Anti-tau antibody compositions, dosage forms, and methods

Abstract

Provided herein are dosage forms comprising an antibody that specifically binds to tau, a method of treating a human subject diagnosed with a tauopathy comprising administering to the human subject an antibody that specifically binds to tau, and a pharmaceutical composition for treating a subject diagnosed with a tauopathy comprising an antibody that specifically binds to tau. The present invention provides an intravenous dosage form comprising an antibody that specifically binds to tau in a single dose amount of about 3 mg / kg to about 90 mg / kg.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 275,045, filed November 3, 2021, U.S. Provisional Patent Application No. 63 / 290,278, filed December 16, 2021, U.S. Provisional Patent Application No. 63 / 316,582, filed March 4, 2022, and U.S. Provisional Patent Application No. 63 / 316,616, filed March 4, 2022. Each of these applications is incorporated herein by reference in its entirety.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in ASCII format herewith, and which is hereby incorporated by reference in its entirety. The ASCII copy, created on October 26, 2022, is named 104018001201_SEQUENCE LISTING.xml and is 17,345 bytes in size.

[0003] The present invention relates to dosage forms comprising an antibody that specifically binds to tau, a method of treating a human subject diagnosed with a tauopathy comprising administering to the subject an antibody that specifically binds to tau, and a pharmaceutical composition for treating a human subject diagnosed with a tauopathy comprising an antibody that specifically binds to tau. [Background technology]

[0004] Tau protein, which belongs to the microtubule-associated protein (MAP) family, is mainly expressed in neurons and is found in axons and dendrites. Tau protein plays a key role in the assembly of tubulin monomers into microtubules that constitute the cytoskeleton and serve as axonal transport pathways. Tau protein is translated from a single gene located on chromosome 17, where alternative mRNA splicing leads to the formation of six different central nervous system tau isoforms, five of which are found in the human mature brain. These isoforms differ in that they contain either three (R1, R3, and R4) or four (R1-R4) repeat regions in the carboxy (C)-terminal portion, and there are variable microtubule-binding regions (MTBRs). The amino (N)-terminal domain is the domain that establishes the connection between the microtubules and other parts of the cytoskeleton or the cell membrane, and there are variable 0, 1, or 2 29 amino acid insertions.

[0005] Tau protein is a key component of intracellular fibrillary tangles described in Alzheimer's disease (AD) and other neurodegenerative disorders called tauopathies. The aggregation of hyperphosphorylated tau into insoluble paired helical filaments (PHFs), which accumulate in neuronal cells, is a crucial process in the formation of neurofibrillary tangles (NFTs), which are the hallmark pathological findings of AD, a secondary tauopathy. NFTs are also pathological findings of primary tauopathies, such as frontotemporal dementia, corticobasal degeneration, Pick's disease, and progressive supranuclear palsy. Recent in vitro and in vivo studies on the development of PHFs and NFTs have shown that pathophysiological tau processes appear to be triggered by the presence of extracellular tau seeds. These small soluble tau seeds containing MTBR induce the spread of tau pathology throughout the brain, possibly transsynaptically, inducing the formation of intracellular insoluble tau aggregates, thereby promoting the development of NFT pathology. In AD, NFTs are present in a neuroanatomically distinctive pattern of increasing severity, typically defined according to Braak stages 1-6, which correlate well with progressive neuronal loss and clinical decline. Consequently, selective targeting and removal of tau seeds is expected to halt or slow disease progression in tauopathies or AD-associated tauopathies. However, at present, there is no cure for these diseases and no means to slow their progression. Thus, there is an urgent and unmet medical need for drugs to slow or prevent the progression of tauopathies. Summary of the Invention [Problem to be solved by the invention]

[0006] It is an object of the present invention to provide a dosage form comprising an antibody that specifically binds to tau, a method of treating a human subject diagnosed with a tauopathy comprising administering to the subject an antibody that specifically binds to tau, and a pharmaceutical composition for treating a human subject diagnosed with a tauopathy comprising an antibody that specifically binds to tau. [Means for solving the problem]

[0007] Provided herein is an intravenous dosage form comprising an antibody that specifically binds to tau, wherein the amount of the antibody in a single dose is about 3 mg / kg to about 90 mg / kg. According to some embodiments, an intravenous dosage form is provided comprising an antibody that specifically binds to tau, wherein the amount of the antibody in a single dose is about 3 mg / kg, about 10 mg / kg, about 30 mg / kg, about 60 mg / kg, or about 90 mg / kg.

[0008] Provided herein is an intravenous dosage form comprising an amount of an antibody that specifically binds to tau, wherein the amount provides a serum C in the range of 6.29 μg / mL to 1960 μg / mL following administration to a human subject. max Further provided herein is an intravenous dosage form comprising an antibody that specifically binds to tau, wherein the amount of the antibody achieves a geometric mean serum C of about 9.55 μg / mL to about 1450 μg / mL after administration to a human subject. max It is a single dose that achieves this.

[0009] Further provided herein is an intravenous dosage form comprising an amount of an antibody that specifically binds to tau, wherein the amount has a serum AUC in the range of 12,300 μg·hr / mL to 194,000 μg·hr / mL following administration to a human subject. (0-inf) Further provided herein is an intravenous dosage form comprising an amount of an antibody that specifically binds to tau, wherein the amount achieves a geometric mean serum AUC of about 12,300 μg hr / mL to about 130,000 μg hr / mL following administration to a human subject. (0-inf) It is a single dose that achieves this.

[0010] Further provided herein is an intravenous dosage form comprising an amount of an antibody that specifically binds to tau, wherein the amount has a serum AUC in the range of 839 μg·hr / mL to 203,000 μg·hr / mL following administration to a human subject. (0-672h)Further provided herein is an intravenous dosage form comprising an amount of an antibody that specifically binds to tau, wherein the amount achieves a geometric mean serum AUC of about 1580 μg hr / mL to about 122000 μg hr / mL following administration to a human subject. (0-672h) It is a single dose that achieves this.

[0011] Provided herein is an intravenous dosage form comprising an amount of an antibody that specifically binds to tau, where the amount results in a CSF C in the range of 13.5 ng / mL to 672 ng / mL following administration to a human subject. max Further provided herein is an intravenous dosage form comprising an amount of an antibody that specifically binds to tau, wherein the amount achieves a geometric mean CSF C of about 15.9 ng / mL to about 404 ng / mL following administration to a human subject. max It is a single dose that achieves this.

[0012] Further provided herein is an intravenous dosage form comprising an amount of an antibody that specifically binds to tau, wherein the amount provides a CSF AUC range of 159 ng·hr / mL to 7690 ng·hr / mL following administration to a human subject. (0-24h) Further provided herein is an intravenous dosage form comprising an amount of an antibody that specifically binds to tau, wherein the amount achieves a geometric mean CSF AUC of about 191 ng hr / mL to about 5320 ng hr / mL following administration to a human subject. (0-24h) It is a single dose that achieves this.

[0013] Also provided herein is a method of treating a human subject diagnosed with a tauopathy, the method comprising intravenously administering to the human subject an amount of an antibody that specifically binds to tau, wherein the amount is a single dose of about 3 mg / kg to about 90 mg / kg. According to some embodiments of the method, the amount is a single dose of about 3 mg / kg, about 10 mg / kg, about 30 mg / kg, about 60 mg / kg, or about 90 mg / kg.

[0014] Also provided herein is a method of treating a human subject diagnosed with a tauopathy, comprising intravenously administering to the human subject an amount of an antibody that specifically binds tau, wherein the amount results in a serum C in the range of 6.29 μg / mL to 1960 μg / mL following administration. max Also provided herein is a method of treating a human subject diagnosed with a tauopathy, comprising intravenously administering to the human subject an amount of an antibody that specifically binds tau, wherein the amount achieves a geometric mean serum C of about 9.55 μg / mL to about 1450 μg / mL after administration. max It is a single dose that achieves this.

[0015] Also provided herein is a method of treating a human subject diagnosed with a tauopathy, comprising intravenously administering to the human subject an amount of an antibody that specifically binds to tau, wherein the amount provides a serum AUC in the range of 12,300 μg hr / mL to 194,000 μg hr / mL following administration. (0-inf) Also provided herein is a method of treating a human subject diagnosed with a tauopathy, comprising intravenously administering to the human subject an amount of an antibody that specifically binds tau, wherein the amount achieves a geometric mean serum AUC of about 12,300 μg hr / mL to about 130,000 μg hr / mL after administration. (0-inf) It is a single dose that achieves this.

[0016] Further provided herein is a method of treating a human subject diagnosed with a tauopathy, comprising intravenously administering to the human subject an amount of an antibody that specifically binds to tau, wherein the amount provides a serum AUC in the range of 839 μg·hr / mL to 203,000 μg·hr / mL following administration. (0-672h) Further provided herein is a method of treating a human subject diagnosed with a tauopathy, comprising intravenously administering to the human subject an amount of an antibody that specifically binds tau, wherein the amount achieves a geometric mean serum AUC of about 1580 μg hr / mL to about 122000 μg hr / mL after administration. (0-672h) It is a single dose that achieves this.

[0017] Also provided herein is a method of treating a human subject diagnosed with a tauopathy, comprising intravenously administering to the human subject an amount of an antibody that specifically binds tau, wherein the amount results in a CSF C value in the range of 13.5 ng / mL to 672 ng / mL following administration to the human subject. max Also provided herein is a method of treating a human subject diagnosed with a tauopathy, comprising intravenously administering to the human subject an amount of an antibody that specifically binds tau, wherein the amount achieves a geometric mean CSF C of about 15.9 ng / mL to about 404 ng / mL after administration to the human subject. max It is a single dose that achieves this.

[0018] Also provided herein is a method of treating a human subject diagnosed with a tauopathy, comprising intravenously administering to the human subject an amount of an antibody that specifically binds to tau, wherein the amount provides a CSF AUC in the range of 159 ng·hr / mL to 7690 ng·hr / mL following administration. (0-24h) Also provided herein is a method of treating a human subject diagnosed with a tauopathy, comprising intravenously administering to the human subject an amount of an antibody that specifically binds tau, wherein the amount achieves a geometric mean CSF AUC of about 191 ng hr / mL to about 5320 ng hr / mL after administration. (0-24h) It is a single dose that achieves this.

[0019] Further provided herein is a pharmaceutical composition for treating a human subject diagnosed with a tauopathy, the pharmaceutical composition comprising an antibody that specifically binds to tau, wherein the antibody that specifically binds to tau is administered to the subject in a single dose of about 3 mg / kg to about 90 mg / kg. According to some embodiments of the pharmaceutical composition for treating a human subject diagnosed with a tauopathy, the antibody that specifically binds to tau is administered to the subject in a single dose of about 3 mg / kg, about 10 mg / kg, about 30 mg / kg, about 60 mg / kg, or about 90 mg / kg.

[0020] According to some embodiments of the pharmaceutical composition for treating a human subject diagnosed with a tauopathy, the antibody that specifically binds tau has a serum C value ranging from 6.29 μg / mL to 1960 μg / mL after administration. max According to some embodiments of the pharmaceutical composition for treating a human subject diagnosed with a tauopathy, the antibody that specifically binds tau is administered to the subject in a single dose that achieves a geometric mean serum C of about 9.55 μg / mL to about 1450 μg / mL after administration. max The subject is administered a single dose that achieves this.

[0021] According to some embodiments of the pharmaceutical composition for treating a human subject diagnosed with a tauopathy, the antibody that specifically binds tau has a serum AUC range of 12,300 μg·hr / mL to 194,000 μg·hr / mL after administration. (0-inf) According to some embodiments of the pharmaceutical composition for treating a human subject diagnosed with a tauopathy, the antibody that specifically binds tau is administered to the subject in a single dose that achieves a geometric mean serum AUC of about 12,300 μg hr / mL to about 130,000 μg hr / mL after administration. (0-inf) The subject is administered a single dose that achieves this.

[0022] According to some embodiments of the pharmaceutical composition for treating a human subject diagnosed with a tauopathy, the antibody that specifically binds tau has a serum AUC range of 839 μg·hr / mL to 203,000 μg·hr / mL after administration. (0-672h) According to some embodiments of the pharmaceutical composition for treating a human subject diagnosed with a tauopathy, the antibody that specifically binds tau is administered to the subject in a single dose that achieves a geometric mean serum AUC of about 1580 μg hr / mL to about 122000 μg hr / mL after administration. (0-672h) The subject is administered a single dose that achieves this.

[0023] According to some embodiments of the pharmaceutical composition for treating a human subject diagnosed with a tauopathy, the antibody that specifically binds tau provides a CSF C value in the range of 13.5 ng / mL to 672 ng / mL after administration. maxAccording to some embodiments of the pharmaceutical composition for treating a human subject diagnosed with a tauopathy, the antibody that specifically binds tau is administered to the subject in a single dose that achieves a geometric mean serum C of about 15.9 ng / mL to about 404 ng / mL after administration. max The subject is administered a single dose that achieves this.

[0024] According to some embodiments of the pharmaceutical composition for treating a human subject diagnosed with a tauopathy, the antibody that specifically binds tau provides a CSF AUC range of 159 ng·hr / mL to 7690 ng·hr / mL after administration. (0-24h) According to some embodiments of a pharmaceutical composition for treating a human subject diagnosed with a tauopathy, an antibody that specifically binds tau is administered to the subject in a single dose that achieves a geometric mean CSF AUC of about 191 ng·hr / mL to about 5320 ng·hr / mL after administration. (0-24h) The subject is administered a single dose that achieves this.

[0025] Provided herein is an intravenous dosage form comprising an amount of an antibody that specifically binds to tau, wherein the amount is a dose of about 750 mg to about 4500 mg. According to some embodiments of an intravenous dosage form comprising an amount of an antibody that specifically binds to tau, wherein the amount is a dose of about 1500 mg to about 4500 mg, about 1500 mg to about 3000 mg, or about 3000 mg to about 4500 mg. According to some embodiments, a dose of the antibody is administered to the subject once every four weeks. According to some embodiments, provided is an intravenous dosage form comprising an amount of an antibody that specifically binds to tau, wherein the amount is a dose of about 750 mg, about 1500 mg, about 3000 mg, or about 4500 mg.

