent Document 13] Amieva H, Le Goff M, Millet X, et al. Prodromal Alzheimer's disease: successive emergence of the clinical symptoms. Ann Neurol. 2008;64(5):492-8. [Non-Patent Document 14] Nelson PT, Abner EL, Schmitt FA et al. Brains with medial temporal lobe neurofibrillary tangles but no neuritic amyloid plaques are a diagnostic dilemma but may have pathogenic aspects distinct from Alzheimer disease. J Neuropathol Exp Neurol 2009 Jul;68(7):774-84. [Non-Patent Document 15] Birks J. Cholinesterase inhibitors for Alzheimer's disease. Cochrane Database Syst Rev. 2006(1):1-94. Art. No.: CD005593. DOI: 10.1002 / 14651858.CD005593. [Non-Patent Document 16] McShane R, Areosa Sastre A, Minakaran N. Memantine for dementia. Cochrane Database Syst Rev. 2006(2):CD003154. [Non-Patent Document 17] [ PMC free article ] [ PubMed ] Black RS, Sperling RA, Safirstein B, Motter RN, Pallay A, Nichols A, et al. A single ascending dose study of bapineuzumab in patients with Alzheimer's disease. Alzheimer's Disease Assoc. 2010 Apr-Jun;24(2):198-203. [ PMC free article ] [ PubMed

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[0015] Thus, there is a need in the art for methods of reducing the incidence of ARIA in susceptible Alzheimer's disease patients during AD treatment protocols. In some embodiments, the methods are effective for treating AD patients without the need to screen patients to exclude those with ARIA risk factors, such as ApoE4 carriers. In other embodiments, the methods are suitable for use in treating ApoE4 carriers. In yet other embodiments, the methods are suitable for use in treating ApoE4 non-carriers. In preferred embodiments, the methods are particularly suited for treating patients using immunotherapeutic approaches to lower AD-associated Aβ. [Means for solving the problem]

[0016] The present invention helps fulfill these needs in the art by providing a method of treating a human patient with Alzheimer's disease (AD), comprising sequentially administering multiple doses of a recombinant, fully human, anti-amyloid beta monoclonal antibody. In a preferred embodiment, the antibody is administered to the patient in increasing amounts over a period of time.

[0017] In one embodiment of the invention, multiple doses of 1 mg / kg of the patient's body weight are administered to the patient at regular intervals.

[0018] In another embodiment of the invention, multiple doses of 3 mg / kg of the patient's body weight are administered to the patient at regular intervals, optionally with or without prior administration of the 1 mg / kg dose.

[0019] In a further embodiment of the invention, after administration of the 1 mg / kg dose and / or after administration of the 3 mg / kg dose, multiple doses of 6 mg / kg of the patient's body weight are administered to the patient at regular intervals.

[0020] In a further embodiment of the invention, after administration of the 1 mg / kg dose and / or after administration of the 3 mg / kg dose and / or after administration of the 6 mg / kg dose, multiple doses of 10 mg / kg of the patient's body weight are administered to the patient at regular intervals.

[0021] In a preferred embodiment of the invention, the dosing protocol is selected based on the ApoE4 status of the patient being treated.

[0022] In another preferred embodiment of the invention, each such interval is about four weeks.

[0023] In a typical treatment method of the present invention, 1 to 5 doses of 1 mg / kg of the patient's body weight are administered to the patient at regular intervals, followed by 1 to 5 doses of 3 mg / kg of the patient's body weight at regular intervals, and then 6 mg / kg of the patient's body weight at regular intervals until the end of the treatment.

[0024] In a preferred embodiment, the method of the present invention reduces cerebral amyloid burden. In a more preferred embodiment, the method of the present invention reduces the patient's susceptibility to ARIA. In certain embodiments, for example, the following are provided: (Item 1) 1. A method of treating a human patient with Alzheimer's disease (AD), comprising: Sequentially administering to said patient multiple doses of a recombinant, fully human, anti-amyloid beta monoclonal antibody in increasing amounts over a period of time; The method. (Item 2) 10. The method of claim 1, wherein multiple doses of 1 mg / kg of the patient's body weight are administered to the patient at regular intervals. (Item 3) 3. The method of any one of items 1 to 2, wherein multiple doses of 3 mg / kg of the patient's body weight are administered to the patient at regular intervals. (Item 4) 4. The method of any one of items 1 to 3, wherein multiple doses of 6 mg / kg of the patient's body weight are administered to the patient at regular intervals. (Item 5) 5. The method of any one of items 2, 3, or 4, wherein each of the intervals is about 4 weeks. (Item 6) 1 to 5 doses of 1 mg / kg of the patient's body weight are administered to the patient; 1 to 5 doses of 3 mg / kg of the patient's body weight are administered to the patient; 6 mg / kg of the patient's body weight is administered to the patient until the end of treatment. The method according to item 4. (Item 7) 7. The method of any one of items 1 to 6, wherein the patient's susceptibility to vasogenic edema (VE) is reduced. (Item 8) 8. The method of any one of items 1 to 7, wherein the patient's susceptibility to microhemorrhages (mH) is reduced. (Item 9) 9. The method according to any one of items 1 to 8, wherein the treatment is a prophylactic method for completely or partially preventing AD or symptoms thereof in the patient. (Item 10) 9. The method according to any one of items 1 to 8, wherein the treatment is a therapy for completely or partially curing AD or symptoms caused by AD in the patient. (Item 11) 1. A method of treating a human patient with Alzheimer's disease (AD), comprising: (A) administering to the patient a recombinant, fully human anti-amyloid beta monoclonal antibody in an amount of 1 mg / kg of body weight of the patient; (B) 4 weeks after step (A), administering the 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 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 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 antibody to the patient in an amount of 3 mg / kg of body weight of the patient; (F) 4 weeks after step (E), administering the antibody to the patient in an amount of 3 mg / kg of body weight of the patient; (G) 4 weeks after step (F), administering the antibody to the patient in an amount of 6 mg / kg of body weight of the patient; and (H) in consecutive intervals of 4 weeks after step (G), administering the antibody to the patient in an amount of 6 mg / kg of body weight of the patient. wherein 14 doses are administered about 4 weeks apart over about 52 weeks; thereby reducing the patient's susceptibility to amyloid-related imaging abnormalities (ARIA); The method. (Item 12) 12. The method of claim 11, wherein the patient's susceptibility to vasogenic edema (VE) is reduced. (Item 13) 13. The method of any one of items 11 to 12, wherein the patient's susceptibility to microhemorrhages (mH) is reduced. (Item 14) 14. The method according to any one of items 11 to 13, wherein the treatment is a prophylactic method for completely or partially preventing AD or symptoms thereof in the patient. (Item 15) The method according to any one of Items 11 to 13, wherein the treatment is a therapy for completely or partially curing AD or symptoms caused by AD in the patient. (Item 16) 16. The method of any one of items 11 to 15, wherein the administration is performed intravenously. (Item 17) the monoclonal antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL); wherein the VH comprises a first complementarity determining region (VHCDR1) with the amino acid sequence SEQ ID NO:3, a VHCDR2 with the amino acid sequence SEQ ID NO:4, and a VHCDR3 with the amino acid sequence SEQ ID NO:5; and wherein the VL comprises a VLCDR1 with the amino acid sequence SEQ ID NO:6, a VLCDR2 with the amino acid sequence SEQ ID NO:7, and a VLCDR3 with the amino acid sequence SEQ ID NO:8; wherein the antibody further comprises a human IgG1 constant region. 17. The method according to any one of items 1 to 16. (Item 18) the monoclonal antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL); wherein said VH comprises SEQ ID NO: 1, and the VL comprises SEQ ID NO:2; 18. The method according to any one of items 1 to 17. (Item 19) 9. The method of any one of items 1, 7, or 8, wherein a fixed dose of 3 mg / kg of body weight is administered to the patient every 4 weeks. (Item 20) 9. The method of any one of items 1, 7, or 8, wherein a fixed dose of 6 mg / kg of body weight is administered to the patient every 4 weeks. (Item 21) 9. The method of any one of items 1, 7, or 8, wherein the patient is an ApoE4 carrier and a fixed dose of 6 mg / kg of body weight is administered to the patient every 4 weeks. (Item 22) 9. The method of any one of items 1, 7, or 8, wherein the patient is an ApoE4 non-carrier and a fixed dose of 10 mg / kg of body weight is administered to the patient every 4 weeks. (Item 23) the patient is an ApoE4 carrier or and an ApoE4 non-carrier, and the method comprises: (A) administering to the patient a recombinant, fully human anti-amyloid beta monoclonal antibody in an amount of 1 mg / kg of body weight of the patient; (B) 4 weeks after step (A), administering the 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 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 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 antibody to the patient in an amount of 3 mg / kg of body weight of the patient; (F) 4 weeks after step (E), administering the antibody to the patient in an amount of 3 mg / kg of body weight of the patient; (G) 4 weeks after step (F), administering the antibody to the patient in an amount of 6 mg / kg of body weight of the patient; and (H) at consecutive intervals of 4 weeks after step (G), administering the antibody to the patient in an amount of 6 mg / kg of body weight of the patient indefinitely. Including, 9. The method of any one of items 1, 7, or 8. (Item 24) 24. The method of claim 23, wherein the patient is an ApoE4 carrier. (Item 25) 24. The method of claim 23, wherein the patient is an ApoE4 non-carrier. (Item 26) 1. A method of treating a human patient with Alzheimer's disease (AD), comprising: (A) administering to the patient a recombinant, fully human anti-amyloid beta monoclonal antibody in an amount of 1 mg / kg of body weight of the patient; (B) 4 weeks after step (A), administering the 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 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 antibody to the patient in an amount of 3 mg / kg of body weight of the patient; (E) 4 weeks after step (F), administering the antibody to the patient in an amount of 6 mg / kg of body weight of the patient; and (F) 4 weeks after step (F), administering the antibody to the patient in an amount of 6 mg / kg of body weight of the patient; and (G) in successive intervals of 4 weeks after step (F), administering the antibody to the patient in an amount of 10 mg / kg of body weight of the patient indefinitely. Including, wherein the patient is an ApoE4 non-carrier. The method. (Item 27) 1. A method of treating a human patient with Alzheimer's disease (AD), comprising: (A) administering the recombinant, fully human anti-amyloid beta monoclonal 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 antibody to the patient in an amount of 1 mg / kg of body weight of the patient; and (C) in consecutive intervals of 4 weeks after step (B), administering the antibody to the patient in an amount of 3 mg / kg of body weight of the patient. Including, wherein the patient is an ApoE4 carrier. The method. (Item 28) 1. A method of treating a human patient with Alzheimer's disease (AD), comprising: administering multiple doses of a recombinant, fully human anti-amyloid beta monoclonal antibody to the patient over a period of time; This includes: wherein the patient is an ApoE4 carrier, and the monoclonal antibody is administered in an effective amount of 1 mg / kg or 3 mg / kg of the patient's body weight. The method. (Item 29) 1. A method of treating a human patient with Alzheimer's disease (AD), comprising: administering to said patient multiple doses of a recombinant, fully human anti-amyloid beta monoclonal antibody over a period of time. Including, wherein the patient is an ApoE4 non-carrier, and the monoclonal antibody is administered in an effective amount of 3 mg / kg, 6 mg / kg, or 10 mg / kg of the patient's body weight. The method. (Item 30) the monoclonal antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL); wherein the VH comprises a first complementarity determining region (VHCDR1) with the amino acid sequence SEQ ID NO:3, a VHCDR2 with the amino acid sequence SEQ ID NO:4, and a VHCDR3 with the amino acid sequence SEQ ID NO:5; and wherein the VL comprises a VLCDR1 with the amino acid sequence SEQ ID NO:6, a VLCDR2 with the amino acid sequence SEQ ID NO:7, and a VLCDR3 with the amino acid sequence SEQ ID NO:8; wherein the antibody further comprises a human IgG1 constant region. 30. The method according to any one of items 26 to 29. (Item 31) the monoclonal antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL); wherein said VH comprises SEQ ID NO: 1; and the VL comprises SEQ ID NO:2. Item 31. The method according to item 30. (Item 32) 1. A method of treating a human patient with Alzheimer's disease (AD), comprising: (A) administering to the patient a first dose of a recombinant, fully human anti-amyloid beta monoclonal antibody in an amount of 1 mg / kg of body weight of the patient, followed by a second dose four weeks after the first dose in an amount of 1 mg / kg of body weight; (B) administering to the patient, at 4-week intervals after the second dose, doses 3, 4, 5, and 6 of the antibody in an amount of 3 mg / kg of body weight; and (C) administering to the patient, four weeks apart after the sixth dose, seventh and eighth doses of the antibody in an amount of 6 mg / kg of body weight; The method. (Item 33) (D) administering doses 9 through 14 of the antibody to the patient in an amount of 6 mg / kg body weight at 4-week intervals after dose 8. 33. The method of claim 32, further comprising: (Item 34) (D) administering doses 9 through 20 of the antibody to the patient in an amount of 6 mg / kg of body weight at 4-week intervals after dose 8. 33. The method of claim 32, further comprising: (Item 35) 35. The method of any one of items 32 to 34, wherein 12 weeks after a final dose of antibody at 6 mg / kg of body weight, the antibody is administered to the patient in an amount of 3 mg / kg at consecutive 12-week intervals. (Item 36) 35. The method of any one of items 32 to 34, wherein 4 weeks after a final dose of antibody at 6 mg / kg of body weight, the antibody is administered to the patient in an amount of 1 mg / kg at consecutive 4-week intervals. (Item 37) 37. The method of claim 35 or 36, wherein the final dose of antibody administered at 6 mg / kg of body weight occurs at dose 14 or 20. (Item 38) 1. A method of treating a human patient with Alzheimer's disease (AD), comprising: (A) administering to the patient a first dose of a recombinant, fully human anti-amyloid beta monoclonal antibody in an amount of 1 mg / kg of body weight of the patient, followed by a second dose four weeks after the first dose in an amount of 1 mg / kg of body weight; (B) administering to the patient, at 4-week intervals after the second dose, a third and fourth dose of the antibody in an amount of 3 mg / kg of body weight; and (C) administering to the patient, at 4 week intervals after the fourth dose, fifth and sixth doses of the antibody in an amount of 6 mg / kg of body weight; and (D) administering to the patient a seventh dose of the antibody in an amount of 10 mg / kg of body weight at four-week intervals after the sixth dose. The method comprising: (Item 39) (D) The method of item 38, further comprising administering doses 8 to 14 of the antibody to the patient in an amount of 10 mg / kg of body weight at 4-week intervals after the 7th dose. (Item 40) (D) administering doses 8 through 20 of the antibody to the patient in an amount of 10 mg / kg of body weight at 4-week intervals after dose 7. Item 39. The method of item 38, further comprising: (Item 41) 41. The method of any one of items 38 to 40, wherein 12 weeks after a final dose of antibody at 10 mg / kg of body weight, the antibody is administered to the patient in an amount of 3 mg / kg at consecutive 12-week intervals. (Item 42) 41. The method of any one of items 38 to 40, wherein 4 weeks after a final dose of antibody at 10 mg / kg of body weight, the antibody is administered to the patient in an amount of 1 mg / kg at consecutive 4-week intervals. (Item 43) 43. The method of claim 41 or 42, wherein the final dose of antibody administered at 10 mg / kg of body weight occurs at dose 14 or dose 20. (Item 44) 1. A method of treating a human patient with Alzheimer's disease (AD), comprising: (A) administering to the patient a first dose of a recombinant, fully human anti-amyloid beta monoclonal antibody in an amount of 1 mg / kg of body weight of the patient; (B) administering to the patient a second dose in an amount of 1 mg / kg of body weight four weeks after the first dose; and (C) administering a third dose to said patient in an amount of 3 mg / kg of body weight four weeks after the second dose. The method comprising: (Item 45) (D) administering doses 4 to 14 of the antibody to the patient in an amount of 3 mg / kg body weight at 4-week intervals after the third dose. Item 45. The method of item 44, further comprising: (Item 46) (D) administering doses 4 through 20 of the antibody to the patient in an amount of 3 mg / kg body weight at 4-week intervals after the third dose. Item 45. The method of item 44, further comprising: (Item 47) 47. The method of any one of items 44 to 46, wherein 12 weeks after dose 14 or dose 20, the antibody is administered to the patient in an amount of 3 mg / kg in consecutive 12-week intervals. (Item 48) 47. The method of any one of items 44 to 46, wherein 4 weeks after a final dose of antibody at 3 mg / kg of body weight, the antibody is administered to the patient in an amount of 1 mg / kg at consecutive 4-week intervals. (Item 49) 49. The method of paragraph 48, wherein the final dose of antibody administered at 3 mg / kg of body weight occurs at dose 14 or dose 20. (Item 50) 1. A method of treating a human patient with Alzheimer's disease (AD), comprising: (A) administering to the patient a first dose of a recombinant, fully human anti-amyloid beta monoclonal antibody in an amount of 1 mg / kg of body weight of the patient, followed by a second dose four weeks after the first dose in an amount of 1 mg / kg of body weight; (B) administering to the patient, at 4-week intervals after the second dose, a third and fourth dose of the antibody in an amount of 3 mg / kg of body weight; and (C) administering to the patient a fifth dose of the antibody in an amount of 6 mg / kg of body weight at four-week intervals after the fourth dose. The method comprising: (Item 51) (D) administering doses 6 through 14 of the antibody to the patient in an amount of 6 mg / kg of body weight at 4-week intervals after dose 5. 51. The method of claim 50, further comprising: (Item 52) (D) administering doses 6 through 20 of the antibody to the patient in an amount of 6 mg / kg of body weight at 4-week intervals after dose 5. 51. The method of claim 50, further comprising: (Item 53) 53. The method of any one of items 50 to 52, wherein 12 weeks after a final dose of antibody at 6 mg / kg of body weight, the antibody is administered to the patient in an amount of 3 mg / kg at consecutive 12-week intervals. (Item 54) 53. The method of any one of items 50 to 52, wherein 4 weeks after a final dose of antibody at 6 mg / kg of body weight, the antibody is administered to the patient in an amount of 1 mg / kg at consecutive 4 week intervals. (Item 55) 55. The method of claim 53 or 54, wherein the final dose of antibody administered at 6 mg / kg of body weight occurs at dose 14 or dose 20. (Item 56) 1. A method of treating a human patient with Alzheimer's disease (AD), comprising: (A) administering to the patient a first dose of a recombinant, fully human anti-amyloid beta monoclonal antibody in an amount of 1 mg / kg of body weight of the patient, followed by a second dose four weeks after the first dose in an amount of 1 mg / kg of body weight; (B) administering to the patient, at 4-week intervals after the second dose, doses 3, 4, 5, and 6 of the antibody in an amount of 3 mg / kg of body weight; and (C) administering to the patient doses 7, 8, 9, 10, and 11 of the antibody in an amount of 6 mg / kg of body weight at 4 week intervals after dose 6; and (D) administering to the patient a twelfth dose of the antibody in an amount of 10 mg / kg of body weight at four-week intervals after the eleventh dose. The method comprising: (Item 57) (E) administering doses 13 and 14 of the antibody to the patient in an amount of 10 mg / kg of body weight at 4-week intervals after dose 12. Item 57. The method of item 56, further comprising: (Item 58) (E) administering doses 13 through 20 of the antibody to the patient in an amount of 10 mg / kg of body weight at 4-week intervals after dose 12. Item 57. The method of item 56, further comprising: (Item 59) 59. The method of any one of items 56 to 58, wherein 12 weeks after a final dose of antibody at 10 mg / kg of body weight, the antibody is administered to the patient in an amount of 3 mg / kg in consecutive 12-week intervals. (Item 60) 59. The method of any one of items 56 to 58, wherein 12 weeks after the final dose of antibody at 10 mg / kg of body weight, the antibody is administered to the patient in an amount of 1 mg / kg in consecutive 4-week intervals. (Item 61) 61. The method of claim 59 or 60, wherein the final dose of antibody administered at 10 mg / kg of body weight occurs at dose 14 or dose 20. (Item 62) 62. The method of any one of items 32 to 61, wherein the patient's susceptibility to vasogenic edema (VE) is reduced. (Item 63) 63. The method of any one of items 32 to 62, wherein the patient's susceptibility to microhemorrhages (mH) is reduced. (Item 64) 64. The method according to any one of items 32 to 63, wherein the treatment is a prophylactic method for completely or partially preventing AD or symptoms thereof in the patient. (Item 65) The method according to any one of Items 32 to 64, wherein the treatment is a therapy for completely or partially curing AD or symptoms caused by AD in the patient. (Item 66) 66. The method of any one of items 32 to 65, wherein the administration is performed intravenously. (Item 67) the monoclonal antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL); wherein (A) the VH comprises a first complementarity determining region (VHCDR1) with the amino acid sequence SEQ ID NO:3, a VHCDR2 with the amino acid sequence SEQ ID NO:4, and a VHCDR3 with the amino acid sequence SEQ ID NO:5; and (B) the VL comprises a VLCDR1 with the amino acid sequence SEQ ID NO:6, a VLCDR2 with the amino acid sequence SEQ ID NO:7, and a VLCDR3 with the amino acid sequence SEQ ID NO:8, and wherein the antibody further comprises a human IgG1 constant region; 67. The method according to any one of items 32 to 66. (Item 68) 68. The method of any one of Items 32 to 67, wherein the monoclonal antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises SEQ ID NO: 1 and the VL comprises SEQ ID NO: 2. [Brief explanation of the drawings]