[0026] Provided herein is an intravenous dosage form comprising an amount of an antibody that specifically binds to tau, wherein the amount provides a serum C in the range of 21.1 μg / mL to 655 μg / mL following administration to a human subject. maxFurther provided herein is an intravenous dosage form comprising an amount of an antibody that specifically binds to tau, wherein the amount achieves a geometric mean serum C of about 35.6 μg / mL to about 509 μg / mL after administration to a human subject. max This is the dose that achieves this.

[0027] Also provided herein is an intravenous dosage form comprising an amount of an antibody that specifically binds to tau, wherein the amount provides a serum AUC in the range of 2690 μg·hr / mL to 58900 μg·hr / mL following administration to a human subject. (0-672h) Further provided herein is an intravenous dosage form comprising an amount of an antibody that specifically binds to tau, wherein the amount achieves a geometric mean serum AUC of about 5360 μg hr / mL to about 30300 μg hr / mL following administration to a human subject. (0-672h) This is the dose that achieves this.

[0028] Also provided herein is a method of treating a human subject diagnosed with a tauopathy, comprising administering to the human subject an amount of an antibody that specifically binds to tau, wherein the amount of the antibody that specifically binds to tau is a dose of about 750 mg to about 4500 mg. According to some embodiments of the method, the amount of the antibody that specifically binds to tau is a dose of about 1500 mg to about 4500 mg, about 1500 mg to about 3000 mg, or about 3000 mg to about 4500 mg. According to some embodiments, the dose of the antibody is administered to the subject once every four weeks. According to some embodiments, the dose of the antibody is administered intravenously to the subject. According to some embodiments of the method, the amount of the antibody that specifically binds to tau is a dose of about 750 mg, about 1500 mg, about 3000 mg, or about 4500 mg. According to some embodiments of the method, the amount of the antibody that specifically binds to tau is a dose of about 750 mg, about 1500 mg, about 3000 mg, or about 4500 mg administered once every four weeks. According to some embodiments of the method, the amount of the antibody that specifically binds to tau is a dose of about 750 mg, about 1500 mg, about 3000 mg, or about 4500 mg administered intravenously.

[0029] Provided herein is a method of treating a human subject diagnosed with a tauopathy, comprising administering to the human subject an amount of an antibody that specifically binds to tau, wherein the amount results in a serum C in the range of 21.1 μg / mL to 655 μg / mL following administration to the human subject. max According to some embodiments, provided herein is a method of treating a human subject diagnosed with a tauopathy, comprising administering to the human subject an amount of an antibody that specifically binds tau, wherein the amount achieves a geometric mean serum C of about 35.6 μg / mL to about 509 μg / mL after administration to the human subject. max This is the dose that achieves this.

[0030] Further provided herein is a method of treating a human subject diagnosed with a tauopathy, comprising administering to the human subject an amount of an antibody that specifically binds to tau, wherein the amount provides a serum AUC in the range of 2690 μg·hr / mL to 58900 μg·hr / mL after administration to the human subject. (0-672h) According to some embodiments, there is provided a method of treating a human subject diagnosed with a tauopathy, comprising administering to the human subject an amount of an antibody that specifically binds tau, wherein the amount achieves a geometric mean serum AUC of about 5360 μg hr / mL to about 30300 μg hr / mL after administration to the human subject. (0-672h) This is the dose that achieves this.

[0031] Further provided herein is a pharmaceutical composition for treating a human subject diagnosed with a tauopathy, the pharmaceutical composition comprising an antibody that specifically binds to tau, wherein the antibody that specifically binds to tau is administered to the subject in an amount of about 750 to about 4500 mg. According to some embodiments of the pharmaceutical composition, the antibody that specifically binds to tau is administered to the subject in an amount of about 1500 mg to about 4500 mg, about 1500 mg to about 3000 mg, or about 3000 mg to about 4500 mg. According to some embodiments, the antibody is administered to the subject once every four weeks. According to some embodiments, the antibody is administered to the subject intravenously. According to some embodiments of the pharmaceutical composition, the antibody that specifically binds to tau is administered in an amount of about 750 mg, about 1500 mg, about 3000 mg, or about 4500 mg. According to some embodiments of the pharmaceutical composition, the antibody that specifically binds to tau is administered once every four weeks in an amount of about 750 mg, about 1500 mg, about 3000 mg, or about 4500 mg. According to some embodiments of the pharmaceutical composition, the antibody that specifically binds to tau is administered intravenously in an amount of about 750 mg, about 1500 mg, about 3000 mg, or about 4500 mg.

[0032] According to some embodiments of the pharmaceutical composition for treating a human subject diagnosed with a tauopathy, the antibody that specifically binds tau has a serum C value ranging from 21.1 μg / mL to 655 μg / mL after administration to the human subject. max According to some embodiments of the pharmaceutical composition for treating a human subject diagnosed with a tauopathy, the antibody that specifically binds tau is administered to the subject at a dose that achieves a geometric mean serum C of about 35.6 μg / mL to about 509 μg / mL after administration to the human subject. max The subject is administered a dose that achieves this.

[0033] According to some embodiments of the pharmaceutical composition for treating a human subject diagnosed with a tauopathy, the antibody that specifically binds tau has a serum AUC in the range of 2690 μg·hr / mL to 58900 μg·hr / mL after administration to the human subject. (0-672h)According to some embodiments of a pharmaceutical composition for treating a human subject diagnosed with a tauopathy, an antibody that specifically binds tau is administered to a subject at a dose that achieves a geometric mean serum AUC of about 5360 μg hr / mL to about 30300 μg hr / mL after administration to a human subject. (0-672h) The subject is administered a dose that achieves this.

[0034] The summary, as well as the following detailed description, will be better understood when read in conjunction with the appended drawings. For the purpose of illustrating the presently disclosed method, there are shown in the drawings exemplary embodiments of the method; however, the method is not limited to the particular embodiments disclosed. [Brief description of the drawings]

[0035] [Figure 1A] Provides procedures and evaluation schedules for the single ascending dose (SAD) component of Study E2814-A001-001. [Figure 1B] Provides procedures and evaluation schedules for the single ascending dose (SAD) component of Study E2814-A001-001. [Figure 1C] Provides procedures and evaluation schedules for the single ascending dose (SAD) component of Study E2814-A001-001. [Diagram 2] Provides an overview of the study design for the single ascending dose component of Study E2814-A001-001. [Figure 3A] Provides procedures and evaluation schedules for the multiple ascending dose (MAD) component of Study E2814-A001-001. [Figure 3B] Provides procedures and evaluation schedules for the multiple ascending dose (MAD) component of Study E2814-A001-001. [Figure 4] Provides an overview of the study design for the multiple ascending dose component of Study E2814-A001-001. [Figure 5A] The demographic and baseline characteristics of the study subjects by cohort for the single ascending dose component of Study E2814-A001-001 are summarized. [Figure 5B] The demographic and baseline characteristics of the study subjects by cohort for the multiple ascending dose component of Study E2814-A001-001 are summarized. [Figure 6] Summarize geometric mean (CV%) E2814 serum PK parameters by study cohort for the single ascending dose component of Study E2814-A001-001. [Figure 7] 1 shows mean (+SD) E2814 serum concentration-time profiles by matrix and dose for the single ascending dose components of Study E2814-A001-001 (preliminary data). [Figure 8] Summarize geometric mean (CV%) E2814 serum CSF parameters by study cohort for the single ascending dose component of study E2814-A001-001. [Figure 9] Shown are mean (+SD) E2814 CSF concentration-time profiles by study cohort for the single ascending dose component of Study E2814-A001-001. [Figure 10] 4 provides geometric mean (gCV%) E2814 serum PK parameters following multiple IV dose administration from the multiple ascending dose component of Study E2814-A001-001. [Figure 11A] 1 shows individual CSF % tau 299 bound versus time in the single ascending dose component of Study E2814-A001-001. [Figure 11B] 1 shows individual CSF % tau354 bound versus time in the single ascending dose component of Study E2814-A001-001. [Figure 12A] 1 shows individual CSF binding (% of total) MTBR tau299 over time by dose for the multiple ascending dose components of Study E2814-A001-001. [Figure 12B]Figure 1 shows individual CSF binding (% of total) MTBR tau354 over time by dose for the multiple ascending dose component of Study E2814-A001-001. MAD dose cohort symbols: open circle 750 mg, filled triangle 1500 mg, filled circle 3000 mg. [Figure 13A] 1 shows individual CSF binding (% of total) MTBR tau299 versus E2814 CSF concentration for the single ascending dose (SAD) and multiple ascending dose (MAD) components of Study E2814-A001-001. [Figure 13B] Individual CSF binding (% of total) MTBR tau354 versus E2814 CSF concentrations for single ascending dose components and multiple ascending dose components of study E2814-A001-001 are shown. SAD dose cohort symbols: filled triangle 3 mg / kg, filled circle 10 mg / kg, open square 30 mg / kg, open diamond 60 mg / kg, open circle 90 mg / kg. MAD dose cohort symbols: open triangle 750 mg, star 1500 mg, plus sign 3000 mg. Three PK outliers excluded based on preliminary data. [Figure 14A] To summarize adverse events for the single ascending dose component of Study E2814-A001-001 by dose, severity, relevance, and terminology. [Figure 14B] To summarize adverse events for the multiple ascending dose component of study E2814-A001-001 by dose, severity, relevance, and terminology. [Figure 15] 1 shows mean (+SD) E2814 serum concentration-time profiles faceted by day and by dose for the multiple ascending dose component of Study E2814-A001-001. [Figure 16] Provide an overview of the study design of the open-label Phase 1b / 2 study (Study E2814-G000-103). [Figure 17A] Provide procedures and evaluation schedule for Study E2814-G000-103. [Figure 17B] Provide procedures and evaluation schedule for Study E2814-G000-103. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0036] The following description provides dosage forms, methods of use, and pharmaceutical compositions of antibodies that specifically bind to tau. In some embodiments, the provided dosage forms, methods, and pharmaceutical compositions may be used to treat a tauopathy in a subject.

[0037] The disclosed dosage forms, methods, and pharmaceutical compositions may be understood more readily by reference to the following detailed description considered in conjunction with the accompanying figures, which form a part of this disclosure: It is to be understood that the disclosed dosage forms, methods, and pharmaceutical compositions are not limited to those specifically described and / or illustrated herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only, and is not intended to be limiting of the claimed dosage forms, methods, and pharmaceutical compositions.

[0038] Unless specifically stated otherwise, any explanation of a possible mechanism or mode of action or reason for improvement is intended to be exemplary only, and the methods of the present disclosure should not be constrained by the precision or imprecision of any such proposed mechanism or mode of action or reason for improvement.

[0039] When a range of numerical values ​​is recited or defined herein, the range includes its endpoints and all individual integers and fractions within the range, and also includes any narrower ranges formed by all the various possible combinations of those endpoints and internal integers and fractions that form a subgroup of the larger group of values ​​within the stated range, to the same extent as if such narrower ranges were expressly recited. When a range of numerical values ​​is recited herein as being greater than the stated value, the range is nevertheless finite and bounded at its upper end by values ​​operable within the context of the invention as described herein. When a range of numerical values ​​is recited herein as being less than the stated value, the range is nevertheless bounded at its lower end by a non-zero value. It is not intended that the scope of the invention be limited to the specific values ​​recited when defining the range. All ranges are inclusive and combinable.

[0040] When values ​​are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another embodiment. Reference to a particular numerical value includes at least the particular value unless the context clearly dictates otherwise.

[0041] It is to be understood that certain features of the methods of the present disclosure, which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the methods of the present disclosure, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any subcombination.

[0042] Throughout this specification and claims, various terms relating to aspects of the present description are used. Unless otherwise indicated, such terms should be given their ordinary meaning in the art. Other specifically defined terms should be interpreted consistent with the definition provided herein.

[0043] As used herein, the singular forms "a," "an," and "the" include the plurals.

[0044] The term "about" when used in connection with a numerical range, cut-off, or specific value, is used to indicate that the recited value may vary by up to 10% from the recited value. Thus, the term "about" is used to encompass a variation of ±10% or less, a variation of ±5% or less, a variation of ±1% or less, a variation of ±0.5% or less, or a variation of ±0.1% or less from the specified value.

[0045] The term "antibody" as used herein is used in a broad sense to refer to an immunoglobulin or antibody molecule, including polyclonal antibodies, monoclonal antibodies, including murine, human, human-adapted, humanized, and chimeric monoclonal antibodies, as well as antibody fragments. In general, an antibody is a protein or peptide chain that exhibits binding specificity to a specific antigen. An intact antibody is a heterotetrameric glycoprotein composed of two identical light chains and two identical heavy chains. Typically, each light chain is linked to a heavy chain by one covalent disulfide bond, while the number of disulfide bonds varies between the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain has a variable domain (VH) at one end followed by a number of constant domains (CRC). Each light chain has a variable domain at one end (VL) and a constant domain at its other end; the constant domain of the light chain is aligned with the first constant domain of the heavy chain and the light chain variable domain is aligned with the variable domain of the heavy chain. The antibody light chains of any vertebrate species can be assigned to one of two clearly distinct types, namely kappa (κ) and lambda (λ), based on the amino acid sequences of their constant domains.

[0046] Immunoglobulins can be assigned to five major classes or isotypes depending on the type of constant domain possessed by their heavy chains, namely IgA, IgD, IgE, IgG and IgM, depending on the heavy chain constant domain amino acid sequence. IgA and IgG are further classified as isotypes IgA1, IgA2, IgG1, IgG2, IgG3 and IgG4. The heavy chain constant domains corresponding to the different immunoglobulin classes are called α, δ, ε, γ and μ, respectively.

[0047] An immunoglobulin light or heavy chain variable region consists of a "framework" region separated by three "antigen-binding sites". The antigen-binding sites are defined using various terms, as follows: (i) the term complementarity determining region (CDR) is based on sequence diversity (Wu and Kabat, J. Exp. Med. 132:211-250, 1970). In general, an antigen-binding site has six CDRs; three in VH (HCDR1, HCDR2, HCDR3) and three in VL (LCDR1, LCDR2, LCDR3). (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991). The "IMGT-CDRs" as proposed by Lefranc (Lefranc et al., Dev.Comparat.Immunol.27:55-77,2003) are based on a comparison of V-domains from immunoglobulins and T-cell receptors. The International Immunogenetics (IMGT) Database (www_imgt_org) provides a standardized numbering and definition of these regions. The correspondence between CDRs and IMGT designations is described in Lefranc et al., Dev.Comparat.Immunol.27:55-77,2003.