[0025] [Figure 1] 1 shows the mean positron emission tomography (PET) composite standardized uptake rate ratio (SUVR) by time point as determined by PET scan in a study of subjects treated with the BIIB037 antibody. [Figure 2] The adjusted mean change from baseline SUVR on PET images of subjects by baseline clinical stage, i.e., prodromal or mild AD, is shown. [Figure 3] 1 shows the adjusted mean change from SUVR on baseline PET images by subject's baseline ApoE4 status. [Figure 4] We report the expected incidence of ARIA-E and / or ARIA-H in a study of AD subjects treated with the BIIB037 antibody. [Figure 5] 1 shows the adjusted mean change from baseline Clinical Dementia Rating Scale-SB (CDR-SB) for patients receiving placebo, or 1 mg / kg, 3 mg / kg, or 10 mg / kg of BIIB037 antibody every 4 weeks for 54 weeks. [Figure 6]Shown is the adjusted mean change from baseline Mini-Mental State Examination (MMSE) + standard error (SE) for patients receiving placebo or 1 mg / kg, 3 mg / kg, or 10 mg / kg of BIIB037 antibody every 4 weeks for 54 weeks. [Figure 7A] Figures 7A-7F show amyloid plaque reduction with aducanumab. Figure 7A shows the mean imaging SUVR over time for the PD analysis population. The dashed line indicates the SUVR cutpoint for florbetapir. Figures 7B-7F show the adjusted mean (±SE) change from baseline in imaging SUVR at 26 and 54 weeks among (Figure 7B) the full PD analysis population, (Figure 7C) ApoE ε4 carriers, (Figure 7D) non-carriers, and (Figure 7E) prodromal AD and (Figure 7F) mild AD patients. [Figure 7B] Figures 7A-7F show amyloid plaque reduction with aducanumab. Figure 7A shows the mean imaging SUVR over time for the PD analysis population. The dashed line indicates the SUVR cutpoint for florbetapir. Figures 7B-7F show the adjusted mean (±SE) change from baseline in imaging SUVR at 26 and 54 weeks among (Figure 7B) the full PD analysis population, (Figure 7C) ApoE ε4 carriers, (Figure 7D) non-carriers, and (Figure 7E) prodromal AD and (Figure 7F) mild AD patients. [Figure 7C] Figures 7A-7F show amyloid plaque reduction with aducanumab. Figure 7A shows the mean imaging SUVR over time for the PD analysis population. The dashed line indicates the SUVR cutpoint for florbetapir. Figures 7B-7F show the adjusted mean (±SE) change from baseline in imaging SUVR at 26 and 54 weeks among (Figure 7B) the full PD analysis population, (Figure 7C) ApoE ε4 carriers, (Figure 7D) non-carriers, and (Figure 7E) prodromal AD and (Figure 7F) mild AD patients. [Figure 7D]Figures 7A-7F show amyloid plaque reduction with aducanumab. Figure 7A shows the mean imaging SUVR over time for the PD analysis population. The dashed line indicates the SUVR cutpoint for florbetapir. Figures 7B-7F show the adjusted mean (±SE) change from baseline in imaging SUVR at 26 and 54 weeks among (Figure 7B) the full PD analysis population, (Figure 7C) ApoE ε4 carriers, (Figure 7D) non-carriers, and (Figure 7E) prodromal AD and (Figure 7F) mild AD patients. [Figure 7E] Figures 7A-7F show amyloid plaque reduction with aducanumab. Figure 7A shows the mean imaging SUVR over time for the PD analysis population. The dashed line indicates the SUVR cutpoint for florbetapir. Figures 7B-7F show the adjusted mean (±SE) change from baseline in imaging SUVR at 26 and 54 weeks among (Figure 7B) the full PD analysis population, (Figure 7C) ApoE ε4 carriers, (Figure 7D) non-carriers, and (Figure 7E) prodromal AD and (Figure 7F) mild AD patients. [Figure 7F] Figures 7A-7F show amyloid plaque reduction with aducanumab. Figure 7A shows the mean imaging SUVR over time for the PD analysis population. The dashed line indicates the SUVR cutpoint for florbetapir. Figures 7B-7F show the adjusted mean (±SE) change from baseline in imaging SUVR at 26 and 54 weeks among (Figure 7B) the full PD analysis population, (Figure 7C) ApoE ε4 carriers, (Figure 7D) non-carriers, and (Figure 7E) prodromal AD and (Figure 7F) mild AD patients. [Figure 8] 1 shows the effect of aducanumab on MMSE. [Figure 9] 1 shows the effect of aducanumab on CDR-SB. [Figure 10] Selected dosing regimens for ApoE4 carriers and non-carriers are depicted. [Figure 11] This represents aducanumab's ability to reduce amyloid plaques. [Figure 12] Figure 1 shows slower decline in CDR-SB with aducanumab. [Figure 13]Figure 1 shows slowing of decline in MMSE with aducanumab. [Figure 14] The study design for PRIME, a multicenter, randomized, double-blind, placebo-controlled, multi-dose trial, is described. Patients (planned N=188) were randomized to one of nine treatment arms (target enrollment: n=30 per active arm) in a staggered, ascending-dose design with a 3:1 active-to-placebo ratio. [Figure 15] The primary and secondary endpoints for the PRIME trial are described. [Figure 16] The time series of the PRIME assessments are given below. Data were analyzed at week 54 for the 1, 3, and 10 mg / kg treatment groups and at week 30 for the 6 mg / kg treatment group. [Figure 17] Depicting patient distribution in the PRIME trial: Of 166 randomized patients, 165 were dosed, 107 (65%) were ApoE ε4 carriers, and 68 (41%) had prodromal AD. [Figure 18] Describe the baseline demographics and disease characteristics associated with the PRIME trial. [Figure 19] To provide an overview of the findings of ARIA and patient allocation in ARIE-E. DETAILED DESCRIPTION OF THE INVENTION

[0026] Alzheimer's disease As used herein, the term "Alzheimer's disease," also referred to as "AD," refers to dementia that is first identified by clinical diagnosis and established by markers of the disease.

[0027] AD is a spectrum of conditions 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 symptoms, form 10 to 20 years prior to the onset of AD dementia. Currently recognized stages of AD include preclinical, prodromal, mild, moderate, and severe. These stages can be further divided into subcategories based on the severity of symptoms and measures of AD progression.

[0028] Because AD does not develop in discrete stages, those skilled in the art will recognize that differences between patient groups may not be apparent in certain clinical settings. Nevertheless, the stages of this clinical disease can be characterized by measures such as amyloid-β accumulation (CSF / PET), synaptic dysfunction (FDG-PET / fMRI), tau-mediated neuropathy (CSF), brain structure (volumetric MRI), cognition, and clinical function, as well as changes in these measures over time. Clifford Jack et al. Lancet. Neurol. 2010 January, 9(1):119.

[0029] The current core clinical criteria for all dementias are referred to as the NINCDS-ADRDA criteria (McKhann, 2011), are known in the art, and can be incorporated into the practice of the present invention. These include cognitive or behavioral impairments involving a decline in the ability to acquire and remember new information, a decline in the ability to reason and process complex tasks, a decline in visuospatial ability, a decline in language function (speaking, reading, writing), and changes in personality, behavior, or attitude. Id. Alzheimer's disease is currently diagnosed using these core criteria and is typically characterized by symptoms that develop gradually over months to years, rather than suddenly within hours or days (insidious onset). There is usually a clear history of worsening symptoms, as reported or observed in subjects with Alzheimer's disease. Id.

[0030] Other diagnostic classification systems are evolving as new information about AD becomes available. 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 incorporated into the diagnosis of AD subjects for treatment according to the methods of the present invention.

[0031] patient The term "patient" is meant to include any human subject in whom diagnosis, prognosis, prevention, or treatment of Alzheimer's disease is desired, and includes a human subject in need of treatment. Those patients in need of treatment include those who already have AD, as well as those who are predisposed to or have suppressed the development of AD. Typical patients are male or female, aged 50 to 90 years. In preferred embodiments, the present invention provides methods of treating patients with AD (including, without limitation, pre-clinical, prodromal, mild, moderate, or severe AD). In further preferred embodiments, the patient has amyloid pathology, e.g., as confirmed by PET imaging.

[0032] AD patients in need of treatment range from subjects with amyloid pathology and early neurodegeneration to those with extensive neurodegeneration and irreversible neuronal loss due to progressive cognitive impairment and functional impairment to those with dementia.

[0033] Patients with pre-symptomatic AD can be identified by an asymptomatic stage with or without memory impairment and episodic memory and higher-level functional deficits, which is typically characterized by the appearance of in vivo molecular markers of AD and the absence of clinical symptoms.

[0034] Prodromal AD patients are in a pre-dementia stage characterized primarily by cognitive deficits and severe functional impairment associated with disease progression. Patients with prodromal AD typically have an MMSE score between 24 and 30 (inclusive), spontaneous memory impairment, objective memory loss defined as a free recall score of 27 or less on the FCSRT, a global CDR score of 0.5, no significant impairment in other cognitive domains, and essentially preserved activities of daily living, as well as the absence of dementia.

[0035] Patients with mild AD typically have an MMSE score between 20 and 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).

[0036] Based on clinical AD diagnosis, patients with mild AD will exhibit noticeable behavior at work, forgetfulness, mood swings, and attention disorders. Patients with moderate AD will exhibit cognitive impairment, restricted daily activities, disorientation, apraxia, agnosia, aphasia, and behavioral abnormalities. Patients with severe AD are characterized by loss of initiative, memory and speech decline, and incontinence.

[0037] 18 Treatment of early-stage patients who are amyloid-positive as assessed by F-AV-45 PET scan is preferred. These patients may be asymptomatic or may only experience transient symptoms of headache, confusion, difficulty walking, or visual disturbances. These patients may or may not be ApoE4 carriers, as determined by ApoE genotyping.

[0038] It is not preferred if the patient has any medical or neurological condition (other than AD) that may be contributing to the subject's cognitive impairment, such as stroke or other cerebrovascular condition, other neurodegenerative disease, history of clinically significant psychiatric illness, acute or subacute micro- or macrohemorrhage, previous major hemorrhage, or superficial cerebral hemosiderosis; however, such patients may still receive treatment following screening and selection by a qualified clinician.

[0039] treatment As used herein, the term "treating" or "treatment" generally refers to obtaining a desired pharmacological and / or physiological effect. This effect may be prophylactic, in that it completely or partially prevents Alzheimer's disease or its symptoms, and / or therapeutic, in that it partially or completely cures AD and / or one or more deleterious effects that contribute to AD. Thus, as used herein, the term "treatment" includes (a) preventing AD from occurring in a subject who may be susceptible to AD but has not yet been diagnosed with AD, (b) inhibiting AD, e.g., suppressing its development, (c) alleviating AD, e.g., causing recovery from AD, or (d) prolonging survival compared to that expected if not treated.

[0040] In preferred embodiments of the invention, the treatment is a prophylactic method for completely or partially preventing AD or symptoms thereof in the patient, or the treatment is a therapeutic method for partially or completely curing AD or symptoms that cause AD in the patient.

[0041] In other preferred embodiments of the invention, the treatment has a disease-modifying effect, meaning that the treatment slows or retards the underlying pathological or pathophysiological disease process and results in an improvement in the clinical signs and symptoms of AD compared to placebo.

[0042] In a further preferred embodiment, treatment results in symptomatic improvement, even if for a limited period of time, which may consist of enhanced cognition, greater independence, and / or improvement in neuropsychiatric and behavioral dysfunction.

[0043] It will be understood that while the goal of any treatment is disease prevention or treatment, the present invention contemplates delaying the clinical end point or progression of the disease or alleviating symptoms. Delaying the clinical end point or progression of the disease has a direct impact on the patient and their caregivers. It delays disability, maintains independence, and allows the patient to lead a normal life for a longer period of time. The best possible symptom relief can result in gradual improvements in cognition, function, and behavior, as well as mood.

[0044] The present invention provides a method for treating AD by administering a recombinant, fully human anti-amyloid beta monoclonal antibody to a human patient. In a preferred embodiment, the monoclonal antibody has an excellent safety profile and is selective for soluble Aβ oligomers and fibril binding with substantial absence of monomer binding. These properties improve Pk, reduce antibody precipitation, and minimize cross-reactivity with off-target APP-expressing tissues. A preferred monoclonal antibody meeting these criteria is the BIIB037 antibody.

[0045] The BIIB037 antibody is a biological therapeutic agent for Alzheimer's disease. It is a non-naturally occurring, recombinant, fully human anti-Aβ monoclonal antibody that recognizes aggregated forms of Aβ, including platelets. BIIB037 is an IgG1 antibody composed of two heavy chains and two kappa light chains linked by interchain disulfide bonds.

[0046] In vitro characterization studies demonstrated that the BIIB037 antibody recognizes a conformational epitope present in Aβ aggregates, the accumulations believed to underlie the development and progression of AD.

[0047] In vivo pharmacology studies showed that a murine IgG2a chimeric form of an antibody with similar properties (chl2F6A) significantly reduced amyloid plaque burden in the brains of aged Tg2576 mice, a mouse model of AD. The reduction in parenchymal amyloid was not accompanied by changes in vascular amyloid, as reported for certain anti-Aβ antibodies [Wilcock and Colton 2009].

[0048] The BIIB037 antibody has the same amino acid sequence as the 12F6A antibody, a recombinant, fully human anti-Aβ IgG1 mAb produced in a different Chinese hamster ovary cell line than BIIB037. The BIIB037 antibody has the same amino acid sequence as the 12F6A antibody, which is a recombinant, fully human anti-Aβ IgG1 mAb produced in a different Chinese hamster ovary cell line than BIIB037. H ) and Table 2(V L ) V H and / or V L It has an antigen-binding domain that includes a variable region and corresponding complementarity-determining regions (CDRs) as depicted in Table 3. [Table 1] [Table 2] [Table 3]

[0049] In addition to the BIIB037 antibody, the present invention contemplates the use of other antibodies, such as antibodies comprising a VH region in Table 1 and a VL region in Table 2. Other antibodies contemplated for use in the present invention include antibodies comprising the variable heavy chain CDRs and variable light chain CDRs in Table 3.

[0050] Antibody BIIB037 and other antibodies used in the present invention can be prepared using conventional methods. In some embodiments, the antibodies are expressed in a suitable Chinese hamster ovary cell line.

[0051] The patient's response to treatment according to the present invention is generally dose-dependent. One embodiment of the present invention comprises administering at least one dose of the monoclonal antibody to the patient at an amount less than the minimum therapeutic dose required to treat the patient with AD. This is followed by administering at least one dose to the patient at approximately the minimum therapeutic dose required to treat the patient with AD. And then administering at least one dose to the patient at an effective amount greater than the minimum therapeutic dose required to treat the patient with AD, but less than the maximum tolerated amount. In a preferred embodiment, the brain amyloid burden is reduced. In a further preferred embodiment, the patient's susceptibility to ARIA is reduced.

[0052] A therapeutically effective amount refers to an amount of the antibody adequate to ameliorate symptoms or pathology associated with Alzheimer's disease. The therapeutic efficacy and toxicity of the monoclonal antibody can be determined by standard pharmaceutical procedures. Ideally, the monoclonal antibody is employed in an amount adequate to restore normal behavior and / or cognitive characteristics in cases of Alzheimer's disease, or at least slow or prevent the progression of AD in the patient.

[0053] In Tg2576 mice, a dose-dependent reduction in brain amyloid was observed after chronic administration of the monoclonal antibody BIIB037 (0.3 mg / kg to 30 mg / kg). Significant amyloid reduction was observed at 3 mg / kg, which was determined to be the minimum therapeutic dose of the BIIB037 antibody in this animal model.

[0054] An effective amount of the monoclonal antibody is the amount of the antibody that produces a clinically significant response in the treatment of Alzheimer's disease. An effective amount of about 1 to 30 mg / kg per month can be employed. The efficacy of BIIB037 antibody can reach a plateau, with safety, at an effective amount between about 10 mg / kg and about 30 mg / kg of the patient's body weight. An effective amount of about 3 mg / kg to about 10 mg / kg of the patient's body weight is contemplated. Preferred effective amounts are about 3 mg / kg, about 6 mg / kg, and about 10 mg / kg of the patient's body weight.

[0055] The maximum tolerated dose of the monoclonal antibody is the amount of the antibody that produces a clinically significant response in the treatment of Alzheimer's disease, consistent with safety. 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. Consistent with achieving these results, doses above about 60 mg / kg should be avoided. The methods of the invention allow for the use of higher doses of BIIB037 antibody in the treatment of AD patients than was possible using known protocols.

[0056] It will be understood that dose adjustments may be made during the treatment protocol. For example, for safety or efficacy reasons, the dose may be increased to enhance the effect of the monoclonal antibody in AD, or decreased to reduce the incidence and severity of ARIA. If a dose is missed, the patient should preferably resume dosing by receiving the missed dose and continuing thereafter according to the described dosing regimen.

[0057] The monoclonal antibody is preferably administered to the patient by intravenous infusion after dilution in saline. Using this mode of administration, each infusion step in the titration regimen of the present invention will typically take about 1 hour.

[0058] The dosage ranges and other numerical values ​​herein include amounts that have the same effect as the numerical amount indicated by treating Alzheimer's disease in the patient and reducing the patient's incidence or susceptibility to ARIA compared to individuals not treated with the method of the invention. At the very least, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding techniques should be applied. 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.

[0059] Dose titration (continuous administration) The occurrence of ARIA in AD patients treated with the BIIB037 antibody was found to be dose-dependent. ARIA was observed after the third and fourth doses in patients receiving 1 mg / kg and 3 mg / kg of the antibody. At doses of 8 mg / kg and 10 mg / kg of body weight, ARIA was observed after the second dose. The methods of the invention include treatment regimens selected to reduce the occurrence of ARIA.

[0060] More specifically, in the method of treating Alzheimer's disease (AD) according to the present invention, the recombinant, fully human, anti-amyloid beta monoclonal antibody is administered to a human patient in increasing amounts over a period of time. This procedure of sequentially administering the antibody to the patient is referred to herein as "titration," as it involves the administration of carefully measured amounts of a standardized pharmaceutical agent of known concentration until completion of the procedure, as evidenced by specific endpoints. In the present invention, the endpoints include the effect of treatment of Alzheimer's disease in the patient and the effect of the treatment in reducing the incidence of ARIA, particularly ARIA-E or ARIA-H, in the treated patient population.

[0061] One advantage of this titration regimen in the present invention is that it allows for the administration of higher doses of the monoclonal antibody to AD patients, particularly apolipoprotein E4 (ApoE4) carriers, without incurring the same degree of ARIA as observed with fixed-dose regimens. Without intending to be limited to any particular mechanism, it is believed that titration results in lower initial amyloid clearance and slower clearance over the entire treatment period.

[0062] The titration of the monoclonal antibody is carried out in multiple doses.For example, two doses of the antibody can be administered to the patient at an amount less than the minimum therapeutic dose per dose, and then four doses of the antibody can be administered at an amount approximately equal to the minimum therapeutic dose per dose.This administration regimen can then be continued with multiple doses at an amount greater than the minimum therapeutic dose but less than the maximum tolerated dose per dose until there is an acceptable change in the patient's AD.For example, the dose can be administered approximately every 4 weeks for approximately 52 weeks (a total of 14 doses).Progress can be monitored by regular evaluation.

[0063] A particularly preferred protocol of the present invention, designated protocol (1), is: (A) administering the recombinant, fully human anti-amyloid beta monoclonal 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 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 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 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 antibody to the patient in an amount of 3 mg / kg of body weight of the patient; (F) 4 weeks after step (E), administering the antibody to the patient in an amount of 3 mg / kg of body weight of the patient; (G) 4 weeks after step (F), administering the antibody to the patient in an amount of 6 mg / kg of body weight of the patient; and (H) in consecutive intervals of 4 weeks after step (G), administering the antibody to the patient in an amount of 6 mg / kg of body weight of the patient.

[0064] In other words, protocol (1) involves administering to the patient a first dose of a recombinant, fully human anti-amyloid beta monoclonal antibody in an amount of 1 mg / kg of body weight of the patient, followed by a second dose in an amount of 1 mg / kg of body weight four weeks after the first dose, followed by administration of doses three, four, five, and six of the antibody in an amount of 3 mg / kg of body weight at four-week intervals after the second dose, and then administering doses seven and eight of the antibody in an amount of 6 mg / kg of body weight every four weeks after administration of dose six.

[0065] Protocol (1) may comprise administering a total of 14 doses, approximately 4-weekly apart, over a period of approximately 52 weeks, optionally continuing with dosing approximately every 4 weeks thereafter, thereby treating AD to reduce the patient's susceptibility to amyloid-related imaging abnormalities (ARIA). In other words, four weeks after administration of dose 8, doses 9-14 may be administered to the patient in an amount of 6 mg / kg of body weight at 4-week intervals. In some embodiments, the antibody continues to be administered to the patient in an amount of 6 mg / kg of body weight at 4-week intervals until at least week 76. In other words, in some embodiments, the method comprises administering doses 9-20 to the patient in an amount of 6 mg / kg of body weight at 4-week intervals following dose 8. In some embodiments, after dose 8, the antibody is administered to the patient in an amount of 6 mg / kg of body weight at 4-week intervals indefinitely. In some embodiments, at 12-week intervals following the final dose at 6 mg / kg body weight, the amount of antibody administered to the patient is 3 mg / kg body weight. In some embodiments, this reduced dose is first administered to the patient 12 weeks after week 52 (i.e., 12 weeks after dose 14), and in other embodiments, this reduced dose is administered to the patient 12 weeks after week 76 (i.e., 12 weeks after dose 20). In some embodiments, at 4-week intervals following the final dose at 6 mg / kg body weight, the amount of antibody administered to the patient is 1 mg / kg body weight. In some embodiments, this reduced dose is first administered to the patient 4 weeks after week 52 (i.e., 4 weeks after dose 14), and in other embodiments, this reduced dose is first administered to the patient 4 weeks after week 76 (i.e., 4 weeks after dose 20).

[0066] Protocol (1) may be employed for patients whose ApoE genotyping identifies them as ApoE4 carriers or non-carriers. In either alternative embodiment of Protocol (1), the antibody may comprise a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises a first complementarity-determining region (VHCDR1) with the amino acid sequence SEQ ID NO:3, a VHCDR2 with the amino acid sequence SEQ ID NO:4, and a VHCDR3 with the amino acid sequence SEQ ID NO:5, and wherein the VL comprises a VLCDR1 with the amino acid sequence SEQ ID NO:6, a VLCDR2 with the amino acid sequence SEQ ID NO:7, and a VLCDR3 with the amino acid sequence SEQ ID NO:8. In a preferred embodiment of Protocol (1), the antibody comprises an IgG1 constant region. In a particularly preferred embodiment of Protocol (1), the VH comprises SEQ ID NO:1, and the VL comprises SEQ ID NO:2.

[0067] Another particularly preferred protocol of the present invention, designated Protocol (2), comprises: (A) administering the recombinant, fully human anti-amyloid beta monoclonal 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 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 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 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 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 antibody to the patient in an amount of 6 mg / kg of body weight of the patient; and (G) in consecutive intervals of 4 weeks after step (F), administering the antibody to the patient in an amount of 10 mg / kg of body weight of the patient. In other words, protocol (2) involves administering a first dose of a recombinant, fully human anti-amyloid beta monoclonal antibody to the patient in an amount of 1 mg / kg of body weight, followed by a second dose in an amount of 1 mg / kg of body weight four weeks after the first dose, doses three and four of the antibody in an amount of 3 mg / kg of body weight every four weeks after the second dose, doses five and six of the antibody in an amount of 6 mg / kg of body weight at four-week intervals after administration of the fourth dose, and then, four weeks after administration of the sixth dose, a seventh dose of the antibody in an amount of 10 mg / kg of body weight is administered to the patient.

[0068] Protocol (2) may involve administering a total of 14 doses, approximately 4-weekly apart, over approximately 52 weeks, optionally continuing with dosing about every 4 weeks thereafter, thereby treating AD to reduce the patient's susceptibility to amyloid-related imaging abnormalities (ARIA). In other words, four weeks after administration of dose 7, doses 8-14 may be administered to the patient in an amount of 10 mg / kg of body weight at 4-week intervals. In some embodiments, the antibody continues to be administered to the patient in an amount of 10 mg / kg of body weight at 4-week intervals until at least week 76. In other words, in some embodiments, the method involves administering doses 8-20 to the patient in an amount of 10 mg / kg of body weight at 4-week intervals following dose 7. In some embodiments, after dose 7, the antibody is administered to the patient in an amount of 10 mg / kg of body weight at 4-week intervals indefinitely. In some embodiments, after the final dose at 10 mg / kg body weight, the amount of antibody is reduced to 3 mg / kg body weight and administered to the patient at 12-week intervals. In some embodiments, this reduced dose is first administered to the patient 12 weeks after week 52 (i.e., 12 weeks after dose 14), and in other embodiments, this reduced dose is administered to the patient 12 weeks after week 76 (i.e., 12 weeks after dose 20). In some embodiments, four weeks after the final dose at 10 mg / kg body weight, the amount of antibody administered to the patient is reduced to 1 mg / kg body weight every four weeks. In some embodiments, this reduced dose begins four weeks after week 52 (i.e., four weeks after dose 14), and in other embodiments, this reduced dose begins four weeks after week 76 (i.e., four weeks after dose 20).