[0048] An antigen-binding fragment is any protein structure that can exhibit binding affinity to a particular antigen. Some antigen-binding fragments are composed of portions of an intact antibody that retain the antigen-binding specificity of the parent antibody molecule. For example, an antigen-binding fragment may contain at least one variable region (either heavy or light chain variable region) or one or more CDRs of an antibody known to bind to a particular antigen. Examples of suitable antigen-binding fragments include, without limitation, diabodies and single chain molecules, as well as Fab, F(ab')2, Fc, Fabc, and Fv molecules, single chain (Sc) antibodies, individual antibody light chains, individual antibody heavy chains, chimeric fusions between antibody chains or CDRs and other proteins, protein scaffolds, heavy chain monomers or dimers, light chain monomers or dimers, dimers consisting of one heavy chain and one light chain, and the like. Any antibody isotype may be used to generate antigen-binding fragments. In addition, antigen-binding fragments may include non-antibody protein frameworks, such as protein scaffolds, into which polypeptide segments may be successfully incorporated in an orientation that confers affinity for a given antigen of interest. Antigen-binding fragments may be produced recombinantly or by enzymatic or chemical cleavage of intact antibodies. The phrase "antibody or antigen-binding fragment thereof" may be used to indicate that a given antigen-binding fragment incorporates one or more amino acid segments of the antibody referred to in the phrase.

[0049] "Biosimilar" (approved originator / biological drug, i.e., biosimilar of a listed drug) refers to a biological product that is so similar to the originator product, despite minor differences in clinically inactive ingredients, that there are no clinically meaningful differences between the biosimilar and the originator product in terms of safety, purity, and potency, based on (a) analytical studies that demonstrate that the biological product is so similar to the originator product, despite minor differences in clinically inactive ingredients; (b) animal studies (including toxicity evaluation); and / or (c) data derived from one or more clinical trials (including immunogenicity and pharmacokinetic or pharmacodynamic evaluation) sufficient to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the originator product has been approved and is intended to be used, and for which approval of the biosimilar is being sought. Biosimilars may be interchangeable products that may be substituted for the originator product at the pharmacy without the intervention of a prescribing healthcare professional. To meet the additional standard of "interchangeability," a biosimilar should be expected to produce the same clinical outcome in any given patient as the originator product; if the biosimilar is administered more than once to an individual, the risks of substituting or switching between the use of the biosimilar and the originator product in terms of reduced safety or efficacy are not greater than the risks of using the originator product without such substitution or switching. The biosimilar utilizes the same mechanism of action for the proposed condition of use to the extent that those mechanisms are known for the originator product. The one or more conditions of use prescribed, recommended, or proposed in the proposed labeling for the biosimilar are those approved for the originator product. The route of administration, dosage form, and / or strength of the biosimilar are the same as the originator product, and the biosimilar is manufactured, processed, packaged, or stored in facilities that meet standards designed to ensure that the safety, purity, and potency of the biosimilar are maintained. Biosimilars may contain minor modifications to the amino acid sequence, such as N- or C-terminal truncations, that are not expected to alter the performance of the biosimilar compared to the originator product.

[0050] "Specific binding" or "specifically binds" refers to an antibody that binds to one antigen with greater affinity than to other antigens. Typically, an antibody binds to an antigen with a greater affinity than to another antigen. -8 M or less, e.g., about 5×10 -9 M or less, approximately 1×10 -9 M or less, approximately 1×10 -10 M or less, or about 1 x 10 -11 Equilibrium dissociation constant K below M D binds to the antigen.

[0051] The term "comprising" is intended to include examples encompassed by the terms "consisting essentially of" and "consisting of;" similarly, the term "consisting essentially of" is intended to include examples encompassed by the term "consisting of."

[0052] "Adverse Event" or "AE" refers to any untoward medical occurrence in a clinical trial subject administered an antibody that specifically binds tau. An AE is not necessarily causally related to treatment. Thus, an AE can be any untoward, unintended sign (including an abnormal finding), symptom, or disease that is temporally related to the use of a medical (clinical or non-clinical) product, whether or not related to an antibody that specifically binds tau.

[0053] "Dosage" refers to the amount of a therapeutic agent or drug that a subject should take and how often the subject should take the therapeutic agent.

[0054] "Dose" refers to the amount or quantity of a therapeutic agent or drug to be taken at each time.

[0055] The term "bioequivalent" or "bioequivalence" is a term of art and is intended to be defined according to the US Department of Health and Human Services' "Approved Drug Products with Therapeutic Equivalence Evaluations", 34th edition, commonly known as the "Orange Book". Bioequivalence of different formulations of the same drug substance involves equivalence with respect to the rate and extent of drug absorption. The extent and rate of absorption of the test formulation is compared to the reference formulation to determine whether the two formulations are bioequivalent. A standard bioequivalence study is performed in a crossover fashion with extensive testing involving administering single doses of the test and reference drugs to a number of volunteers, usually 12-24 normal healthy adults, and then measuring the blood, serum or plasma levels of the drug over time. Detailed guidelines for establishing the bioequivalence of a drug product to a reference product have been issued by the FDA Office of Generic Drugs, Division of Bioequivalence.

[0056] Two dosage forms that differ in rate and extent of absorption by no more than -20% / +25% are generally considered to be "bioequivalent". Another approach to average bioequivalence involves the calculation of a 90% confidence interval for the ratio of the means (population geometric means) of the measurements of the test and reference products. To establish BE, the calculated confidence interval should usually be within 80-125% of the ratio of the product means. In addition to this general approach, other approaches may be useful in establishing bioequivalence, including (1) logarithmic transformation of pharmacokinetic data, (2) methods to determine order effects, and (3) methods to determine outlier data. For example, in (1) above, the confidence interval for the difference in the means of logarithmic transformed PK parameters should usually be within 80-125%.

[0057] "mg / kg" refers to dosing of drug in milligrams per kilogram of subject's body mass.

[0058] The term "mean" refers to the geometric mean value. max Pharmacokinetic parameters such as "mean AUC" or "average AUC" are max Or it refers to the geometric mean of AUC.

[0059] The term "treating" or "treatment" refers to any successful or evidence of successful attenuation or amelioration of an injury, lesion or condition, including any objective or subjective parameter, such as alleviation, remission, reduction of symptoms or making the condition more tolerable to the patient, slowing the rate of degeneration or decline, lessening the eventual wear and tear of degeneration, improving the subject's physical or mental well-being, or increasing the length of survival. Treatment may be assessed by objective or subjective parameters, including the results of a physical examination, a neurological examination, or a psychiatric evaluation. In a detailed embodiment, the tauopathy symptom is cognitive impairment. In a specific embodiment, the tauopathy symptom is learning and / or memory impairment. In a specific embodiment, the tauopathy symptom is long-term memory loss. In a specific embodiment, the tauopathy symptom is dementia. In some embodiments, the tauopathy symptom is confusion, irritability, aggression, mood swings, or language impairment. In some embodiments, a symptom of a tauopathy is impairment or loss of one or more cognitive functions, such as reasoning, situational judgment, memory capacity, and / or learning.

[0060] A "therapeutic regimen" refers to a combination of dosage, frequency of administration, and / or duration of treatment. An "effective therapeutic regimen" refers to a therapeutic regimen that will result in a beneficial response in the patient receiving the treatment. An "effective amount" or "effective dose" of a drug refers to an amount or dose effective, for a period of time necessary, to achieve a desired result. For example, a "therapeutically effective amount" refers to an amount of an antibody effective, for a period of time necessary, to produce a therapeutic effect in a human subject.

[0061] As used herein, a "therapeutic effect" is any type of outcome of medical treatment that is deemed desirable and beneficial. This is true whether the outcome is expected, unexpected, or even an unintended outcome of the treatment. Therapeutic effect may also be an objectively identifiable improvement as noted by a clinician or other qualified observer. In a detailed embodiment, the therapeutic effect of an antibody that specifically binds to tau may be detected by determining the binding of the antibody to MTBR tau. MTBR tau fragments are measurable in the cerebrospinal fluid (CSF) of AD patients (Alzheimer's & Dementia Volume 15, Issue 7, Supplement, July 2019, Pages P1598-P1599). MTBR tau is significantly increased in the CSF of AD patients compared to healthy adults.

[0062] As used herein, "administering" and similar terms refer to the procedure of injecting a pharmaceutical formulation into a subject.

[0063] The term "subject" as used herein is intended to mean any animal, particularly a mammal. The method is applicable to humans and non-human animals, but most preferably for human application. In some embodiments, the subject has a mutation in at least one of three genes: amyloid precursor protein (APP), presenilin 1 (PSEN1), or presenilin 2 (PSEN2). In some embodiments, the subject has a mutation in the APP gene. In some embodiments, the subject has a mutation in the PSEN1 gene. In some embodiments, the subject has a mutation in the PSEN2 gene. Specific mutations in the APP, PSEN1, or PSEN2 genes that contribute to DIAD are known in the art (e.g., Cruts & Van Broeckhoven, Hum Mutat. 1998;11(3):183-90; Cruts, Theuns, & Van Broeckhoven, Hum Mutat., 2012 Sep;33(9):1340-4; Ryman et al., Symptom onset in autosomal dominant Alzheimer disease: a systematic review and metaanalysis. Neurology, 83(3), 253-260; Sherva, R., & Kowall, N. (2018). Genetics of Alzheimer disease-UpToDate. In J. Wilterdink (Ed.), UpToDate. Retrieved from www_uptodate_com / contents / genetics-of-alzheimerdisease?sectionName=GENETIC%20TESTING&topicRef=5071&anchor=H900056&source=see_link#H900056). "Subject" and "patient" can be used interchangeably herein.

[0064] Provided herein is an intravenous dosage form comprising an amount of an antibody that specifically binds to tau, wherein the amount is a single dose of about 3 mg / kg to about 90 mg / kg. According to some embodiments, an intravenous dosage form is provided comprising an amount of an antibody that specifically binds to tau, wherein the amount is a single dose of about 3 mg / kg, about 10 mg / kg, about 30 mg / kg, about 60 mg / kg, or about 90 mg / kg.

[0065] Provided herein is an intravenous dosage form comprising an amount of an antibody that specifically binds to tau, wherein the amount provides a serum C in the range of 6.29 μg / mL to 1960 μg / mL following administration to a human subject. max Further provided herein is an intravenous dosage form comprising an amount of an antibody that specifically binds to tau, wherein the amount achieves a geometric mean serum C of about 9.55 μg / mL to about 1450 μg / mL after administration to a human subject. max It is a single dose that achieves this.

[0066] Further provided herein is an intravenous dosage form comprising an amount of an antibody that specifically binds to tau, wherein the amount has a serum AUC in the range of 12,300 μg·hr / mL to 194,000 μg·hr / mL following administration to a human subject. (0-inf) Further provided herein is an intravenous dosage form comprising an amount of an antibody that specifically binds to tau, wherein the amount achieves a geometric mean serum AUC of about 12,300 μg hr / mL to about 130,000 μg hr / mL following administration to a human subject. (0-inf) It is a single dose that achieves this.

[0067] Further provided herein is an intravenous dosage form comprising an amount of an antibody that specifically binds to tau, wherein the amount has a serum AUC in the range of 839 μg·hr / mL to 203,000 μg·hr / mL following administration to a human subject. (0-672h) Further provided herein is an intravenous dosage form comprising an amount of an antibody that specifically binds to tau, wherein the amount achieves a geometric mean serum AUC of about 1580 μg hr / mL to about 122000 μg hr / mL following administration to a human subject.(0-672h) It is a single dose that achieves this.

[0068] Provided herein is an intravenous dosage form comprising an amount of an antibody that specifically binds to tau, where the amount results in a CSF C in the range of 13.5 ng / mL to 672 ng / mL following administration to a human subject. max Further provided herein is an intravenous dosage form comprising an amount of an antibody that specifically binds to tau, wherein the amount achieves a geometric mean CSF C of about 15.9 ng / mL to about 404 ng / mL following administration to a human subject. max It is a single dose that achieves this.

[0069] Further provided herein is an intravenous dosage form comprising an amount of an antibody that specifically binds to tau, wherein the amount provides a CSF AUC range of 159 ng·hr / mL to 7690 ng·hr / mL following administration to a human subject. (0-24h) Further provided herein is an intravenous dosage form comprising an amount of an antibody that specifically binds to tau, wherein the amount achieves a geometric mean CSF AUC of about 191 ng hr / mL to about 5320 ng hr / mL following administration to a human subject. (0-24h) It is a single dose that achieves this.

[0070] Provided herein is an intravenous dosage form comprising an amount of an antibody that specifically binds to tau, wherein the amount is a dose of about 750 mg to about 4500 mg. According to some embodiments of an intravenous dosage form comprising an amount of an antibody that specifically binds to tau, the amount is a dose of about 1500 mg to about 4500 mg, about 1500 mg to about 3000 mg, or about 3000 mg to about 4500 mg. According to some embodiments, a dose of the antibody is administered to the subject once every four weeks. According to some embodiments, an intravenous dosage form is provided comprising an amount of an antibody that specifically binds to tau, wherein the amount is a dose of about 750 mg, about 1500 mg, about 3000 mg, or about 4500 mg.

[0071] Provided herein is an intravenous dosage form comprising an amount of an antibody that specifically binds to tau, wherein the amount provides a serum C in the range of 21.1 μg / mL to 655 μg / mL following administration to a human subject. max Further provided herein is an intravenous dosage form comprising an amount of an antibody that specifically binds to tau, wherein the amount achieves a geometric mean serum C of about 35.6 μg / mL to about 509 μg / mL after administration to a human subject. max This is the dose that achieves this.

[0072] Also provided herein is an intravenous dosage form comprising an amount of an antibody that specifically binds to tau, wherein the amount provides a serum AUC in the range of 2690 μg·hr / mL to 58900 μg·hr / mL following administration to a human subject. (0-672h) Further provided herein is an intravenous dosage form comprising an amount of an antibody that specifically binds to tau, wherein the amount achieves a geometric mean serum AUC of about 5360 μg hr / mL to about 30300 μg hr / mL following administration to a human subject. (0-672h) This is the dose that achieves this.