[0069] Protocol (2) is particularly suitable for treating ApoE4 non-carriers. In any alternative embodiment of Protocol (2), the antibody may comprise a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises a first complementarity-determining region (VHCDR1) with the amino acid sequence SEQ ID NO:3, a VHCDR2 with the amino acid sequence SEQ ID NO:4, and a VHCDR3 with the amino acid sequence SEQ ID NO:5, and wherein the VL comprises a VLCDR1 with the amino acid sequence SEQ ID NO:6, a VLCDR2 with the amino acid sequence SEQ ID NO:7, and a VLCDR3 with the amino acid sequence SEQ ID NO:8. In a preferred embodiment of Protocol (2), the antibody comprises an IgG1 constant region. In a particularly preferred embodiment of Protocol (2), the VH comprises SEQ ID NO:1, and the VL comprises SEQ ID NO:2.

[0070] The present invention provides another particularly preferred protocol for treating ApoE4 carriers, designated Protocol (3). This embodiment of the present invention comprises: (A) administering the recombinant, fully human anti-amyloid beta monoclonal 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 antibody to the patient in an amount of 1 mg / kg of body weight of the patient; and (C) in consecutive intervals of 4 weeks after step (B), administering the antibody to the patient in an amount of 3 mg / kg of body weight of the patient. In other words, protocol (3) involves administering to the patient a first dose of the recombinant, fully human anti-amyloid beta monoclonal antibody in an amount of 1 mg / kg of the patient's body weight, four weeks after the first dose a second dose of the antibody in an amount of 1 mg / kg of body weight, and then four weeks after the second dose a third dose of the antibody in an amount of 3 mg / kg of body weight.

[0071] Protocol 3 may involve administering a total of 14 doses at approximately 4-week intervals over approximately 52 weeks, optionally continuing with dosing about every 4 weeks thereafter, thereby treating AD to reduce the patient's susceptibility to amyloid-related imaging abnormalities (ARIA). In other words, four weeks after administration of dose 3, doses 4 through 14 may be administered to the patient in an amount of 3 mg / kg of body weight at 4-week intervals. In some embodiments, the antibody continues to be administered to the patient in an amount of 3 mg / kg of body weight at 4-week intervals until at least week 76. In other words, in some embodiments, the method involves administering doses 4 through 20 to the patient in an amount of 3 mg / kg of body weight at 4-week intervals following dose 3. In some embodiments, after dose 3, the antibody is administered to the patient in an amount of 3 mg / kg of body weight at 4-week intervals indefinitely. In some embodiments, after a predetermined period of time, the amount of antibody administered to the patient may be reduced to 3 mg / kg of body weight every 12 weeks. In some embodiments, this 12-week dosing interval begins after week 52 (i.e., after dose 14), and in other embodiments, this 12-week dosing interval begins after week 76 (i.e., after dose 20). In some embodiments, after a predetermined period of time, the amount of antibody administered to the patient may be reduced to 1 mg / kg of body weight every 4 weeks. In some embodiments, this reduced dosing begins 4 weeks after week 52 (i.e., 4 weeks after dose 14), and in other embodiments, this reduced dosing begins 4 weeks after week 76 (i.e., 4 weeks after dose 20).

[0072] Protocol (3) may be used in ApoE4 carriers, as determined by ApoE genotyping. In any alternative embodiment of Protocol (3), the antibody may comprise a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises a first complementarity determining region (VHCDR1) with the amino acid sequence SEQ ID NO:3, a VHCDR2 with the amino acid sequence SEQ ID NO:4, and a VHCDR3 with the amino acid sequence SEQ ID NO:5, and wherein the VL comprises a VLCDR1 with the amino acid sequence SEQ ID NO:6, a VLCDR2 with the amino acid sequence SEQ ID NO:7, and a VLCDR3 with the amino acid sequence SEQ ID NO:8. In a preferred embodiment of Protocol (3), the antibody comprises an IgG1 constant region. In a particularly preferred embodiment of Protocol (3), the VH comprises SEQ ID NO:1, and the VL comprises SEQ ID NO:2.

[0073] Another particularly preferred protocol of the present invention, designated Protocol (4), comprises: (A) administering the recombinant, fully human anti-amyloid beta monoclonal 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 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 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 antibody to the patient in an amount of 3 mg / kg of body weight of the patient; and (E) 4 weeks after step (D), administering the antibody to the patient in an amount of 6 mg / kg of body weight of the patient. In other words, protocol (4) involves administering a first dose of a recombinant, fully human anti-amyloid beta monoclonal antibody to the patient in an amount of 1 mg / kg of body weight, followed by a second dose four weeks after the first dose in an amount of 1 mg / kg of body weight. At four-week intervals after the second dose, doses three and four are administered to the patient in an amount of 3 mg / kg of body weight. And then, four weeks after administration of the fourth dose of the antibody, a fifth dose is administered to the patient in an amount of 6 mg / kg of body weight.

[0074] Protocol (4) may involve administering a total of 14 doses, approximately 4-weekly apart, over approximately 52 weeks, optionally continuing with dosing approximately every 4 weeks thereafter, thereby treating AD to reduce the patient's susceptibility to amyloid-related imaging abnormalities (ARIA). In other words, four weeks after administration of dose 5, doses 6-14 may be administered to the patient in an amount of 6 mg / kg of body weight every 4 weeks. In some embodiments, the antibody continues to be administered to the patient in an amount of 6 mg / kg of body weight every 4 weeks until at least week 76. In other words, in some embodiments, the method involves administering doses 6-20 to the patient in an amount of 6 mg / kg of body weight every 4 weeks following dose 5. In some embodiments, after dose 5, the antibody is administered to the patient in an amount of 6 mg / kg of body weight every 4 weeks indefinitely. In some embodiments, following a final dose of 6 mg / kg body weight, at 12-week intervals, the amount of antibody administered to the patient is reduced to 3 mg / kg body weight. In some embodiments, this reduced dose is initially administered to the patient 12 weeks after week 52 (i.e., 12 weeks after dose 14), and in other embodiments, this reduced dose is initially administered to the patient 12 weeks after week 76 (i.e., 12 weeks after dose 20). In some embodiments, after a final dose of 10 mg / kg body weight, the amount of antibody administered to the patient is reduced to 1 mg / kg body weight every four weeks. In some embodiments, this reduced dose begins four weeks after week 52 (i.e., four weeks after dose 14), and in other embodiments, this reduced dose begins four weeks after week 76 (i.e., four weeks after dose 20).

[0075] In any embodiment of Protocol (4), the antibody may comprise a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises a first complementarity determining region (VHCDR1) with the amino acid sequence SEQ ID NO:3, a VHCDR2 with the amino acid sequence SEQ ID NO:4, and a VHCDR3 with the amino acid sequence SEQ ID NO:5, and wherein the VL comprises a VLCDR1 with the amino acid sequence SEQ ID NO:6, a VLCDR2 with the amino acid sequence SEQ ID NO:7, and a VLCDR3 with the amino acid sequence SEQ ID NO:8. In a preferred embodiment of Protocol (4), the antibody comprises an IgG1 constant region. In a particularly preferred embodiment of Protocol (4), the VH comprises SEQ ID NO:1, and the VL comprises SEQ ID NO:2.

[0076] Yet another particularly preferred protocol according to the present invention, designated as protocol (5), comprises: (A) administering the recombinant, fully human anti-amyloid beta monoclonal 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 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 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 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 antibody to the patient in an amount of 3 mg / kg of body weight of the patient; (F) 4 weeks after step (E), administering the antibody to the patient in an amount of 3 mg / kg of body weight of the patient; (G) in consecutive intervals of 4 weeks after step (F), administering the antibody to the patient in an amount of 6 mg / kg of body weight of the patient; (H) in consecutive intervals of 4 weeks after step (G), administering the antibody to the patient in an amount of 6 mg / kg of body weight of the patient; (I) in consecutive intervals of 4 weeks after step (H), administering the antibody to the patient in an amount of 6 mg / kg of body weight of the patient; (J) in consecutive intervals of 4 weeks after step (I), administering the antibody to the patient in an amount of 6 mg / kg of body weight of the patient; (K) in consecutive intervals of 4 weeks after step (J), administering the antibody to the patient in an amount of 6 mg / kg of body weight of the patient; and (L) in consecutive intervals of 4 weeks after step (K), administering the antibody to the patient in an amount of 10 mg / kg of body weight of the patient. In other words, Protocol 5 involves administering a first dose of a recombinant, fully human anti-amyloid beta monoclonal antibody to the patient in an amount of 1 mg / kg of body weight, followed by a second dose four weeks after the first dose in an amount of 1 mg / kg of body weight. At four-week intervals after the second dose, doses three, four, five, and six of the antibody are administered to the patient in an amount of 3 mg / kg of body weight. At four-week intervals after administration of dose six, doses seven, eight, nine, ten, and eleven are administered to the patient in an amount of 6 mg / kg of body weight. And then, four weeks after administration of dose eleven, dose twelfth of the antibody is administered to the patient in an amount of 10 mg / kg of body weight.

[0077] Protocol (5) may involve administering a total of 14 doses, approximately 4-weekly apart, over a period of approximately 52 weeks, optionally continuing with dosing approximately every 4 weeks thereafter, thereby treating AD to reduce the patient's susceptibility to amyloid-related imaging abnormalities (ARIA). In other words, four weeks after administration of dose 12, doses 13-14 may be administered to the patient in an amount of 10 mg / kg of body weight every 4 weeks. In some embodiments, the antibody continues to be administered to the patient in an amount of 10 mg / kg of body weight every 4 weeks until at least week 76. In other words, in some embodiments, the method involves administering doses 13-20 to the patient in an amount of 6 mg / kg of body weight every 4 weeks following dose 12. In some embodiments, after dose 12, the antibody is administered to the patient in an amount of 10 mg / kg of body weight every 4 weeks indefinitely. In some embodiments, after the final dose at 10 mg / kg body weight, the amount of antibody administered to the patient is reduced to 3 mg / kg body weight every four weeks. In some embodiments, this reduced dose is initially administered to the patient 12 weeks after week 52 (i.e., 12 weeks after dose 14), and in other embodiments, this reduced dose is initially administered to the patient 12 weeks after week 76 (i.e., 12 weeks after dose 20). In some embodiments, after the final dose at 10 mg / kg body weight, the amount of antibody administered to the patient is reduced to 1 mg / kg body weight every four weeks. In some embodiments, this reduced dose is initiated four weeks after week 52 (i.e., four weeks after dose 14), and in other embodiments, this reduced dose is initiated four weeks after week 76 (i.e., four weeks after dose 20).

[0078] In any embodiment of Protocol (5), the antibody may comprise a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises a first complementarity determining region (VHCDR1) with the amino acid sequence SEQ ID NO:3, a VHCDR2 with the amino acid sequence SEQ ID NO:4, and a VHCDR3 with the amino acid sequence SEQ ID NO:5, and wherein the VL comprises a VLCDR1 with the amino acid sequence SEQ ID NO:6, a VLCDR2 with the amino acid sequence SEQ ID NO:7, and a VLCDR3 with the amino acid sequence SEQ ID NO:8. In a preferred embodiment of Protocol (5), the antibody comprises an IgG1 constant region. In a particularly preferred embodiment of Protocol (5), the VH comprises SEQ ID NO:1, and the VL comprises SEQ ID NO:2.

[0079] Exemplary dosing regimens for ApoE4 carriers and non-carriers are set forth in Table 10 of Example 8 and in FIG.

[0080] These particularly preferred protocols optimize efficacy with safety requirements. In preferred embodiments of the invention, the patient's susceptibility to vasogenic edema (VE) is reduced, or the patient's susceptibility to cerebral microhemorrhages (mH) is reduced, or both VE and mH are reduced in the patient.

[0081] Variations of these preferred protocols are also possible. A dosing regimen can be employed, with multiple doses of 1 mg / kg of the patient's body weight at regular intervals, followed by multiple doses of 3 mg / kg at regular intervals. For example, a dosing regimen could include two doses of 1 mg / kg of the patient's body weight at four-week intervals, followed by four doses of 3 mg / kg at four-week intervals. Another example of this regimen includes two doses of 1 mg / kg of the patient's body weight at four-week intervals, followed by multiple doses of 3 mg / kg at four-week intervals until the end of treatment. Another example of this regimen includes four doses of 1 mg / kg of the patient's body weight at four-week intervals, followed by multiple doses of 3 mg / kg at four-week intervals until the end of treatment. Given that ARIA typically occurs between the second and fifth doses, this simplified protocol can provide additional safety margins. In this situation, the patient need not continue titrating to 6 mg / kg, but rather the dose increase can be stopped at about 3 mg / kg of the patient's body weight.

[0082] Other variations of these preferred embodiments include multiple doses of 1 mg / kg of the patient's body weight at regular intervals of dosing, followed by multiple doses of 3 mg / kg at regular intervals, which may include a final multiple dose of 6 mg / kg of the patient's body weight at regular intervals until treatment is terminated. An example of this dosing regimen includes two doses of 1 mg / kg of the patient's body weight at four week intervals of dosing, followed by four doses of 3 mg / kg at four week intervals, which may include a final multiple dose of 6 mg / kg of the patient's body weight until treatment is terminated.

[0083] In a further embodiment of the invention, titration of the monoclonal antibody for the patient may be waived if the patient exhibits an adequate response without this titration step. In this situation, for example, an ApoE4 carrier may be administered a dose of the monoclonal antibody of 1 mg / kg or 3 mg / kg of the patient's body weight, and an ApoE4 non-carrier may be administered a dose of 3 mg / kg, 6 mg / kg, or 10 mg / kg of the patient's body weight. A total of 14 doses may be administered at approximately 4-week intervals over approximately 52 weeks, optionally with continued dosing approximately every 4 weeks thereafter, thereby treating AD to reduce the patient's susceptibility to amyloid-related imaging abnormalities (ARIA).

[0084] composition The BIIB037 antibody can be formulated as a pharmaceutical composition. The pharmaceutical composition employed in the present invention can be formulated according to methods known in the art, see, for example, Remington: The Science and Practice of Pharmacy (2000) by the University of Sciences in Philadelphia, ISBN 683-306472. The composition can further comprise a pharmaceutically acceptable carrier. Examples of suitable pharmaceutical carriers are known in the art and include phosphate-buffered saline solution, water, emulsions such as oil / water emulsions, various types of wetting agents, sterile solutions, etc.

[0085] Additionally, the pharmaceutical composition may comprise an additional agent, for example, an additional agent for use in treating Alzheimer's disease may be selected from the group consisting of small organic molecules, other anti-Abeta antibodies, anti-tau antibodies, and combinations thereof.

[0086] Administration of the composition can be achieved in different ways, for example by intravenous, intraperitoneal, subcutaneous, intramuscular, topical, or intradermal administration.

[0087] Measuring and reducing AD symptoms Measurement of the risk, presence, severity, and progression of Alzheimer's disease can be determined by clinical diagnosis over time, by assessment of the patient's overall level of functioning, by evaluation of daily living abilities or behavioral deficits, by volumetric analysis of brain structure, by in vivo measurement of pathological deposits of abnormal proteins in the brain (e.g., PET beta-amyloid imaging), or by biochemical variables in body fluids (e.g., tau protein or Abeta peptide), and by comparison with the natural course or history of the disease.

[0088] The following clinical assessments can be used to determine a patient's stage of Alzheimer's disease progression: CDR, FCSRT, Neuropsychiatric Inventory-Questionnaire (NPI-Q), and a neuropsychological assessment battery including the Rey Auditory Verbal Learning Test (RA VLT), Immediate and Delayed Recall, Wechsler Memory Scale (WMS), and Verbal Pair Associate. Learning Test Immediate and Delayed Recall, Delis-Kaplan Executive Function System Verbal Fluency Conditions 1 and 2, and Wechsler Adult Intelligence Scale Fourth Edition Symbol Search and Coding Subsets, and the Cognitive Drug Research computerized test battery.

[0089] The preferred diagnostic scheme is the Clinical Dementia Rating (CDR) scale, a neuropsychological assessment battery, and the Cognitive Drug This will include determining change from baseline on the Research computerized test battery, Free and Cued Selective Reminding Test (FCSRT), Mini Mental State Examination (MMSE), Columbia Suicide Severity Rating Scale (C-SSRS), and Neuropsychiatric Inventory-Questionnaire (NPI-Q).

[0090] Biomarkers have emerged as essential for defining AD and staging its spectrum. Biomarker phenotypes can bridge the gap between clinical phenotypes and pathological phenotypes such as amyloid plaques, neurofibrillary tangles, inflammation, and neurodegeneration. AD biomarkers include ApoE isotype, CSF Aβ42, amyloid PET, CSF tau, and hippocampal volume (HCV) MRI.

[0091] Amyloid plaque burden in specific brain regions can be measured using 18F-AV-45 PET. 18F-AV-45 is an amyloid ligand developed by Avid Radiopharmaceuticals (Philadelphia, Pennsylvania). It binds to fibrillar Aβ with high affinity (Kd = 3.1 nM). Results with 18F-AV-45 PET imaging showed that AD patients exhibited selective retention of the tracer in brain regions expected to be highly amyloid-rich, while healthy controls exhibited rapid loss from these regions, with only minimal cortical tracer accumulation. Significant differences in mean 18F-AV-45 uptake were observed between AD and age-matched control subjects. Test-retest variability with 18F-AV-45 PET imaging was low (<5%) in both AD patients and cognitively healthy controls. Visual interpretation of the 18F-AV-45 images and mean quantitative estimates of cortical uptake correlated with the presence and amount of amyloid pathology at autopsy, as measured by immunohistochemical and silver-stained neuritic plaque scores [Clark et al. 2011].

[0092] The radiation dose of 18F-AV-45 is within the range of typical PET ligands. The average human whole-body effective dose is estimated to be 0.019 mSv / MBq. A dose of 370 MBq per injection has also been shown to produce good imaging results.

[0093] Patients with AD have a characteristic decrease in regional glucose metabolism as measured by FDG PET, which correlates with the progression of cognitive impairment [Landau 2011, Mselke 1994]. The efficacy of BIIB037 in halting the progression of glucose metabolic deficiencies can be assessed periodically using FDG PET measurements. The radiation dose of FDG is within the range of typical PET ligands. The average human whole-body effective dose is estimated to be 0.019 mSv / MBq. Standard FDG imaging protocols use a dose of 185 MBq per injection. In the present invention, patients typically receive up to 185 MBq per scan.

[0094] Measurement of Aβ1-42 and T-tau or P-tau levels in CSF has gained acceptance as predictive biomarkers for AD. Evidence suggests that tau aggregation pathology is a very early event in the pathogenesis of the disease. Duyckaerts (2011) Lancet Neurol. 10, 774-775, and Braak et al., (2013) Acta Neuropath., 126:631-41.

[0095] Alzheimer's disease-related biomarkers can also be employed, including, but not limited to, pyroglutamated Aβ, Aβ40, and Aβ42 in the blood, and total tau, phosphorylated tau, pyroglutamated tau, Aβ40, and Aβ42 in the CSF.

[0096] Morphological MRI measurements can also aid in the assessment of AD. These include whole brain volume, hippocampal volume, ventricular volume, and cortical gray matter volume. Cerebral blood flow, as measured by ASL-MRI, and functional connectivity, as measured by tf-fMRI, can be included in the assessment protocol.

[0097] Use of BIIB037 antibody in treating patients with Alzheimer's disease according to the present invention results in an improvement from baseline measurements in one or more of these parameters, at least preventing or slowing the progression of AD from one stage to the next.

[0098] Measuring and reducing ARIA Patients with Alzheimer's disease generally respond to the monoclonal antibody in a dose-dependent manner. Therefore, using a high dose is advantageous for maximum efficacy. However, increasing the dose of the antibody may increase the incidence or rate of ARIA in certain patient populations. The present invention makes it possible to reduce the incidence of ARIA in susceptible patients undergoing treatment for Alzheimer's disease, particularly those receiving treatment with high doses of the monoclonal antibody, as well as ApoE4 carriers. Specifically, the present invention reduces the incidence of amyloid-related imaging abnormalities - edema (ARIA-E), or amyloid-related imaging abnormalities - hemorrhage or hemosiderosis (ARIA-H), or both ARIA-E and ARIA-H.

[0099] Amyloid-related imaging abnormalities (ARIA), including edema (ARIA-E) and hemorrhage or hemosiderosis (ARIA-H), are readily detectable by MRI (i.e., fluid-attenuated inversion recovery (FLAIR / T2 for ARIA-E and T2 for ARIA-H)). * / Gradient echo)) [Sperling 2012]. T2 * Susceptibility-weighted imaging (SWI) [Sperling 2011], a potentially more sensitive MRI technique compared to gradient echo, can also be employed.

[0100] Signs of vasogenic edema include hyperintense signals on T2-weighted and FLAIR sequences, generally confined to the white matter, and often associated with gyral swelling. Symptoms of vasogenic edema, when present, include headache, cognitive deterioration, altered consciousness, seizures, unsteadiness, and vomiting.

[0101] Patients who remain clinically asymptomatic throughout treatment and experience mild ARIA-E can continue their current dose. MRIs should be performed approximately every 4 weeks until the ARIA-E resolves. MMSE should be performed periodically until the ARIA-E resolves.

[0102] Patients who experience moderate or severe ARIA-E without any clinical symptoms should have their treatment discontinued. If, on repeat MRI follow-up, approximately every 4 weeks, the ARIA-E has resolved and the subject remains asymptomatic, the patient may resume treatment at the next lower dose level. Patients should undergo MMSE periodically until the ARIA-E has resolved before resuming medication.

[0103] At any time, patients experiencing mild, moderate, or severe ARIA-E accompanied by moderate, severe, or critical clinical symptoms should permanently discontinue treatment.

[0104] ARIA-H can be monitored by MRI and is considered an imaging finding without clinical correlation (i.e., patients are asymptomatic) [Sperling 2011]. In particular, hemorrhages are detectable using gradient-echo, T1-weighted, T2-weighted, and FLAIR MRI sequences. Microhemorrhages are usually asymptomatic, while large hemorrhages typically have focal signs and symptoms reflecting the affected brain region, along with nonspecific symptoms, including those for vasogenic edema. The frequency of MRI acquisition is dictated by the need for safety monitoring.

[0105] Patients who develop asymptomatic ARIA-H (fewer than four microbleeds) during treatment may continue treatment at their current dose at any time. Repeat MRIs should be performed approximately every two weeks until the condition is deemed stable. Subjects should undergo MMSE periodically until their ARIA-H is deemed stable.

[0106] Treatment should be interrupted for patients who develop ARIA-H (fewer than four microhemorrhage episodes) with mild clinical symptoms, or for subjects with a single hemosiderosis (or superficial hemosiderosis) episode who are asymptomatic or have mild clinical symptoms. Repeat MRIs should be obtained approximately every two weeks until the condition is deemed stable. Once the ARIA-H (microhemorrhage / hemosiderosis) is deemed stable and the clinical symptoms have resolved, the patient may resume treatment at the next lower dose level. Patients should undergo MMSE periodically until the ARIA-H / hemosiderosis is deemed stable.

[0107] Subjects who develop ARIA-H (<4 microbleed events) accompanied by moderate, severe, or critical clinical symptoms, >4 microbleed events, any major bleeding events, or >1 hemosiderosis event should permanently discontinue treatment. [Example]

[0108] Example 1 In vivo toxicity testing of BIIB037 Tg2576 mice and cynomolgus monkeys were used in toxicity studies of BIIB037. Of these two species, Tg2576 mice were considered the primary pharmacologically relevant species because they accumulate amyloid plaques in the brain parenchyma and blood vessels.