[0073] Also provided herein is a method of treating a human subject diagnosed with a tauopathy, the method comprising intravenously administering to the human subject an amount of an antibody that specifically binds to tau, wherein the amount is a single dose of about 3 mg / kg to about 90 mg / kg. According to some embodiments of the method, the amount of the antibody that specifically binds to tau is a single dose of about 3 mg / kg, about 10 mg / kg, about 30 mg / kg, about 60 mg / kg, or about 90 mg / kg.

[0074] According to some embodiments of the method of treating a human subject diagnosed with a tauopathy, the amount of antibody that specifically binds tau is in the range of 6.29 μg / mL to 1960 μg / mL serum C after administration. max According to some embodiments of the method of treating a human subject diagnosed with a tauopathy, the amount of antibody that specifically binds tau is a single dose that achieves a geometric mean serum C of about 9.55 μg / mL to about 1450 μg / mL after administration. max It is a single dose that achieves this.

[0075] According to some embodiments of the method of treating a human subject diagnosed with a tauopathy, the amount of antibody that specifically binds tau is administered to provide a serum AUC range of 12,300 μg hr / mL to 194,000 μg hr / mL. (0-inf) According to some embodiments of the method of treating a human subject diagnosed with a tauopathy, the amount of an antibody that specifically binds tau is a single dose that achieves a geometric mean serum AUC of about 12,300 μg hr / mL to about 130,000 μg hr / mL after administration. (0-inf) It is a single dose that achieves this.

[0076] According to some embodiments of the method of treating a human subject diagnosed with a tauopathy, the amount of antibody that specifically binds tau is administered to provide a serum AUC range of 839 μg hr / mL to 203,000 μg hr / mL. (0-672h) According to some embodiments of the method of treating a human subject diagnosed with a tauopathy, the amount of an antibody that specifically binds tau is a single dose that achieves a geometric mean serum AUC of about 1580 μg hr / mL to about 122,000 μg hr / mL after administration. (0-672h) It is a single dose that achieves this.

[0077] According to some embodiments of the method of treating a human subject diagnosed with a tauopathy, the amount of an antibody that specifically binds tau is in the range of 13.5 ng / mL to 672 ng / mL of CSF C after administration to the human subject. max According to some embodiments of the method of treating a human subject diagnosed with a tauopathy, the amount of an antibody that specifically binds tau achieves a geometric mean CSF C of about 15.9 ng / mL to about 404 ng / mL after administration to the human subject. max It is a single dose that achieves this.

[0078] According to some embodiments of the method of treating a human subject diagnosed with a tauopathy, the amount of antibody that specifically binds tau provides a CSF AUC range of 159 ng·hr / mL to 7690 ng·hr / mL after administration. (0-24h)According to some embodiments of the methods of treating a human subject diagnosed with a tauopathy, the amount of an antibody that specifically binds tau is a single dose that achieves a geometric mean CSF AUC of about 191 ng hr / mL to about 5320 ng hr / mL after administration. (0-24h) It is a single dose that achieves this.

[0079] Also provided herein is a method of treating a human subject diagnosed with a tauopathy, comprising administering to the human subject an amount of an antibody that specifically binds to tau, wherein the amount of the antibody that specifically binds to tau is a dose of about 750 mg to about 4500 mg. According to some embodiments of the method, the amount of the antibody that specifically binds to tau is a dose of about 1500 mg to about 4500 mg, about 1500 mg to about 3000 mg, or about 3000 mg to about 4500 mg. According to some embodiments, the dose of the antibody is administered to the subject once every four weeks. According to some embodiments, the dose of the antibody is administered intravenously to the subject. According to some embodiments of the method, the amount of the antibody that specifically binds to tau is a dose of about 750 mg, about 1500 mg, about 3000 mg, or about 4500 mg. According to some embodiments of the method, the amount of the antibody that specifically binds to tau is a dose of about 750 mg, about 1500 mg, about 3000 mg, or about 4500 mg administered once every four weeks. According to some embodiments of the method, the amount of the antibody that specifically binds to tau is a dose of about 750 mg, about 1500 mg, about 3000 mg, or about 4500 mg administered intravenously.

[0080] According to some embodiments of the method, the amount of the antibody that specifically binds to tau is about 750 mg administered once every 4 weeks for 3 dosing cycles or 12 weeks, followed by a dose of about 1500 mg administered once every 4 weeks. According to some embodiments of the method, the amount of the antibody that specifically binds to tau is about 1500 mg administered once every 4 weeks for 3 dosing cycles or 12 weeks, followed by a dose of about 3000 mg administered once every 4 weeks. According to some embodiments of the method, the amount of the antibody that specifically binds to tau is about 3000 mg administered once every 4 weeks for 3 dosing cycles or 12 weeks, followed by a dose of about 4500 mg administered once every 4 weeks. According to some embodiments of the method, the amount of the antibody that specifically binds to tau is about 750 mg administered once every 4 weeks for 3 dosing cycles or 12 weeks, followed by a dose of 1500 mg administered once every 4 weeks for 3 dosing cycles or 12 weeks, followed by a dose of about 3000 mg administered once every 4 weeks. According to some embodiments of the method, the amount of the antibody that specifically binds to tau is about 750 mg administered once every 4 weeks for 3 dosing cycles or 12 weeks, followed by 1500 mg administered once every 4 weeks for 3 dosing cycles or 12 weeks, followed by about 3000 mg administered once every 4 weeks for 3 dosing cycles or 12 weeks, followed by a dose of about 4500 mg every 4 weeks.

[0081] According to some embodiments of the method of treating a human subject diagnosed with a tauopathy, the amount of an antibody that specifically binds tau is in the range of 21.1 μg / mL to 655 μg / mL of serum C after administration to the human subject. max According to some embodiments of the method of treating a human subject diagnosed with a tauopathy, the amount of an antibody that specifically binds tau is a dose that achieves a geometric mean serum C of about 35.6 μg / mL to about 509 μg / mL after administration to the human subject. max This is the dose that achieves this.

[0082] According to some embodiments of the method of treating a human subject diagnosed with a tauopathy, the amount provides a serum AUC range of 2690 μg hr / mL to 58900 μg hr / mL after administration to the human subject. (0-672h)According to some embodiments of the methods of treating a human subject diagnosed with a tauopathy, the amount of an antibody that specifically binds tau is a dose that achieves a geometric mean serum AUC of about 5,360 μg hr / mL to about 30,300 μg hr / mL after administration to the human subject. (0-672h) This is the dose that achieves this.

[0083] Further provided herein is a pharmaceutical composition for treating a human subject diagnosed with a tauopathy, the pharmaceutical composition comprising an antibody that specifically binds to tau, wherein the antibody that specifically binds to tau is administered to the subject in a single dose of about 3 mg / kg to about 90 mg / kg. According to some embodiments of the pharmaceutical composition for treating a human subject diagnosed with a tauopathy, the antibody that specifically binds to tau is administered to the subject in a single dose of about 3 mg / kg, about 10 mg / kg, about 30 mg / kg, about 60 mg / kg, or about 90 mg / kg.

[0084] According to some embodiments of the pharmaceutical composition for treating a human subject diagnosed with a tauopathy, the antibody that specifically binds tau has a serum C value ranging from 6.29 μg / mL to 1960 μg / mL after administration. max According to some embodiments of the pharmaceutical composition for treating a human subject diagnosed with a tauopathy, the antibody that specifically binds tau is administered to the subject in a single dose that achieves a geometric mean serum C of about 9.55 μg / mL to about 1450 μg / mL after administration. max The subject is administered a single dose that achieves this.

[0085] According to some embodiments of the pharmaceutical composition for treating a human subject diagnosed with a tauopathy, the antibody that specifically binds tau has a serum AUC range of 12,300 μg·hr / mL to 194,000 μg·hr / mL after administration. (0-inf) According to some embodiments of the pharmaceutical composition for treating a human subject diagnosed with a tauopathy, the antibody that specifically binds tau is administered to the subject in a single dose that achieves a geometric mean serum AUC of about 12,300 μg hr / mL to about 130,000 μg hr / mL after administration. (0-inf) The subject is administered a single dose that achieves this.

[0086] According to some embodiments of the pharmaceutical composition for treating a human subject diagnosed with a tauopathy, the antibody that specifically binds tau has a serum AUC range of 839 μg·hr / mL to 203,000 μg·hr / mL after administration. (0-672h) According to some embodiments of the pharmaceutical composition for treating a human subject diagnosed with a tauopathy, the antibody that specifically binds tau is administered to the subject in a single dose that achieves a geometric mean serum AUC of about 1580 μg hr / mL to about 122000 μg hr / mL after administration. (0-672h) The subject is administered a single dose that achieves this.

[0087] According to some embodiments of the pharmaceutical composition for treating a human subject diagnosed with a tauopathy, the antibody that specifically binds tau provides a CSF C value in the range of 13.5 ng / mL to 672 ng / mL after administration. max According to some embodiments of the pharmaceutical composition for treating a human subject diagnosed with a tauopathy, the antibody that specifically binds tau is administered to the subject in a single dose that achieves a geometric mean serum C of about 15.9 ng / mL to about 404 ng / mL after administration. max The subject is administered a single dose that achieves this.

[0088] According to some embodiments of the pharmaceutical composition for treating a human subject diagnosed with a tauopathy, the antibody that specifically binds tau provides a CSF AUC range of 159 ng·hr / mL to 7690 ng·hr / mL after administration. (0-24h) According to some embodiments of a pharmaceutical composition for treating a human subject diagnosed with a tauopathy, an antibody that specifically binds tau is administered to the subject in a single dose that achieves a geometric mean CSF AUC of about 191 ng·hr / mL to about 5320 ng·hr / mL after administration. (0-24h) The subject is administered a single dose that achieves this.

[0089] Further provided herein is a pharmaceutical composition for treating a human subject diagnosed with a tauopathy, the pharmaceutical composition comprising an antibody that specifically binds to tau, wherein the antibody that specifically binds to tau is administered to the subject in an amount of about 750 to about 4500 mg. According to some embodiments of the pharmaceutical composition, the antibody that specifically binds to tau is administered to the subject in an amount of about 1500 mg to about 4500 mg, about 1500 mg to about 3000 mg, or about 3000 mg to about 4500 mg. According to some embodiments, the antibody is administered to the subject once every four weeks. According to some embodiments, the antibody is administered to the subject intravenously. According to some embodiments of the pharmaceutical composition, the antibody that specifically binds to tau is administered in an amount of about 750 mg, about 1500 mg, about 3000 mg, or about 4500 mg. According to some embodiments of the pharmaceutical composition, the antibody that specifically binds to tau is administered in an amount of about 750 mg, about 1500 mg, about 3000 mg, or about 4500 mg once every four weeks. According to some embodiments of the pharmaceutical composition, the antibody that specifically binds to tau is administered in an amount of about 750 mg, about 1500 mg, about 3000 mg, or about 4500 mg intravenously. According to some embodiments of the pharmaceutical composition, the antibody that specifically binds to tau is administered in an amount of about 750 mg once every four weeks for three dosing cycles or 12 weeks, followed by about 1500 mg once every four weeks. According to some embodiments of the pharmaceutical composition, the antibody that specifically binds to tau is administered in an amount of about 1500 mg once every four weeks for three dosing cycles or 12 weeks, followed by about 3000 mg once every four weeks. According to some embodiments of the pharmaceutical composition, the antibody that specifically binds to tau is administered in an amount of about 3000 mg administered once every 4 weeks for 3 dosing cycles or 12 weeks, followed by about 4500 mg administered once every 4 weeks. According to some embodiments of the pharmaceutical composition, the antibody that specifically binds to tau is administered in an amount of about 750 mg administered once every 4 weeks for 3 dosing cycles or 12 weeks, followed by about 1500 mg administered once every 4 weeks for 3 dosing cycles or 12 weeks, followed by about 3000 mg administered once every 4 weeks.According to some embodiments of the pharmaceutical composition, the antibody that specifically binds to tau is administered in an amount of about 750 mg administered once every 4 weeks for 3 dosing cycles or 12 weeks, followed by about 1500 mg administered once every 4 weeks for 3 dosing cycles or 12 weeks, followed by about 3000 mg administered once every 4 weeks for 3 dosing cycles or 12 weeks, followed by about 4500 mg every 4 weeks.

[0090] According to some embodiments of the pharmaceutical composition for treating a human subject diagnosed with a tauopathy, the antibody that specifically binds tau has a serum C value ranging from 21.1 μg / mL to 655 μg / mL after administration to the human subject. max According to some embodiments of the pharmaceutical composition for treating a human subject diagnosed with a tauopathy, the antibody that specifically binds tau is administered to the subject at a dose that achieves a geometric mean serum C of about 35.6 μg / mL to about 509 μg / mL after administration to the human subject. max The subject is administered a dose that achieves this.

[0091] According to some embodiments of the pharmaceutical composition for treating a human subject diagnosed with a tauopathy, the antibody that specifically binds tau has a serum AUC in the range of 2690 μg·hr / mL to 58900 μg·hr / mL after administration to the human subject. (0-672h) According to some embodiments of a pharmaceutical composition for treating a human subject diagnosed with a tauopathy, an antibody that specifically binds tau is administered to a subject at a dose that achieves a geometric mean serum AUC of about 5360 μg hr / mL to about 30300 μg hr / mL after administration to a human subject. (0-672h) The subject is administered a dose that achieves this.

[0092] According to some embodiments, the provided dosage forms, methods, and pharmaceutical compositions may be used to treat a tauopathy in a subject. Exemplary tauopathies that can be treated with the disclosed anti-tau antibodies include Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and frontotemporal dementia (FTD). An exemplary FTD that can be treated is Pick's disease (PiD). An exemplary AD that can be treated is dominantly inherited AD (DIAD) or sporadic AD.