[0109] In addition to standard histopathological evaluation in mice, Peris staining for hemosiderin (a breakdown product of hemoglobin) was performed to quantify microhemorrhages. Microhemorrhages have been observed both as a background finding in transgenic mice for AD [Winkler et al. 2001], including Tg2576 mice [Kumar-Singh et al. 2005], and as a drug-related finding in transgenic mice treated with several anti-Aβ antibodies [Pfeifer et al. 2002, Racke et al. 2005, Wilcock and Colton 2009].

[0110] Example 2: Short-term in vivo testing of BIIB037 In a 13-week study, Tg2576 mice were administered 4-weekly doses of 10 or 70 mg / kg ch12F6A, or 500 mg / kg ch12F6A or BIIB037. Minimal mild acute hemorrhages were observed in two mice dosed at ≥70 mg / kg / week, as assessed by standard histopathological staining. Additional findings included a slight increase in the incidence and / or severity of meningeal vascular inflammation in mice treated at ≥70 mg / kg / week compared with control animals, and the occurrence of thrombosis in two animals dosed at 500 mg / kg / week. At the end of a 6-week drug-free recovery period, the incidence and severity of findings observed in mice treated with ch12F6A and BIIB037 were within the range observed in the control groups throughout this study.

[0111] In addition to standard brain histopathology, the presence of microhemorrhages was assessed by Perris staining, and there was no significant difference in microhemorrhages between the ch12F6A / BIIB037 and control treatment groups after 13 weeks of dosing.

[0112] The increased incidence and / or severity of meningeal vascular inflammation and acute hemorrhage observed at or above 70 mg / kg / week contributed to the determination of a no observed adverse effect level (NOAEL) of 10 mg / kg / week.

[0113] Example 3 Long-term in vivo studies of BIIB037 In a 6-month study, Tg2576 mice were administered 4-weekly doses of 10 or 40 mg / kg ch12F6A, or 250 mg / kg ch12F6A or BIIB037. There were no treatment-related changes in any of the parameters assessed during the main and recovery periods, except for a slight increase in the combined incidence and / or severity of meningeal / cerebrovascular inflammation and vascular thickening in the brains of main and early-death animals treated with chimeric 12F6A containing the murine constant region (ch12F6A) at doses of 40 mg / kg or higher, and microhemorrhages in a small group of animals treated with 250 mg / kg ch12F6A.

[0114] In Tg2576 mice receiving weekly intravenous injections of 250 mg / kg BIIB037, there were no treatment-related findings, no increase in the incidence and / or severity of meningeal / cerebral vascular inflammation and vascular thickening, and no statistically significant differences in the percent area of ​​multiple lesions and / or microhemorrhages in the brains of animals receiving ch12F6A or BIIB037.

[0115] After a 6-week recovery period, the incidence and / or severity of the vascular inflammation or thickening was similar across treatment and control groups. Although a potential treatment-related worsening of these changes cannot be completely ruled out, the vascular inflammation, thickening, and potentially worsening microhemorrhages in the brain were considered to be of equivocal association with treatment and potentially due to age-related progressive changes unique to this disease model. Therefore, the NOAEL from this study is 250 mg / kg / week.

[0116] A 4-week monkey study showed no treatment-related findings, with a NOAEL of 300 mg / kg / week.

[0117] In summary, the toxicity assessment of BIIB037 was consistent with a toxicity profile consistent with the antibody's binding to deposited Aβ.

[0118] Example 4 Reduction of amyloid beta in vivo A dose-dependent reduction in brain amyloid was observed in Tg2576 mice after chronic administration of ch12F6A (0.3 mg / kg to 30 mg / kg). Significant amyloid reduction was observed at 3 mg / kg, which was determined to be the minimally effective dose, and efficacy appeared to plateau between 10 mg / kg and 30 mg / kg. The no-observed-adverse-effect level (NOAEL) obtained in a 13-week toxicity study in Tg2576 mice (10 mg / kg / week) was used for safety margin determination purposes.

[0119] Mean steady-state exposure (AUC ) of BIIB037 at 1 and 3 mg / kg in humans 0~4週間 ) was calculated as the non-clinical NOAEL dose exposure (AUC 0~4週間 The mean steady-state exposure of BIIB037 after a 10 mg / kg dose is estimated to be equivalent to the NOAEL dose. The highest dose, 30 mg / kg, is estimated to achieve mean steady-state exposures two to three times the NOAEL and one-third the exposure at the 70 mg / kg dose, where a slight increase in the severity of meningeal vascular inflammation and the occurrence of cerebral hemorrhage were observed.

[0120] Example 5 Clinical Experience with BIIB037 The first clinical trial was a Phase 1, randomized, blinded, placebo-controlled, single ascending dose (SAD) study of the safety, tolerability, and pharmacokinetics (PK) of BIIB037 in subjects with mild to moderate AD. Fifty-three subjects were enrolled in the SAD study.

[0121] The starting dose of BIIB037 was 0.3 mg / kg, and the initial dose was 500 mg / kg (AUCTAU = 402,000 μg * The doses were increased to 60 mg / kg, a dose predicted to provide a mean exposure (AUC inf ) not exceeding that of Tg2576 mice given a dose of 0.3, 1, 3, 10, 20, and 30 mg / kg. Doses up to 30 mg / kg (0.3, 1, 3, 10, 20, and 30 mg / kg) were generally well tolerated.

[0122] Two serious adverse events (SAEs), symptomatic amyloid-related imaging abnormalities-edema (ARIA-E), and one asymptomatic ARIA-E adverse event (AE) were reported in the 60 mg / kg cohort. Further enrollment in the 60 mg / kg cohort was terminated per study protocol. Deaths and withdrawals due to AEs were reported in the SAD study. Serum exposure of BIIB037 demonstrated a linear trend up to doses of 30 mg / kg.

[0123] Example 6 A. Phase 1b Clinical Trial of BIIB037 in Human AD Subjects A Phase 1b clinical trial was conducted. This was a randomized, blinded, placebo-controlled, ascending-dose study of BIIB037 in subjects with prodromal to mild AD and positive amyloid scans. The primary endpoint of the study was safety. Secondary endpoints included evaluation of the effect on cerebral amyloid plaque content, as measured by 18F-AV-45 PET imaging. Changes from baseline in 18F-AV-45 PET signal were assessed in specific brain regions. Exploratory endpoints assessed the subjects' cognition. Subjects received 1, 3, 6, or 10 mg / kg of BIIB037 or placebo, based on their body weight.

[0124] B. Pre-Specified Interim Analysis #1 Pre-specified interim analysis #1 provided 26-week data for the 1, 3, and 10 mg / kg groups, as well as the placebo group.

[0125] The AD subjects were randomly assigned to four groups: placebo, BIIB037 at 1 mg / kg of the patient's body weight, BIIB037 at 3 mg / kg of the patient's body weight, and BIIB037 at 10 mg / kg of the patient's body weight. There were approximately 31 subjects in each group. The mean age of the subjects was approximately 72 years (mean). ApoE4 carriers comprised 63%, 61%, 66%, and 63% of the groups, respectively.

[0126] The subjects were assessed for clinical stage of AD. Subjects with prodromal AD comprised 47%, 32%, 44%, and 41% of the subjects in each group, respectively. Subjects with mild AD comprised 53%, 68%, 56%, and 59% of the subjects in each group, respectively.

[0127] A static PET acquisition protocol was employed. A tracer was injected into each subject and a single scan was performed. The tracer was AV45, a fibrillar Aβ plaque-targeting PET ligand.

[0128] The results of this amyloid PET imaging protocol are a measure of the uptake of the β-amyloid ligand used in PET imaging and are expressed as a standardized uptake ratio corresponding to the amount of β-amyloid present. This standardized uptake ratio normalizes the PET signal by taking the ratio of the target region to the reference region. In the target region, specific binding and changes in binding signal reflect treatment-induced pharmacological alterations. In the reference region, nonspecific binding indicates the absence of a treatment effect.

[0129] A dose-dependent reduction in amyloid was observed. At 26 weeks, there was a statistically significant reduction observed at 3 mg / kg and 10 mg / kg. This effect appeared to continue through 54 weeks based on the small cohort of subjects. No clear ApoE repair effect was observed. Greater benefit was observed in subjects with higher baseline standardized intake rates.

[0130] The safety and tolerability of the treatment were assessed. Adverse events were generally mild or moderate. Headache was the most common adverse event and appeared to be dose-dependent. There were no significant changes in chemistry, hematology, urinary, electrocardiogram, or vital signs. Twenty-seven subjects developed ARIA-E or ARIA-E / H.

[0131] A higher incidence of ARIA was observed with higher BIIB037 doses and with ApoE4 delivery. Homozygous and heterozygous E4 carriers appeared to be at similar risk for ARIA.

[0132] The onset of ARIA-E generally occurred early in the course of treatment. ARIA-E occurred after 3 to 5 doses (week 18 or week 10) at doses of 1 and 3 mg / kg. No cases were detected after the fifth dose. ARIA-E occurred after 2 doses (week 6) and week 30 at doses of 6 and 10 mg / kg. Imaging findings generally resolved within 4 to 12 weeks, indicating that ARIA-E is reversible.

[0133] All subjects with an ARIA-H event also had an ARIA-E event. The incidence of ARIA-E was higher than the incidence of ARIA-H in each of the 3 mg / kg and 10 mg / kg treatment groups. The incidence of each event in the group receiving the 1 mg / kg dose was the same.

[0134] C. Pre-Specified Interim Analysis #2 Pre-specified interim analysis #2 provided 54-week data for the 1, 3, and 10 mg / kg groups and the placebo group, as well as 26-week data for the 6 mg / kg group.

[0135] Figure 1 shows the mean PET composite standardized uptake ratio (SUVR) values ​​for each treatment group based on the observed data. Figure 1 shows that there was a reduction in amyloid burden in each of the treatment groups receiving BIIB037 antibody between baseline and week 26. There was a further reduction in amyloid burden in each of the treatment groups receiving BIIB037 between week 26 and week 54. The placebo group did not show a corresponding reduction in amyloid burden.

[0136] Figure 1 also shows that the reduction in amyloid burden with BIIB037 was dose-dependent. Higher doses of BIIB037 were associated with greater amyloid reduction in the brain using amyloid scans. A similar effect was not observed in the placebo group.

[0137] Figure 2 shows the adjusted mean change from baseline PET composite SUVR at week 26 by baseline clinical stage, i.e., prodromal or mild AD. Figure 2 is based on observed data. Figure 2 shows that amyloid reduction was dose-dependent in this amyloid scan.

[0138] Figure 3 shows the reduction in amyloid burden by subject ApoE4 status. Both carrier and non-carrier groups showed a reduction in amyloid burden compared to placebo. In each case, the reduction was dose-dependent.

[0139] The incidence of ARIA-E and / or ARIA-H in this study was estimated. The results are shown in Figure 4. The incidence of ARIA in ApoE4 carriers and non-carriers is also reported in Figure 4. The incidence was dose-dependent and dependent on the ApoE4 delivery at 6 and 10 mg / kg. ARIA-E usually occurred early in the course of treatment. ARIA-E was generally reversible. ARIA-H was stable. Imaging findings generally resolved within 4 to 12 weeks.

[0140] D. Clinical assessment of the patient's cognition Clinical assessments were used to measure changes in Alzheimer's disease symptoms in treated patients. Specifically, the Clinical Dementia Rating (CDR) and the Mini Mental State Examination (MMSE) were used to determine change from baseline. The results of these assessments based on observed data are summarized in Figures 5 and 6.