[0093] According to certain embodiments of the provided dosage forms, methods, and pharmaceutical compositions, an antibody that specifically binds to tau (also referred to herein as an "anti-tau antibody") comprises a heavy chain variable domain (VH), a light chain variable domain (VL), and / or a complementarity determining region (CDR) comprising an amino acid sequence as set forth in Tables 1-5. In certain exemplary embodiments, an anti-tau antibody that can be used in the context of the disclosed dosage forms, methods, and pharmaceutical compositions comprises a heavy chain complementarity determining region (HCDR) of the heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO:2, and a light chain complementarity determining region (LCDR) of the light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:5. According to certain embodiments, the anti-tau antibody comprises three HCDRs (HCDR1, HCDR2 and HCDR3) and three LCDRs (LCDR1, LCDR2 and LCDR3), where HCDR1 comprises the amino acid sequence of SEQ ID NO:7; HCDR2 comprises the amino acid sequence of SEQ ID NO:8; HCDR3 comprises the amino acid sequence of SEQ ID NO:9; LCDR1 comprises the amino acid sequence of SEQ ID NO:10; LCDR2 comprises the amino acid sequence of SEQ ID NO:11; and LCDR3 comprises the amino acid sequence of SEQ ID NO:12, where the CDRs are defined according to the method of Kabat. According to certain embodiments, the anti-tau antibody comprises three HCDRs (HCDR1, HCDR2 and HCDR3) and three LCDRs (LCDR1, LCDR2 and LCDR3), where HCDR1 comprises the amino acid sequence of SEQ ID NO: 13; HCDR2 comprises the amino acid sequence of SEQ ID NO: 14; HCDR3 comprises the amino acid sequence of SEQ ID NO: 15; LCDR1 comprises the amino acid sequence of SEQ ID NO: 16; LCDR2 comprises the amino acid sequence of SEQ ID NO: 17; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 18, where the CDRs are defined according to the IMGT method. In yet other embodiments, the anti-tau antibody comprises a VH comprising SEQ ID NO: 2 and a VL comprising SEQ ID NO: 5. In certain embodiments, the anti-tau antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 1 and / or a light chain comprising the amino acid sequence of SEQ ID NO: 4.An exemplary anti-tau antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:1 and a light chain comprising the amino acid sequence of SEQ ID NO:4 is antibody E2814, also known as antibody 7G6-HCzu25-LCzu18, disclosed in WO 2019 / 077500, which is incorporated by reference in its entirety. According to certain exemplary embodiments, the anti-tau antibody is antibody E2814 or a biosimilar thereof.

[0094] [Table 1]

[0095] [Table 2]

[0096] [Table 3]

[0097] [Table 4]

[0098] [Table 5]

[0099] In a further aspect, the invention provides pharmaceutical formulations comprising any of the antibodies that specifically bind to tau as described herein, for example, for use in any of the methods provided herein. In some embodiments, the pharmaceutical formulations comprise any of the antibodies that specifically bind to tau provided herein and a pharma- ceutically acceptable carrier, diluent, and / or excipient (Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)). Pharmaceutically acceptable carriers, diluents, and excipients are generally non-toxic to recipients at the dosages and concentrations employed. Formulations to be used for in vivo administration are generally sterile. Any of the antibodies that specifically bind to tau (or formulations thereof) provided herein may be used in the methods of the present disclosure.

[0100] In certain embodiments, there is provided an anti-tau antibody for use in a method for treating a tauopathy.

[0101] According to some embodiments, the dose of the anti-tau antibody for use in the method for treating a tauopathy is about 3 mg / kg to about 90 mg / kg. According to some embodiments, the dose of the anti-tau antibody for use in the method for treating a tauopathy is about 3 mg / kg to about 10 mg / kg, about 10 mg / kg to about 30 mg / kg, about 30 mg / kg to about 60 mg / kg, or about 60 mg / kg to about 90 mg / kg. For example, the dose of the anti-tau antibody may be about 3 mg / kg, about 10 mg / kg, about 30 mg / kg, about 60 mg / kg, or about 90 mg / kg. In certain embodiments, the tauopathy is any one of the tauopathies described above.

[0102] In a further aspect, also provided herein is the use of an anti-tau antibody as described herein in the manufacture or preparation of a medicament. In some embodiments, the medicament is a medicament for the treatment of a tauopathy. According to some embodiments, the medicament comprises an anti-tau antibody at a dose of about 3 mg / kg to about 90 mg / kg. According to some embodiments, the medicament comprises an anti-tau antibody at a dose of about 3 mg / kg to about 10 mg / kg, about 10 mg / kg to about 30 mg / kg, about 30 mg / kg to about 60 mg / kg, or about 60 mg / kg to about 90 mg / kg. For example, the dose of the anti-tau antibody may be about 3 mg / kg, about 10 mg / kg, about 30 mg / kg, about 60 mg / kg, or about 90 mg / kg. In certain embodiments, the tauopathy is any one of the tauopathies described above.

[0103] According to some embodiments, the dose of the anti-tau antibody for use in the method for treating a tauopathy is about 750 mg to about 4500 mg. According to some embodiments, the dose of the anti-tau antibody for use in the method for treating a tauopathy is about 1500 mg to about 4500 mg, about 1500 mg to about 3000 mg, or about 3000 mg to about 4500 mg. For example, the dose of the anti-tau antibody may be about 750 mg, about 1500 mg, about 3000 mg, or about 4500 mg. In certain embodiments, the tauopathy is any one of the tauopathies described above.

[0104] In a further aspect, the present specification also provides the use of an anti-tau antibody as described herein in the manufacture or preparation of a medicament. In some embodiments, the medicament is a medicament for treating a tauopathy. According to some embodiments, the medicament comprises an anti-tau antibody at a dose of about 750 mg to about 4500 mg. According to some embodiments, the medicament comprises an anti-tau antibody at a dose of about 1500 mg to about 4500 mg, about 1500 mg to about 3000 mg, or about 3000 mg to about 4500 mg. For example, the dose of the anti-tau antibody may be about 750 mg, about 1500 mg, about 3000 mg, or about 4500 mg. In certain embodiments, the tauopathy is any one of the tauopathies described above.

[0105] Suitable routes of administration include parenteral administration. According to some aspects of the invention, an anti-tau antibody as described herein is administered parenterally, e.g., by injection, such as intravenous injection.

[0106] In some embodiments, an anti-tau antibody as described herein is administered in a single dose.

[0107] Depending on the type and severity of the disease, a single dose of about 3 mg / kg to about 90 mg / kg of anti-tau antibody can be administered to a patient. Exemplary doses of anti-tau antibody administered in one treatment session or visit are about 3 mg / kg, about 10 mg / kg, about 30 mg / kg, about 60 mg / kg, or about 90 mg / kg. According to some embodiments, the anti-tau antibody is administered to a subject as a dose of about 3 mg / kg to about 10 mg / kg, about 10 mg / kg to about 30 mg / kg, about 30 mg / kg to about 60 mg / kg, or about 60 mg / kg to about 90 mg / kg.

[0108] Depending on the type and severity of the disease, about 750 mg to about 4500 mg of anti-tau antibody can be administered to the patient in a single dose. Exemplary doses of anti-tau antibody administered in one treatment session or visit are about 750 mg, about 1500 mg, about 3000 mg, or about 4500 mg. According to some embodiments, the anti-tau antibody is administered to the subject once every four weeks. According to some embodiments, the anti-tau antibody is administered to the subject in a dose of about 1500 mg to about 4500 mg, about 1500 mg to about 3000 mg, or about 3000 mg to about 4500 mg. According to some embodiments, the anti-tau antibody is administered to the subject in a dose of about 750 mg, about 1500 mg, about 3000 mg, or about 4500 mg. According to some embodiments, the anti-tau antibody is administered to a subject once every four weeks as a dose of about 750 mg, about 1500 mg, about 3000 mg, or about 4500 mg.

[0109] According to some embodiments, the dose of anti-tau antibody administered to the subject is increased after the third dose.For example, the subject may receive 3 doses of 750mg of anti-tau antibody every 4 weeks, followed by a dose of 1500mg every 4 weeks.The subject may receive 3 doses of 1500mg of anti-tau antibody every 4 weeks, followed by a dose of 3000mg every 4 weeks.According to some embodiments, the subject may receive 3 doses of 3000mg of anti-tau antibody every 4 weeks, followed by a dose of 4500mg every 4 weeks.

[0110] To further illustrate some of the embodiments disclosed herein, the following examples are provided, which are intended to illustrate, but not limit, the disclosed embodiments. [Example]

[0111] Example 1. A Randomized, Double-Blind, Placebo-Controlled, Combination Single Ascending Dose and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Immunogenicity, and Pharmacodynamics of Intravenous Infusion of E2814 in Healthy Subjects (Study E2814-A001-001)

[0112] Study rationale and design: Study E2814-A001-001 is a randomized, double-blind, placebo-controlled, combination single ascending dose (SAD) and multiple ascending dose (MAD) study to evaluate the safety, tolerability, pharmacokinetics (PK), immunogenicity, and pharmacodynamics (PD) (target engagement [TE]) of intravenous infusion of E2814 in healthy subjects.

[0113] The study has two components: 1) The SAD component will evaluate the safety, tolerability, PK, immunogenicity, and exploratory TE of E2814 by assessing intravenous doses of 3, 10, 30, 60, and 90 mg / kg in healthy subjects. The SAD component will consist of two phases: a pre-randomization phase (consisting of a screening period (day -28 to day -2)) and a randomization phase (consisting of a treatment period and a follow-up period). During this treatment period, subjects have / will have a baseline assessment on day -1 after screening procedures are completed (Figure 1). The SAD component consists of five dose cohorts (3, 10, 30, 60, and 90 mg / kg); in each cohort, eight subjects are / will be randomized (3:1) to receive a single dose of E2814 or E2814-matching placebo (placebo solution matching E2814). All subjects will / have received a single E2814 or E2814-matching placebo intravenous infusion on Day 1. Two subjects per dose level will be randomized to receive E2814 and one subject to receive placebo on Day 1. The remaining six subjects in each cohort will / will be randomized and dosed at least 24 hours later. The end of the SAD component of the study will be the date of the last study assessment for the last subject. An overview of the design for the SAD component of the study is presented in Figure 2. 2) The MAD component will evaluate the safety, tolerability, PK, and immunogenicity of E2814 after multiple-dose intravenous administration in healthy subjects by assessing four fixed doses administered intravenously on three occasions every four weeks (Q4W). The doses are 750, 1500, 3000, and 4500 mg (Q4W). This MAD component will consist of two phases: a pre-randomization phase (consisting of a screening period (day -28 to day -2)) and a randomization phase (consisting of a treatment period and a follow-up period). During this treatment period, subjects were / will be assessed at baseline on day -1 after screening procedures were completed (Figure 3). In each cohort (750, 1500, 3000, and 4500 mg (Q4W)), eight healthy subjects were / will be randomized (3:1) to receive three Q4W doses of E2814 or E2814-matched placebo (placebo solution corresponding to E2814). The planned dose escalation scheme is 750, 1500, 3000, and 4500 mg. TE was / will be determined by measuring free and bound tau species in cerebrospinal fluid (CSF). The end of the MAD component of the study will be the date of the last study visit evaluation for the last subject. An overview of the study design for the MAD component of the study is presented in Figure 4.

[0114] Research Objective The primary objective of the SAD component of this study is to determine the safety and tolerability of a single intravenous infusion of E2814 in healthy adult subjects.The primary objective of the MAD component of this study is to determine the safety and tolerability of three Q4W intravenous infusions of E2814 in healthy adult subjects.

[0115] Secondary objectives of the SAD component of the study are to assess the PK of E2814 in serum, plasma, and cerebrospinal fluid (CSF); and to assess the immunogenicity of E2814 (serum [or plasma] anti-E2814 antibody production). Secondary objectives of the MAD component of the study are to assess the PK of E2814 in serum, plasma, and CSF following three Q4W intravenous infusions; and to assess the immunogenicity of E2814 (serum [or plasma] anti-E2814 antibody production) following three Q4W intravenous infusions.

[0116] The exploratory objectives of both the SAD and MAD components of this study are to compare the PK, safety, and tolerability of E2814 between healthy adult non-Japanese and Japanese subjects; to determine the TE of E2814 on CSF MTBR tau species; and to explore the effects of E2814 on CSF and / or plasma biomarkers.

[0117] Study population Inclusion Criteria. To be included in the study, subjects must meet the following criteria: 1. Healthy male or female subjects who are non-smokers. 2. Age 20 to 55 at the time of informed consent

[0118] Exclusion Criteria. Subjects meeting any of the following criteria will be excluded from the study: 1. Clinically significant illness requiring medical treatment within 8 weeks or clinically significant infection requiring medical treatment within 4 weeks of treatment. 2. Women who are breastfeeding or pregnant at screening or baseline 3. Women of childbearing potential: Those who had not used a highly effective method of contraception within 28 days prior to study enrollment Those who do not agree to use highly effective contraception throughout the study and for 16 weeks after discontinuing study drug. 4. Men who have not had a successful vasectomy or men and their female partners who do not meet the above criteria (i.e., not of childbearing potential or who use highly effective contraception throughout the study and for 5 half-lives of the study drug plus 90 days after discontinuation of study drug) and who will not agree to use latex or synthetic condoms at that time, throughout the study and for 90 days after discontinuation of study drug, if their female partner is pregnant. 5. Evidence of disease within 4 weeks prior to dosing that may affect study outcomes; e.g., psychiatric disorders and subjects with disorders of the gastrointestinal tract, liver, kidneys, respiratory system, endocrine system, blood system, nervous system, or cardiovascular system, or congenital abnormalities of metabolism. 6. Any clinically abnormal symptoms or organ dysfunction requiring medical treatment as determined by medical history, physical examination, vital signs, electrocardiogram (ECG), or laboratory test results at screening or baseline. 7. ECG-documented QT prolongation (i.e., Fridericia-corrected QTc interval >450 ms) at screening or baseline. Personal history of risk factors for Torsades de Pointes (e.g., heart failure, hypokalemia, family history of long QT syndrome). 8. Sustained systolic blood pressure (SBP) > 130mmHg or diastolic blood pressure (DBP) > 85mmHg at screening or baseline. 9. Heart rate <45 beats / min or >100 beats / min at screening or baseline. 10. Known clinically significant history of drug allergy at screening or baseline 11. Known food allergy history or current significant seasonal or perennial allergies at screening or baseline 12. Any history of hypersensitivity reaction to foreign proteins with clinical features of grade 2-4 as described in the National Cancer Institute-Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, Immunoglobulin A (IgA) deficiency, or significant autoimmune disease or disorder. 13. Known human immunodeficiency virus (HIV) positive at screening. 14. Active or chronic (including asymptomatic) viral hepatitis (A, B or C) as documented by positive serology at screening. 15. Subjects with a history of drug or alcohol dependence or abuse within 2 years prior to screening, or a positive urine drug test or breath (or urine) alcohol test at screening or baseline. 16. Taking over-the-counter medications within 2 weeks prior to administration. 17.Currently enrolled in another clinical trial or has used any investigational drug or device within 30 days (or within 5 half-lives, whichever is longer) prior to informed consent 18. Exposure to any biological agent within 90 days or at least 5 half-lives (whichever is longer) prior to screening, or within 4 weeks for vaccines, with the exception of influenza and COVID-19 vaccinations, which are permitted up to 7 days prior to administration. 19. Involvement in strenuous exercise within 2 weeks prior to the admission procedure. 20. Contraindication to serial CSF sampling by either placement of a lumbar catheter or by lumbar puncture (LP) 21. Any history or current condition of an uncontrolled blood clotting or bleeding disorder including platelet count <50,000, International Normalized Ratio (INR) >1.3, or partial thromboplastin time (PTT) >upper limit of normal (ULN), or fibrinogen <1.8 g / L or >4.3 g / L at screening or baseline. Subjects receiving anticoagulant therapy or identified as at risk for bleeding. 22. Any life-long suicidal behavior or psychiatric illness. 23. Any current or past history of suicidal behavior or psychiatric illness identified by a psychiatrist at the screening visit.

[0119] Research evaluation 1. Pharmacokinetic (PK) assessment. Serum, plasma, and CSF concentrations of E2814 have been / will be measured by a validated electrochemiluminescence (ECL) assay method or by validated immunoprecipitation / purification followed by liquid chromatography-tandem mass spectrometry (LC-MS / MS) methods, where available.

[0120] SAD: Blood samples for serum and plasma PK assessment were / will be collected pre-dose, immediately after the end of infusion, and 0.5, 1, 2, 4, 8, 12, and 24 hours after the end of infusion, as well as single samples were / will be collected on each of days 4, 8, 15, 22, 29, 43, 57, 85, and 113 (EOS / ET visits) (if applicable). Serum E2814 concentrations will be analyzed by non-compartmental methods to determine relevant PK parameters. In addition, in cohorts 1-3 only, plasma samples collected for PD biomarkers will also be used to determine E2814 concentrations in plasma. CSF samples for PK / PD assessment will be collected by intrathecal route pre-dose, 2, 4, 8, 12, and 24 hours after the end of infusion, and a single sample will be collected by LP on day 29.

[0121] MAD: Blood and CSF samples were / will be collected from each subject as specified in Figure 3. Blood samples for serum and plasma PK evaluation were / will be collected according to the following schedule: - Pre-dose and immediately after completion of the first infusion on Day 1, and 0.5, 1, 2, 4, 8, 12, 24 hours, and 72 hours after completion of the infusion on Day 4. Single samples were / will be collected at the outpatient visits on Days 8 and 15. A single sample taken before administration on day 29 (second infusion) and on day 43 - Pre-dose on Day 57 and immediately after the end of the third infusion, and 0.5, 1, 2, 4, 8, 12, 24 hours (Day 58), and 72 hours (Day 60) after the end of the infusion. Single samples were / will be collected at outpatient visits on Days 64, 71, 85, 113, 141, and 169 (End of Study / Early Discontinuation (EOS / ET) visits) (if applicable).

[0122] Serum and plasma E2814 concentrations have been analyzed by non-compartmental methods to determine / will determine relevant PK parameters.

[0123] CSF samples were / will be collected by LP pre-dose on Day 1, pre-dose on Day 57, and on Day 85 for PK and PD assessments.

[0124] Pharmacokinetic Analysis. E2814 concentrations in serum, plasma, and CSF were / will be tabulated by nominal sample collection times and summarized by dose using summary statistics. Serum, plasma, and CSF concentration-time profiles were / will be plotted. PK parameters were / will be determined by analyzing E2814 concentrations in serum / plasma (SAD and MAD) and CSF (SAD only) using non-compartmental analysis.

[0125] As shown in Table 6, serum and plasma PK parameters of the SAD and MAD components include (but are not limited to) Cmax, time to reach maximum drug concentration (tmax), AUC(0-24h), AUC(0-72h), terminal elimination half-life (t 1 / 2 ), clearance (CL), and volume of distribution (Vz) were / will be included. AUC(0-inf) was / will be estimated for the SAD component only, and AUC(0-tau), accumulation ratio of Cmax (Rac(Cmax), and accumulation ratio of AUC (Rac(AUC)) were / will be estimated for the MAD component only. CSF E2814 PK parameters include (but are not limited to) Cmax, tmax, and AUC(0-24h). For the MAD component, CSF PK parameters will not be estimated.

[0126] [Table 6]

[0127] 2. Pharmacodynamic evaluation Blood and CSF samples were / will be collected as specified in the procedure / assessment schedule in Figure 1 for SAD and Figure 3 for MAD.

[0128] SAD: CSF samples were / will be collected by intrathecal catheterization for the establishment of TE analysis methods in humans through the measurement of bound MTBR tau species (e.g., MTBR tau 354 and MTBR tau 299) and free MTBR tau species and calculation of total MTBR tau. On day 29, LP was / will be performed. Plasma samples for PD biomarkers were / will be collected pre-dose, immediately after the end of infusion, and at 0.5, 1, 2, 4, 8, 12, and 24 hours after the end of infusion, as well as single samples were / will be collected on days 4, 8, 15, 22, 29, 43, 57, 85, and 113 (EOS / ET visits). Plasma samples for PD biomarkers may also be used to determine E2814 concentrations in plasma and, if necessary, anti-E2814 antibodies.

[0129] To determine MAD:TE, CSF samples were / will be collected via LP sampling at pre-dose on day 1, pre-dose on day 57, and on day 85. Blood samples for plasma PD biomarkers were / will be collected pre-dose and immediately after the end of infusion on days 1, 29, and 57. Single samples were / will be collected at the outpatient visit on day 85 and the EOS / ET visit on day 169.

[0130] Pharmacodynamic analyses. Biomarker measurements and changes from baseline have / will be summarized by time point and by dose and / or treatment group and presented graphically. These analyses have / will be performed on both CSF and plasma, if data permits. Dose-response relationships have / will be determined, as appropriate. Further exploratory analyses of biomarkers in CSF and plasma may be performed.

[0131] 3. Pharmacokinetic-pharmacodynamic evaluation The PK-PD relationships between E2814 exposure and CSF and / or plasma biomarkers have been / will be evaluated, which may include, but is not limited to, characterization of the PK / TE relationship between E2814 concentration in CSF and MTBR tau binding.

[0132] PK-PD Analysis. If the data permits, the relationship between PK and PD was / will be determined by visual inspection of plots. This may include, but is not limited to, graphical exploration of the PK / TE relationship between E2814 concentration in CSF and MTBR tau binding.

[0133] 4. Safety Assessment Safety evaluations consisted / will consist of monitoring and recording of all AEs; regular monitoring of hematology (including coagulation in all cohorts in the SAD [Cohorts 4 and 5] component and in the MAD-only component), clinical chemistry, and urine values; regular measurement of vital signs and ECG; regular assessment of suicidality using the C-SSRS (MAD only), and performance of physical examinations (including psychiatric assessments) will be performed as detailed in the Procedures / Evaluation Schedule for the SAD component (Figure 1) and for the MAD component (Figure 3).

[0134] Safety Analysis. Safety data adjudicated / to be adjudicated include AEs, clinical laboratory results, vital signs, ECG, C-SSRS (MAD only), and physical examination (including psychiatric assessments). Descriptive statistics (e.g., mean, SD, median, minimum, and maximum for continuous variables and number and percentage for categorical variables) and changes from baseline for clinical laboratory, vital signs, and ECG were / will be adjudicated by dose.

[0135] 5. Laboratory Measurements Laboratory tests to be performed include hematology (including coagulation in the MAD component only), clinical chemistry, and urinalysis. The procedure / assessment schedule (Figure 1 for the SAD component and Figure 3 for the MAD component) shows the visits and time points at which blood for laboratory tests and urine for urinalysis were / will be collected in the study.

[0136] 6. Immunogenicity Anti-E2814 antibodies have / will be measured by a suitably validated ECL assay method. Immunogenicity will be assessed by measuring the presence of anti-E2814 antibodies in serum (and / or plasma) at various time points after dosing. In addition, the study has / will perform clinical measurements to monitor for inflammation that may be related to immunogenicity, including close monitoring of changes in white blood cell (WBC) / red blood cell (RBC) counts and differentials, and blood levels of two acute phase inflammatory markers, C-reactive protein (CRP) and fibrinogen. Further safety evaluation of subjects suspected of having an immune response may include measurements of cytokine responses, lymphocyte counts and subsets, immunoelectrophoresis, or any other clinically appropriate evaluation.

[0137] Numbers (proportions) of subjects with ADA positive and negative and ADA titer categories (>0, 5, 25, 125, etc.) by visit and dose will be summarized. In addition, correlations between ADA titers and PK profiles have / will be determined using, at a minimum, descriptive statistics and summary plots.

[0138] Study endpoints 1. Primary endpoint. The primary endpoints for the SAD and MAD components are the incidence of treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (SAEs), clinical laboratory parameters, vital signs, and ECGs.

[0139] 2. Secondary endpoints SAD: ·PK parameters derived by non-compartmental analysis using E2814 concentrations in serum, plasma, and CSF; Serum (and / or plasma) anti-E2814 antibody concentration.

[0140] MAD: ·PK parameters derived by noncompartmental analysis using serum and plasma E2814 concentrations after infusion on days 1 and 57, and CSF E2814 concentrations pre-dose on day 57 and on day 85 (i.e., 28 days after the second and third infusions, respectively); Serum (and / or plasma) anti-E2814 antibody concentration.

[0141] 3. Exploratory endpoints SAD and MAD: Change from baseline in CSF-free and -bound MTBR tau and total MTBR tau Changes from baseline in CSF and / or plasma biomarkers, including t-tau and p-tau

[0142] Analysis population: The safety analysis population was the group of subjects who received at least one dose of study drug and had at least one post-dose safety assessment. The PK analysis population was the group of subjects who received at least one dose of study drug and had sufficient PK data to derive at least one PK parameter. The PD analysis population was the group of subjects who received at least one dose of study drug and had sufficient PD data to derive at least one PD parameter.

[0143] Preliminary results: Clinical safety. SAD Components (Study E2814-A001-001): The SAD component of Study E2814-A001-001 has completed adjudication of three cohorts corresponding to E2814 dose levels of 3, 10, and 30 mg / kg. Within each cohort, six subjects received E2814 and two subjects received E2814-matching placebo. A total of 24 healthy subjects were randomized into the SAD component of Study E2814-A001-001, of which 18 received E2814 and six received placebo. All 24 subjects enrolled in the study received at least one dose of placebo or E2814 and were included in the safety analysis population. Subject demographics and baseline characteristics are summarized in Figure 5A.

[0144] SAD component safety results (Cohorts 1-5; Figure 14A) demonstrate that E2814 has an adequate safety and tolerability profile as indicated by the absence of clinically significant drug-related laboratory, ECG, or clinical safety findings or dose-limiting adverse events (AEs) at all doses assessed: 3, 10, 30, 60, and 90 mg / kg. There were no serious adverse events or severe AEs that occurred during treatment. Two AEs, skin rash and headache, were both mild in severity and considered related to study drug by the investigator. One subject in Cohort 3 had elevated C-reactive protein (CRP) levels compared to baseline, particularly on days 2 and 3, which was asymptomatic and resolved without treatment. A maximum tolerated dose (MTD) was not identified.

[0145] Additionally, six subjects have received E2814 and two subjects have received E2814-matching placebo to date in each of Cohort 4 (60 mg / kg) and Cohort 5 (90 mg / kg). Preliminary data from these cohorts demonstrated that there were no treatment-emergent serious or severe adverse events and no clinically significant findings on vital signs, EEG, or clinical laboratory data.

[0146] MAD Components (Research E2814-A001-001): Subject demographics and baseline characteristics are summarized in Figure 5B.

[0147] The MAD component of study E2814-A001-001 determined two cohorts corresponding to E2814 dose levels of 750 mg and 1500 mg every 4 weeks (Q4W) for a total of three doses, with data available through Day 169 (last study visit) and Day 85, respectively. In each MAD cohort, six subjects received E2814 and two subjects received E2814-matching placebo. A total of 16 healthy subjects were randomized, of which 12 subjects received intravenous E2814 (six active per cohort) and four subjects received placebo (two per cohort). A total of three subjects withdrew for reasons other than drug-related safety events: Two subjects withdrew after dosing on Day 1 due to pre-existing medical conditions (one infectious skin rash [750 mg] and one asymptomatic M spike [1500 mg]) that were not identified at the baseline visit and prior to study drug administration. The third subject withdrew before receiving the third dose because the visit schedule for dosing could not be adjusted to fall within the per-protocol tolerance window. This subject had mild respiratory symptoms (COVID-19 PCR was negative), which were considered unrelated to study drug.

[0148] MAD component safety results demonstrate that E2814 has an adequate safety and tolerability profile, as indicated by the absence of clinically significant drug-related laboratory, vital sign, ECG, or physical examination safety findings or dose-limiting AEs across the adjudicated doses of 750 and 1500 mg Q4W. In total, 8 of 12 subjects (66.7%) treated with E2814 and 2 of 4 subjects (50.0%) treated with placebo experienced at least one TEAE during the study. There were no treatment-emergent serious or severe AEs. All abnormal laboratory findings were not related to the subject's symptoms and were deemed not clinically significant by the principal investigator. Across all subjects in the MAD cohort treated with E2814, the most common TEAEs were headache (16.7%, 2 subjects), back pain (16.7%, 2 subjects), and skin rash (16.7%, 2 subjects). The maximum tolerated dose (MTD) was not identified.

[0149] Additionally, in cohort 3 (3000 mg Q4W), five subjects have received E2814 and two subjects have received E2814-matching placebo to date in this cohort. Preliminary data from this cohort also demonstrated that E2814 at a dose of 3000 mg Q4W exhibited an acceptable safety and tolerability profile in healthy volunteers. Treatment-emergent adverse events (TEAEs) were generally mild in intensity, with three moderate (two headaches [one related], one nausea [related]). There were no treatment-emergent or severe adverse events, and no clinically significant findings in vital signs, EEG, and laboratory data. Safety data for the MAD component of study E2814-A001-001 are summarized in Figure 14B.