[0141] Figure 5 shows the adjusted mean change from baseline in CDR-SB for patient populations receiving 1 mg / kg, 3 mg / kg, or 10 mg / kg of BIIB037 antibody compared to patients receiving placebo. Measurements were taken at week 54 of treatment at the specified doses.

[0142] Figure 6 shows the adjusted mean change from baseline in MMSE for patients receiving placebo compared to patient populations receiving 1 mg / kg, 3 mg / kg, or 10 mg / kg of BIIB037 antibody. Measurements were taken at week 54 of treatment at the specified doses.

[0143] Example 7 A Randomized, Double-Blind, Placebo-Controlled Phase 1b Study of Aducanumab (BIIB037), an Anti-Aβ Monoclonal Antibody, in Patients with Prodromal or Mild Alzheimer's Disease: Interim Results by Disease Stage and ApoE ε4 Status Aducanumab (BIIB037) is a human monoclonal antibody selective for aggregated forms of beta-amyloid (Aβ) peptide, including soluble oligomers and insoluble fibrils. A single ascending dose study of aducanumab demonstrated acceptable safety in patients with mild to moderate AD at doses up to 30 mg / kg. This Phase 1b study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of aducanumab in patients with prodromal or mild AD.

[0144] The objective was to provide interim safety and Aβ clearance (changes in florbetapir [18-AV-45] positron emission tomography [PET] results) with aducanumab by disease stage and ApoE ε4 status.

[0145] Test Design PRIME is a multicenter, randomized, double-blind, placebo-controlled, multiple-dose trial [NCT01677572].

[0146] Patients were aged 50-90 years, had consistent concomitant medications, had a Mini-Mental State Examination (MMSE) score of 20 or greater, and met the following clinical and radiological criteria: Prodromal AD: spontaneous memory impairment with an MMSE of 24-30, a total free recall score of 27 or less on the Free and Cued Selective Reminding Test, a score of 0.5 on the Global Clinical Dementia Rating (CDR), no significant level of impairment in other cognitive domains, essentially preserved activities of daily living, no dementia, and a positive florbetapir PET scan on visual assessment. Mild AD: MMSE 20-26, global CDR 0.5 or 1.0, met the National Institute on Aging-Alzheimer's Association core clinical criteria for probable AD, and had a positive florbetapir PET scan by visual assessment.

[0147] The PRIME study design is shown in Figure 14. Patients (planned N=188) were randomized to one of nine treatment arms (target enrollment: n=30 per active arm) in a staggered, ascending-dose design in a 3:1 active-to-placebo ratio. Primary and secondary endpoints are provided in Figure 15. A timeline of the PRIME evaluations is shown in Figure 16. PRIME is ongoing. Data were analyzed for interim analyses at week 54 for the 1, 3, and 10 mg / kg arms and at week 30 for the 6 mg / kg arm. patient Of the 166 patients, 165 were randomized to treatment; 107 (65%) were ApoE ε4 carriers, and 68 (41%) had prodromal AD. Patient distribution is shown in Figure 17. Baseline demographics and disease characteristics were generally balanced across treatment groups, as shown in Figure 18.

[0148] safety Adverse events (AEs) were reported in 84% to 98% of patients across treatment groups. The most common AE and serious AE (SAE) was amyloid-related imaging abnormalities (ARIA; MRI-based) (Table 9); other AEs / SAEs were consistent with the patient population. Figure 19 provides an overview of the distribution of patients with ARIA findings and ARIE-E.

[0149] Three patient deaths were reported (two with placebo and one with 10 mg / kg aducanumab), none of which were considered treatment-related (two occurred after study discontinuation).

[0150] The incidence of isolated ARIA-edema (ARIA-E) was dose- and ApoEε4 status-dependent (FIG. 19). The overall incidence of ARIA-E among ApoE ε4 carriers was 5%, 5%, 43%, and 55% for 1, 3, 6, and 10 mg / kg aducanumab, respectively, compared with 0% for placebo. The corresponding incidence rates among ApoE ε4 non-carriers were 0%, 9%, 11%, and 17%, compared with 0% for placebo. The incidence of isolated ARIA-microhemorrhage / hemosiderosis (ARIA-H) was similar across doses and ApoE ε4 status (data not shown).

[0151] Based on the small sample size, there was no clear difference in the incidence of ARIA-E between patients with prodromal and mild AD when accounting for ApoE ε4 status (FIG. 19).

[0152] Most ARIE-E events (92%) were observed within the first 5 doses, and 65% of ARIE-E events were asymptomatic. If present, symptoms usually resolved within 4 weeks. MRI findings usually resolved within 4 to 12 weeks.

[0153] The majority of patients (54%) who developed ARIA-E continued treatment (93% of those who continued did so at a reduced dose). No patients developed recurrent ARIA-E. Treatment discontinuation in patients with ARIA-E was consistent across mild and prodromal subgroups (data not shown).

[0154] There were no significant changes in chemistry, hematology, urine, electrocardiogram, or vital signs.

[0155] Reduction of brain Aβ plaques Brain Aβ plaque reduction was assessed by a composite SUVR from the volumes of six regions: frontal, parietal, lateral temporal, sensorimotor cortex, anterior cingulate, and posterior cingulate.

[0156] Dose- and time-dependent reductions in brain Aβ plaques (supported by SUVR reductions) at weeks 26 and 54 were generally consistent across subgroups of mild and prodromal AD, as well as across ApoE ε4 carriers and non-carriers, within the doses tested, as shown in Figure 7.

[0157] Clinical endpoints There was a statistically significant, dose-dependent slowing of decline in exploratory endpoints, MMSE (Figure 8) and CDR-sb (Figure 9) at 1 year.

[0158] conclusion Relative to placebo, there was a significant dose- and time-dependent reduction in brain Aβ plaques as measured by PET imaging, an effect that was still evident after 6 months and 1 year of treatment.

[0159] The pattern of effect of aducanumab versus placebo in reducing Aβ plaques was generally consistent across disease stage and ApoE ε4 status.

[0160] A statistically significant, dose-dependent slowing of decline in MMSE and CDR-sb was observed after 1 year.

[0161] Aducanumab demonstrated an acceptable safety profile over 54 weeks. ARIA was the primary safety and tolerability finding and was monitorable and manageable. The incidence of ARIA was dose- and ApoE ε4 status-dependent. ARIA was usually observed early in the course of treatment and was asymptomatic or had mild, transient symptoms.

[0162] Interim Analysis #3 Interim Analysis #3 includes data through 54 weeks for the 6 mg / kg arm and the matching placebo arm (embedded in the placebo population pooled for this analysis).

[0163] Reduction of brain Aβ plaques Brain Aβ plaque reduction was assessed by a composite SUVR from the volumes of six regions: frontal, parietal, lateral temporal, sensorimotor cortex, anterior cingulate, and posterior cingulate. As shown in Figure 11, there was a dose-dependent reduction in brain Aβ plaques (supported by a reduction in SUVR) at 54 weeks.

[0164] Clinical endpoints There was a statistically significant, dose-dependent slowing of decline in exploratory endpoints, MMSE (Figure 13) and CDR-sb (Figure 12) at 1 year.

[0165] Example 8 A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Aducanumab (BIIB037) in Patients with Early Alzheimer's Disease A study was conducted to evaluate the efficacy and safety of aducanumab compared to placebo in patients with early AD, including subjects with mild cognitive impairment (MCI) due to AD and a subgroup with mild AD.

[0166] The dosing regimen selected for this study was based on the observed PK and PD relationships for cerebral amyloid clearance, and efficacy, safety, tolerability, and PD data on CDR-SB and MMSE.

[0167] Dose- and time-dependent reductions in brain amyloid burden observed with aducanumab treatment were statistically significant at 3, 6, and 10 mg / kg doses after 6 months of treatment and at 3 and 10 mg / kg doses after 12 months of treatment. Effects on mean reduction from baseline in CDR-SB after 12 months of treatment were observed at both 3 and 10 mg / kg, reaching statistical significance at 10 mg / kg. Effects on mean reduction from baseline in MMSE score were statistically significant at 3 and 10 mg / kg. These data indicate that 3 mg / kg is an acceptable dose; however, given the dose-dependent nature of these findings, the use of higher doses (6 and 10 mg / kg) provides greater benefit at acceptable risk.

[0168] ARIA has been identified as a potential event caused by anti-amyloid target drug candidates and is considered to be of particular interest. To date, the incidence of ARIA has been observed to be both dose- and ApoEε4 delivery-dependent, particularly at the highest doses.

[0169] A titration treatment regimen will be used to maximize the dose-dependent reductions and benefits in CDR-SB and MMSE observed at doses of 3 mg / kg and higher, while maintaining ARIA incidence, severity, and associated discontinuation rates within acceptable levels.

[0170] Given the tolerability and apparent efficacy of aducanumab, the doses used in the titration regimen are 3 and 6 mg / kg for ApoE ε4 carriers and 6 and 10 mg / kg for ApoE ε4 non-carriers, starting at 1 mg / kg and escalating to 3, 6, and 10 mg / kg, as detailed below.

[0171] Medication scheme Placebo-controlled period Doses are administered approximately 4 weeks apart for approximately 76 weeks (20 total doses). Subjects are assigned to one of three treatment groups (450 subjects each) based on their ApoE ε4 carrier status in a 1:1:1 ratio (low dose aducanumab vs. high dose aducanumab vs. placebo) as follows (see Table 4 and Figure 10): ApoEε4 carriers ·Low dose (3mg / kg) 1 mg / kg for the first 2 doses, then 3 mg / kg thereafter ·High dose (6mg / kg) 1 mg / kg for the first 2 doses, 3 mg / kg for the next 4 doses, and 6 mg / kg thereafter ·placebo Saline injection ApoEε4 non-carrier ·Low dose (6mg / kg) 1 mg / kg for the first 2 doses, 3 mg / kg for the next 4 doses, and 6 mg / kg thereafter ·High dose (10mg / kg) 1 mg / kg for the first 2 doses, 3 mg / kg for the next 2 doses, 6 mg / kg for the next 2 doses, and 10 mg / kg placebo thereafter Saline injection [Table 4]

[0172] Correction of medication scheme The dosing may be modified in the following circumstances: High-dose safety and tolerability If any of the high doses (10 mg / kg in ApoE ε4 non-carriers and 6 mg / kg in ApoE ε4 carriers) are not accepted, enrollment in that high dose group(s) may be terminated and subjects will not be replaced. Subjects randomized to the discontinued dose will be de-escalated to the next available dose according to their ApoE ε4 carrier status. ·Dose setting If titration is not beneficial, it is removed and thereafter subjects who are ApoE ε4 carriers receive a fixed dose of 3 or 6 mg / kg, and non-carriers receive 6 or 10 mg / kg.

[0173] Long term extension (LTE) Subjects who received aducanumab during the placebo-controlled period and entered an LTE will continue to receive the same dose of aducanumab they received at the end of the placebo-controlled period. Subjects will be dosed using the same treatment regimen described for the placebo-controlled period (see Table 4 and Figure 10). Modifications to the dosing scheme (i.e., termination of the high-dose group and reversal of titration with fixed dosing) will be implemented in the LTE.

[0174] The efficacy of monthly doses of aducanumab on cognitive decline and functional impairment is measured by the change in CDR-SB scores.

[0175] A secondary measure is to assess the effect of monthly doses of aducanumab on clinical progression as measured by the MMSE. The endpoint for this measure is change from baseline in MMSE score at week 78.

[0176] Another secondary measure will be to evaluate the effect of monthly doses of aducanumab on clinical progression as measured by the ADAS-Cog 13. The endpoint for this measure is the change from baseline in the ADAS-Cog 13 score at week 78.

[0177] Another secondary measure will be to evaluate the effect of monthly doses of aducanumab on clinical progression as measured by the ADCS-ADL-MCI. The endpoint for this measure is the change from baseline in the ADCS-ADL-MCI score at week 78.

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[Claim 1] A composition or method as described in the specification.

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