[0150] Safety results from the SAD and MAD components of study E2814-A001-001 demonstrate that E2814 has an adequate single- and multiple-dose safety and tolerability profile in all adjudicated cohorts, with no clinically significant drug-related safety findings or dose-limiting adverse events (AEs) on clinical laboratory, coagulation parameters (fibrinogen, INR, PT, aPTT), vital signs, ECG or physical examination. There were no dose-limiting events (DLEs) up to the highest adjudicated doses of 90 mg / kg and 3000 mg Q4W in the SAD and MAD components, respectively.

[0151] Preliminary Results: Clinical Pharmacology Single-dose PK and TE of E2814 were investigated in a total of 18 healthy adult male and female subjects in the SAD component of study E2814-A001-001. PK and TE were determined after three repeated Q4W infusions in a total of 12 subjects in the MAD component of the same study.

[0152] Preliminary Results: Clinical Pharmacokinetics (PK) SAD Components-PK and ADA (Research E2814-A001-001) The mean serum concentration-time profiles of E2814 following single intravenous dose administration in the SAD component are shown in Figure 7. The geometric mean serum PK parameters are presented in Figure 6.

[0153] PK results indicate that there was a dose-dependent increase in serum E2814 exposure (Figure 6). The observed serum AUC and C max The time to reach the maximum serum E2814 concentration (t max The median time to ischemia was 1 to 2.5 hours. Across all dose groups, E2814 had a distribution volume (V z ), clearance (CL) of 0.04-0.07 L / hour, and half-life (t 1 / 2) range. Serum-to-CSF concentration ratios ranged from 0.1% to 0.3% (Figure 6). Mean CSF concentration-time profiles of E2814 are shown in Figure 9. Geometric mean CSF PK parameters are presented in Figure 8. CSF PK results were consistent across the dose range of 3 to 60 mg / kg. max and AUC (0-24h) The results indicate a greater than dose-proportional increase in t max The median time was 25 hours.

[0154] Eight of 24 E2814-treated subjects (three subjects in the 3 mg / kg cohort, one subject in the 30 mg / kg cohort, and four subjects in the 60 mg / kg cohort) had confirmed presence of anti-E2814 antibodies (ADA) in serum. Of these total eight subjects, five subjects had transient low-level serum anti-E2814 antibody titers by Day 113 (end of study, EOS). All positive subjects returned to baseline status during follow-up, except for one in the 3 mg / kg cohort. Observed E2814 pharmacokinetics in ADA-positive subjects was comparable to ADA-negative subjects.

[0155] MAD Components - PK and ADA (Research E2814-A001-001) The mean serum concentration-time profiles of E2814 after multiple intravenous dose administration in the MAD component are shown in Figure 15. The geometric mean serum PK parameters are presented in Figure 10. The E2814 concentration-time profiles after administration on days 1 and 57 show that serum concentrations peaked immediately after the end of each infusion. There was a dose-dependent increase in serum E2814 concentrations at the three MAD doses examined. The time to reach maximum serum E2814 concentrations (t max ) was 1.5-2.25 hours on day 1, and after the third infusion, t max There appeared to be a median delay (5-7 hours). The observed serum geometric mean AUC values ​​on Day 1 and Day 57 increased in a dose-proportional manner. max The increase in the volume of distribution (V) of approximately 28–32 L was observed. z), a clearance (CL) of about 0.04-0.06 L / hour, and a serum half-life (t 1 / 2 ) range, which is similar to the observed SAD component values. The accumulation factor is C max 1.28 to 1.43, and AUC (0-672h) The range was 1.27 to 1.79.

[0156] Serum ADA was determined in the 750 mg and 1500 mg dose groups. Only one subject in the 750 mg dose group tested positive prior to dosing on Day 1.

[0157] Preliminary Results: Target Engagement in Humans Target engagement (TE) was determined in CSF by measuring E2814-bound and free MTBR tau surrogate peptide concentrations (MTBR tau 354 and MTBR tau 299 containing epitopes in R4 and R2, respectively). Preliminary data in healthy subjects indicates that following E2814 administration, there is an increase in bound MTBR tau and a decrease in free MTBR tau levels in CSF related to E2814 concentration following single 3-90 mg / kg doses, as well as multiple 750 mg, 1500 mg, and 3000 mg doses. Target engagement was calculated as the ratio of E2814-bound MTBR tau to total (free + bound) MTBR tau expressed as a percentage. Target engagement levels appeared to persist from 24 hours to approximately 672 hours (28 days) after single dose administration (Figures 11A and 11B) and from days 56 to 84 after multiple dose administration (Figures 12A and 12B). Based on available CSF TE data from study E2814-A001-001 in healthy volunteers, the highest multiple dose of 3000 mg, resulting in CSF concentrations in the range of 200-400 ng / mL, appears to result in approximately 80% binding saturation for MTBR tau299 and approximately 70% binding saturation for MTBR tau354 (Figures 13A and 13B).

[0158] Example 2. An Open-Label Phase 1b / 2 Study Evaluating the Safety and Target Engagement of E2814 in Subjects with Mild-to-Moderate Cognitive Impairment Due to Dominantly Inherited Alzheimer's Disease (Study E2814-G000-103) Study rationale and study design This is an open-label Phase 1b / 2 study to determine safety and target engagement (TE) following intravenous (IV) infusion of two different doses of E2814 on MTBR tau species in cerebrospinal fluid (CSF) in subjects with dominantly inherited Alzheimer's disease (DIAD) and exhibiting mild to moderate cognitive impairment. The study will target individuals known to have disease-causing mutations confirmed by genetic testing. Subjects in this study will be those who have confirmed mutation positive for genes known to be associated with DIAD. Mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2) and amyloid precursor protein (APP) associated with DIAD have extremely high penetrance (nearly 100%).

[0159] The study will also evaluate the pharmacokinetics (PK), immunogenicity, and other pharmacodynamic (PD) effects of E2814.

[0160] The study will consist of two phases: a pre-treatment phase consisting of a screening period (days -60 to -2; screening assessments will include tau PET, amyloid PET, and safety magnetic resonance imaging (MRI) and genetic testing to confirm mutation status) and a treatment phase consisting of 3 periods: 1b, 2, and follow-up.

[0161] Phase 1b Treatment Period. The Phase 1b treatment period will initially include eight subjects receiving open-label treatment with 750 mg E2814 intravenous infusion every four weeks (Q4W) for three 12-week infusions. At the conclusion of the Phase 1b treatment period on Day 84, subjects will undergo a safety evaluation. CSF samples will be collected on Days 1 and 84 for assessment of TE and CSF E2814 concentrations. Subjects will then progress to the Phase 2 treatment period.

[0162] Phase 2 Treatment Period. The Phase 2 Treatment Period will involve subjects who tolerated the 750 mg dose of E2814 and completed all evaluations in the Phase 1b Treatment Period receiving an initial dose of 1500 mg Q4W for at least 3 doses (12 weeks), followed by an additional 96 weeks of IV E2814 at a dose of 3000 mg Q4W for the remaining weeks.

[0163] From Day 86 onwards, all subsequent visits will occur every 4 weeks for the duration of the study. On Day 84 (Week 12), CSF samples will be collected for assessment of TE and CSF E2814 concentrations; thereafter, lumbar puncture (LP) samples will be collected 12 weeks after each dose adjustment on Day 169 (Week 24, i.e., 12 weeks after initiation of the 1500 mg dose), Day 253 (Week 36, i.e., 12 weeks after initiation of the 3000 mg dose [if an increase to the 3000 mg dose occurs after Day 169, this collection can occur on a later study date]), and on Days 421 (Week 60) and 757 (Week 108) for assessment of biomarkers and PK endpoints. Subjects will also undergo annual tau and amyloid PET scans (three times throughout the study: screening, Day 421, and Day 757) and semi-annual cognitive performance assessments. For subjects discontinuing early, an early discontinuation CSF draw and PET scan will be performed unless a PET evaluation has been performed within the previous 3 months.

[0164] Follow-up Period. Subjects will be followed for safety for a period of 12 weeks after the final dose.

[0165] Study completion will be the date of the last study visit for the last subject in the study.

[0166] An overview of the study design is presented in Figure 16.

[0167] Research Objective The main objectives of this study are: To evaluate the safety and tolerability of intravenous (IV) infusion of E2814 in subjects with DIAD; To determine the TE of E2814 on MTBR tau species in CSF in subjects with DIAD.

[0168] The secondary objectives of this study are: To evaluate the PK of E2814 in serum, plasma, and CSF; To assess the immunogenicity of E2814 (production of anti-E2814 antibodies); To evaluate the effects of E2814 on CSF, blood, and imaging biomarkers.

[0169] The exploratory objectives of this study are to: To evaluate the effect of E2814 on the clinical progression of DIAD as assessed using clinical tests such as the Clinical Dementia Scale-Sum of Items (CDR-SB) and multiple cognitive and clinical endpoints; Collecting genomic samples for potential exploratory studies of heterogeneity in drug response and clinical features of disease.

[0170] Study population Inclusion Criteria. To be included in the study, subjects must meet all of the following criteria: 1. Male or female, aged 18-80 years at the time of informed consent 2. Individuals with confirmed positive mutations in the PSEN1, APP, or PSEN2 genes associated with DIAD 3. Clinical Dementia Scale-Summary Items (CDR-SB) score of 5-12 at screening 4. Evidence of positive amyloid status based on records or amyloid PET at screening 5. Able to undergo MRI, LP, and positron emission tomography (PET) and complete all study-related tests and evaluations. 6. Have a research partner who, in the investigator's judgment, can provide accurate information regarding the subject's cognitive and functional abilities and who agrees to provide information during study visits that require informant input for completion of scales.

[0171] Exclusion Criteria. Subjects meeting any of the following criteria will be excluded from the study: 1. Clinically significant illness requiring medical treatment within 8 weeks prior to the first dose or clinically significant infection requiring medical treatment within 4 weeks prior to the first dose 2. Women who are breastfeeding or pregnant at screening or baseline 3. Females of childbearing potential who have not used highly effective contraception within 3 months prior to screening or who do not agree to use highly effective contraception throughout the study and for 16 weeks after discontinuation of study drug. 4. Any neurological condition that may contribute to cognitive impairment beyond that caused by AD in a subject 5. History of transient ischemic attack, stroke, or seizure within 12 months of screening 6. History of clinically significant carotid or vertebrobasilar stenosis, plaque, or other significant stroke or cerebral hemorrhage risk factors (including atrial fibrillation and anticoagulation). 7. Any current psychiatric diagnosis or condition in the subject that may interfere with study procedures (e.g., hallucinations, major depression, or delusions) 8. Geriatric Depression Scale (GDS) score ≥8 at screening 9. Contraindications to MRI scanning, including but not limited to pacemakers / defibrillators, neurostimulators, ferromagnetic metal implants (e.g., cranial and cardiac devices other than those approved as safe for use in MRI scanners). 10. Evidence of other clinically significant brain MRI lesions at screening that may indicate a dementia diagnosis other than AD 11. Other significant brain MRI pathology at screening, including but not limited to: >15-20 microhemorrhages (defined as ≤10 mm in greatest diameter); any gross hemorrhages (>10 mm in greatest diameter) currently symptomatic at screening; any areas of superficial iron deposition currently symptomatic at screening, evidence of vasogenic edema; evidence of cerebral contusion, encephalomalacia, aneurysm, vascular malformation, or infectious foci; evidence of 2 or more lacunar infarcts or stroke involving major vascular territories, severe small vessels, or white matter disease; space-occupying lesions; or brain tumor (however, lesions <1 cm in greatest diameter diagnosed as meningiomas or arachnoid cysts may not be excluded) 12. Hypersensitivity to E2814 or any of the excipients, or to any mAb treatment 13. Any immune disorder that is not adequately controlled or requires treatment with immunoglobulins, systemic monoclonal antibodies (or monoclonal antibody derivatives), systemic immunosuppressants, or plasmapheresis during the study. 14. Exclude individuals with a bleeding disorder who are currently taking chronic anticoagulants (e.g., warfarin, dabigatran, rivaroxaban, or apixaban) or clopidogrel. Limited (occasional or one-off) use of anticoagulants / antiplatelet compounds in cases such as surgical procedures. 15. Thyroid stimulating hormone outside the normal range. Other thyroid function test results outside the normal range must be excluded only if the investigator considers them to be clinically significant. This applies to all subjects, whether or not they are taking thyroid replacement therapy. 16. HgbA1c >8% (retesting permitted if elevation is minor) or poorly controlled insulin-dependent diabetes mellitus (including hypoglycemic episodes). Subjects may be screened again in 3 months to allow for optimization of diabetic control. 17. Abnormally low serum vitamin B12 laboratory level (if subject is taking vitamin B12 injections, level must be equal to or greater than the lower limit of normal [LLN]). Vitamin B12 levels may be confirmed with reflex testing, such as methylmalonic acid analysis, if available locally. 18. History of human immunodeficiency virus (HIV) infection, hepatitis B infection within the past year, hepatitis C infection that has never been adequately treated, or spirochete infection of the central nervous system (e.g., syphilis, Lyme disease, or borreliosis) 19. Any other clinically significant abnormalities in physical examination, vital signs, laboratory tests, or ECG at screening or baseline that, in the opinion of the investigator, require further investigation or treatment or that may interfere with study procedures or safety. 20. Malignant neoplasm (excluding basal cell or squamous intraepithelial carcinoma of the skin, or localized prostate cancer in men, or localized breast cancer in women) within 3 years of screening. Subjects who have had a malignant neoplasm but have documented uninterrupted remission for at least 3 years prior to screening may not be excluded. 21. Columbia-Suicide Severity Rating Scale (C-SSRS) suicidal ideation type 4 or 5 within 6 months prior to screening, at screening, or at the baseline visit, or a "yes" response to any suicidal behavior assessment, or a lifetime history of hospitalization or treatment for any suicidal behavior. 22. Known or suspected history of drug or alcohol abuse or dependence within 2 years prior to screening, or a positive urine drug test at screening. Subjects with a positive urine drug test result for benzodiazepines or opioids may not be excluded if, in the investigator's clinical opinion, it is due to the subject's use of prior / concomitant medication containing benzodiazepines or opioids for a medical condition and not due to drug abuse. 23. Any other medical condition that is not stable and adequately controlled or that, in the opinion of the investigator, may affect the subject's safety or interfere with the study evaluations (e.g., cardiac, respiratory, gastrointestinal, renal disease). 24. Concurrent participation in a clinical trial involving any anti-amyloid therapy (including any mAb therapy) within 6 months prior to screening 25. Concurrent participation in a clinical trial involving any anti-tau therapy. 26. Participation in any other investigational drug therapy or device study for 3 months or 5 half-lives of drug therapy (whichever is longer) prior to screening 27. Planned surgery requiring general anesthesia that will be performed during the study. 28. Vision or hearing impairment that would prevent the subject from accurately performing psychological testing procedures.

[0172] Research evaluation Screening Assessments. Screening assessments will be conducted as specified in the Procedures / Assessment Schedule (Figure 17). At the screening visit, subject demographic information (age, sex, race / ethnicity) will be collected. Medical and surgical history and current medical conditions will be recorded at the screening visit. Blood samples for Hepatitis B Core Antibody (HBcAb), Hepatitis B Surface Antigen (HBsAg), Hepatitis C Virus Antibody (HCVAb) and HIV testing will be taken at the screening visit.

[0173] Clinical Efficacy Assessments and Analyses. Cognitive assessments will be performed at baseline (Day -1), every 24 weeks throughout the study, and at the end-study visit. These assessments will include the Global Clinical Dementia Scale (CDR), CDR-SB, Mini-Mental State Examination (MMSE), and multiple cognitive and clinical assessments, including the following tests: Free and Cued Selective Recall Test (FCSRT), Wechsler Memory Scale-Revised (WMS-R) Logical Memory, Wechsler Adult Intelligence Scale-Revised (WAIS-R) Digit Sign Substitution Test, Trail Making Test A and B, Animal Naming, WMS-R Digit Span, Memory Assessment Questionnaire (MAC-Q), Functional Assessment Scale (FAS), GDS, and Neuropsychiatric Inventory-Questionnaire (NPI-Q). Changes from baseline in cognitive assessments will be summarized by visit.

[0174] Pharmacokinetic (PK) Evaluation. During the Phase 1b treatment period (750 mg E2814 dose), blood samples for PK evaluation will be collected according to the following schedule: On day 1, before dosing, immediately after the first infusion, and 4, 8, and 24 hours after the end of the infusion Single samples will be collected at outpatient visits on days 15, 29 (pre-dose), and 57 (pre-dose).

[0175] During the Phase 2 treatment period (1500 mg and 3000 mg E2814 doses), the following PK samples will be taken: -Before dosing and immediately after the end of the infusion on day 85 and 4, 8, and 24 hours after the end of the infusion, then before dosing and immediately after the end of the infusion on day 169, and every 12 weeks thereafter.

[0176] Serum and plasma E2814 concentrations will be analyzed by non-compartmental methods to determine relevant PK parameters.

[0177] CSF samples will be collected by LP pre-dose on Day 1, on Day 84 (Week 12 [this collection may occur on Day 85 as long as it occurs pre-dose]). Thereafter, LP sampling will occur after each dose adjustment and 12 weeks thereafter; e.g., on Day 169 (12 weeks after initiation of the 1500 mg dose), on Day 253 (12 weeks after initiation of the 3000 mg dose [this collection may occur on a later study date if an increase to the 3000 mg dose occurs after Day 169]), on Day 421, and on Day 757 for PK and pharmacodynamic (PD) evaluations.

[0178] E2814 concentrations will be measured in serum, plasma, and CSF by a validated electrochemiluminescence assay and / or a validated immunoprecipitation / purification followed by liquid chromatography-tandem mass spectrometry, if available. Anti-E2814 antibodies will be measured by a validated electrochemiluminescence assay.

[0179] Serum and plasma E2814 concentrations will be tabulated by nominal sample collection time and summarized by dose using summary statistics. Serum and plasma concentration-time profiles will be plotted. Serum and plasma E2814 PK parameters will include (but are not limited to) C at 1 and 85 days. max , the time to reach the maximum drug concentration (t max ) and the area under the concentration-time curve from time 0 to the end of the dosing interval (AUC (0-672h) ) will be included. A comprehensive population analysis of E2814 PK will be performed by pooling data from all available studies.

[0180] Pharmacodynamic evaluation. CSF samples will be collected by LP pre-dose on Days 1 and 84 (Week 12 [this LP may be performed on Day 85 as long as it is pre-dose]). Thereafter, LP sampling will be performed pre-dose on Days 1, 29, 57, and 85 and 12 weeks thereafter; e.g., Day 169 (12 weeks after initiation of the 1500 mg dose), Day 253 (12 weeks after initiation of the 3000 mg dose [if an increase to the 3000 mg dose occurs after Day 169, this collection may occur on a later study day]) to determine MTBR tau TE (free / bound MTBR tau species) and CSF E2814 concentrations, followed by annual CSF collections on Days 421 (Week 60) and 757 (Week 108) for evaluation of biomarkers and PK endpoints. Blood samples for plasma PD biomarkers will be collected pre-dose on Days 1, 29, 57, and 85 and immediately after the end of the infusion. Blood samples for plasma PD biomarkers will also be taken on days 15, 169, and every 12 weeks thereafter during Phase 2 treatment.

[0181] Biomarker measurements (body fluids and imaging) and changes from baseline will be summarized by time point and dose and presented graphically. These analyses will be performed on CSF, plasma, and serum. Dose-response relationships will be determined.

[0182] The relationship between PK and PD will be determined by visual inspection using plots, which may include, but are not limited to, graphical exploration of the PK / TE relationship between E2814 concentration and MTBR-tau binding in the CSF.

[0183] Pharmacogenomic (PGx) assessment. During screening, PGx blood samples will be taken for confirmatory PSEN1, APP, or PSEN2 gene mutation testing. CSF and plasma biomarkers. CSF and plasma concentrations of AD-related biomarkers will be measured, including but not limited to Aβ40, Aβ42, neurogranin, neurofilament light chain, total tau [t-tau], and phosphorylated tau biomarkers.

[0184] Imaging biomarkers. Longitudinal tau (MK-6240) and amyloid PET (e.g., C-Pittsburgh compound B or NAV4694) will be performed at screening and then annually during Phase 2 treatment. An early-discontinuation PET scan will be performed unless a PET assessment has been performed within the past 3 months.

[0185] Safety Assessments. For both the Phase 1b and Phase 2 treatment periods, safety assessments will consist of monitoring and recording of all adverse events (AEs); regular monitoring of hematology, clinical chemistry, and urine values; regular measurement of vital signs and ECGs; regular assessment of suicidality using the C-SSRS, and performance of physical examinations. Safety MRIs will be performed at screening, upon completion of the Phase 1b treatment period, and then annually during the Phase 2 treatment period.

[0186] Safety data to be adjudicated include AEs, clinical laboratory results, vital signs, ECG, C-SSRS, and physical examination. Safety data from the Phase 1b and Phase 2 treatment periods will be summarized separately. TEAEs will be summarized by dose. Descriptive statistics (e.g., mean, SD, median, minimum, and maximum for continuous variables and number and percentage for categorical variables) and changes from baseline for clinical laboratory, vital signs, and ECG will be adjudicated by dose.

[0187] Immunogenicity assessment. Immunogenicity will be assessed by measuring the presence of anti-E2814 antibodies prior to dosing on days 1, 15, 29, 57, 85, 113, and 169, and every 12 weeks during Phase 2 treatment. In addition, the study will perform clinical measurements to monitor inflammation that may be related to immunogenicity. These assessments will include close monitoring of changes in white blood cell / red blood cell counts and differentials, as well as changes in blood levels of two acute phase inflammatory markers: C-reactive protein and fibrinogen. Additional safety assessments for subjects suspected of having an immunological response may include measurements of cytokine responses, lymphocyte counts and subsets, immunoelectrophoresis, or any other clinically appropriate assessment.

[0188] Statistical and analytical plan Primary endpoint: Incidence of treatment-emergent adverse events (TEAEs) and SAEs, clinical laboratory parameters, vital signs, and ECGs Changes from baseline in CSF-free and -bound MTBR tau and total MTBR tau at 12 weeks

[0189] Secondary Endpoints: Serum and plasma PK parameters after dosing on days 1 and 85 ·CSF E2814 concentration Serum (or plasma) anti-E2814 antibody concentration Change from baseline in CSF and / or plasma biomarkers, including total tau (t-tau) and phosphorylated tau biomarkers Change from baseline in tau PET signal

[0190] Exploratory endpoints: Change from baseline in cognitive and clinical assessments Change from baseline in amyloid PET signal

[0191] Definition of the analysis population The safety analysis population is the group of all randomized subjects who received at least one dose of study drug. Inclusion in the analysis of each specific parameter requires at least one clinical laboratory, vital sign, or ECG measurement obtained after at least one dose of study treatment. A baseline measurement is also required to assess change from baseline. This is the analysis population used for all safety analyses that will be based on the as-treated principle.

[0192] The PK analysis population is the group of subjects who received at least one dose of study drug and for whom there are sufficient PK data to derive at least one PK parameter.

[0193] The PD analysis population is the group of subjects who received at least one dose of study drug and who have sufficient PD data to derive at least one PD parameter.

[0194] The definitions of these analysis populations will be the same for both the Phase 1b and Phase 2 treatment periods; the actual determination of these analysis populations will be made separately for each study period.

Claims

1. An intravenous dosage form comprising an antibody that specifically binds to tau in a single dose amount of about 3 mg / kg to about 90 mg / kg.

2. 10. The intravenous dosage form of claim 1, wherein the amount of the single dose is about 3 mg / kg, about 10 mg / kg, about 30 mg / kg, about 60 mg / kg, or about 90 mg / kg.

3. An intravenous dosage form comprising an amount of an antibody that specifically binds to tau, wherein said amount of said antibody is from about 750 mg to about 4500 mg.

4. 4. The intravenous dosage form of claim 3, wherein the amount of the antibody is about 750 mg, about 1500 mg, about 3000 mg, or about 4500 mg.

5. 5. The intravenous dosage form of any one of claims 1 to 4, wherein the intravenous dosage form is for use in treating a subject diagnosed with a tauopathy.

6. 6. The intravenous dosage form of claim 5, wherein the tauopathy is Alzheimer's disease, frontotemporal dementia, or progressive supranuclear palsy.

7. 7. The intravenous dosage form of claim 6, wherein the frontotemporal dementia is Pick's disease.

8. 7. The intravenous dosage form of claim 6, wherein the Alzheimer's disease is dominantly inherited Alzheimer's disease or sporadic Alzheimer's disease.

9. 1. A pharmaceutical composition for treating a human subject diagnosed with a tauopathy, comprising an antibody that specifically binds to tau, wherein the antibody that specifically binds to tau is administered to the subject as a single dose of about 3 mg / kg to about 90 mg / kg.

10. 10. The pharmaceutical composition for treating a human subject diagnosed with a tauopathy of claim 9, wherein the antibody that specifically binds to tau is administered to the subject as a single dose of about 3 mg / kg, about 10 mg / kg, about 30 mg / kg, about 60 mg / kg, or about 90 mg / kg.

11. 1. A pharmaceutical composition for treating a human subject diagnosed with a tauopathy, comprising an antibody that specifically binds to tau, wherein the antibody that specifically binds to tau is administered to the subject at a dose of about 750 mg to about 4500 mg.

12. 12. The pharmaceutical composition for treating a human subject diagnosed with a tauopathy of claim 11, wherein the antibody that specifically binds to tau is administered as a dose of about 750 mg, about 1500 mg, about 3000 mg, or about 4500 mg.

13. 13. The pharmaceutical composition for treating a human subject diagnosed with a tauopathy according to claim 11 or 12, wherein the antibody that specifically binds to tau is administered once every four weeks.

14. The pharmaceutical composition for treating a human subject diagnosed with a tauopathy according to any one of claims 9 to 12, wherein the antibody that specifically binds to tau is administered intravenously.

15. The pharmaceutical composition for treating a human subject diagnosed with a tauopathy according to any one of claims 9 to 12, wherein the tauopathy is Alzheimer's disease, frontotemporal dementia, or progressive supranuclear palsy.

16. The pharmaceutical composition for treating a human subject diagnosed with a tauopathy according to claim 15, wherein the frontotemporal dementia is Pick's disease.

17. 16. The pharmaceutical composition for treating a human subject diagnosed with a tauopathy according to claim 15, wherein the Alzheimer's disease is dominantly inherited Alzheimer's disease or sporadic Alzheimer's disease.

18. A pharmaceutical composition for treating a human subject diagnosed with a tauopathy according to any one of claims 9 to 12, comprising at least one pharmaceutically acceptable carrier.

19. 13. The intravenous dosage form of any one of claims 1 to 4, or the pharmaceutical composition of any one of claims 9 to 12, wherein the anti-tau antibody comprises a heavy chain complementarity determining region (HCDR) of a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 2 and a light chain complementarity determining region (LCDR) of a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO:

5.

20. The intravenous dosage form of any one of claims 1 to 4, or the pharmaceutical composition of any one of claims 9 to 12, wherein the anti-tau antibody comprises three HCDRs (HCDR1, HCDR2, and HCDR3) and three LCDRs (LCDR1, LCDR2, and LCDR3), wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 7; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 8; the HCDR3 comprises the amino acid sequence of SEQ ID NO: 9; the LCDR1 comprises the amino acid sequence of SEQ ID NO: 10; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 11; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 12, and the CDRs are defined according to the Kabat method.

21. The intravenous dosage form of any one of claims 1 to 4, or the pharmaceutical composition of any one of claims 9 to 12, wherein the anti-tau antibody comprises three HCDRs (HCDR1, HCDR2, and HCDR3) and three LCDRs (LCDR1, LCDR2, and LCDR3), wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 13; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 14; the HCDR3 comprises the amino acid sequence of SEQ ID NO: 15; the LCDR1 comprises the amino acid sequence of SEQ ID NO: 16; the LCDR2 comprises KVS; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 18, and the CDRs are defined according to the IMGT method.

22. 13. The intravenous dosage form of any one of claims 1 to 4, or the pharmaceutical composition of any one of claims 9 to 12, wherein the anti-tau antibody comprises a VH comprising SEQ ID NO:2 and a VL comprising SEQ ID NO:

5.

23. 13. The intravenous dosage form of any one of claims 1 to 4, or the pharmaceutical composition of any one of claims 9 to 12, wherein the anti-tau antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 1 and / or a light chain comprising the amino acid sequence of SEQ ID NO:

4.

24. The intravenous dosage form of any one of claims 1 to 4, or the pharmaceutical composition of any one of claims 9 to 12, wherein the anti-tau antibody is antibody E2814 or a biosimilar thereof.

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