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WO2025196217A1 - Traitement de tauopathies avec des anticorps se liant à la protéine tau - Google Patents

Traitement de tauopathies avec des anticorps se liant à la protéine tau

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Publication number
WO2025196217A1
WO2025196217A1 PCT/EP2025/057692 EP2025057692W WO2025196217A1 WO 2025196217 A1 WO2025196217 A1 WO 2025196217A1 EP 2025057692 W EP2025057692 W EP 2025057692W WO 2025196217 A1 WO2025196217 A1 WO 2025196217A1
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WO
WIPO (PCT)
Prior art keywords
tau
antigen
binding
binding fragment
seq
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2025/057692
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English (en)
Inventor
Colin EWEN
Massimiliano GERMANI
Timothy John BUCHANAN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
UCB Biopharma SRL
Original Assignee
UCB Biopharma SRL
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Filing date
Publication date
Application filed by UCB Biopharma SRL filed Critical UCB Biopharma SRL
Publication of WO2025196217A1 publication Critical patent/WO2025196217A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/54—F(ab')2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]

Definitions

  • the present invention relates to the treatment of tauopathies, in particular the treatment of tauopathies such as Progressive Supranuclear Palsy (PSP) and/or Alzheimer’s Disease (AD) with a tau-binding antibody or antigen-binding fragment thereof.
  • tauopathies such as Progressive Supranuclear Palsy (PSP) and/or Alzheimer’s Disease (AD) with a tau-binding antibody or antigen-binding fragment thereof.
  • tau has been shown to contribute to the development of the group of neurodegenerative diseases which are classed as tauopathies. Tauopathies occur as a result of misfolding and aggregation of the tau protein, which then affects normal neuronal function (Zhang et al., Mol Neuro, 2022). Tau is coded for by the microtubule-associated protein tau gene (MAPT), that is widely distributed in neurons and also expressed in glial cells. In its nonpathological state, tau is a highly soluble protein, which occurs in the central nervous system in 6 main isoforms due to alternative MAPT gene splicing, ranging from 352 to 441 amino acids in length.
  • MTT microtubule-associated protein tau gene
  • isoforms can have 0, 1, or 2 N-terminal inserts (ON, IN, or 2N), and either 3 or 4 C-terminal “repeat” sequences (3R or 4R). These 30 to 32 amino acid C-terminal repeat sequences, Rl, R2, R3, and R4, together constitute the tau MTBR (microtubule binding region).
  • tau exists in equal balance between 3R and 4R isoforms (Irwin, Parkinsonism Relat Disord. 2016;22 Suppl 1 : S29-33), is mainly concentrated in the distal part of axons, and is natively unfolded (Huang et al, Cell Mol Life Sci. 2016;73(l): 1-21).
  • tauopathies are usually classified as 3R tauopathies (i.e., Pick’s disease), 3R/4R tauopathies (i.e., Alzheimer’s disease (AD)), and 4R tauopathies (i.e., progressive supranuclear palsy (PS), corticobasal degeneration (CBD), argyrophilic grain disease, and globular glial tauopathies) (Irwin, Parkinsonism Relat Disord. 2016;22 Suppl 1 : S29-33).
  • 3R tauopathies i.e., Pick’s disease
  • 3R/4R tauopathies i.e., Alzheimer’s disease (AD)
  • 4R tauopathies i.e., progressive supranuclear palsy (PS), corticobasal degeneration (CBD), argyrophilic grain disease, and globular glial tauopathies
  • PSP is a rare and fatal tauopathy, whose pathology begins with the accumulation of tau in the subcortical and brain stem nuclei, as well as regions related to symptoms such as sleeping disorders, motor dysfunction and Parkinsonism (Coughlin et al., Parkinsonism Relat Disord 2020 Apr;73: 105-116).
  • the progression of PSP results in the reduction of quality of life (QoL) and autonomy of people living with the disease, as they experience worsening dysarthria, cognitive difficulties, and physical disability (Agarwal and Gilbert, StatPearls Publishing 2023), which in turn affects the quality of life of their caregivers and families.
  • AD Alzheimer’s disease
  • the hyperphosphorylation of tau contributes to the amyloid cascade which is responsible for the development of the disease
  • AD aducanumab and lecanemab two beta-amyloid targeting antibodies
  • AD pathology is characterised by formation of both neuronal tau fibrils and extracellular amyloid plaques.
  • the behavioral symptoms of AD correlate with the accumulation of plaques and tangles, and they are a direct consequence of the damage and destruction of synapses that mediate memory and cognition.
  • WO 2017/005734 describes tau-binding antibodies with a specificity to the central region of human tau. In a tau seeding experiment, these antibodies blocked the seeding of both human AD and PSP tau. Based on these results, targeting the central region of tau blocked the seeding of human tau, whereas targeting the N-terminal region did not.
  • the invention provides a tau-binding antibody or antigen-binding fragment thereof for use in a method of treating a tauopathy in a human subject in need thereof, the method comprising administering to the human subject at least one dose of 30 mg/kg to 120 mg/kg of the tau-binding antibody or antigen-binding fragment thereof, wherein the tau-binding antibody or antigen-binding fragment thereof comprises: a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3; and a heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No.: 6.
  • the invention further provides a fixed dosing approach based on which of two weight ranges a subject falls in.
  • the present invention further provides a tau-binding antibody or antigen-binding fragment thereof for use in a method of treating a tauopathy in a human subject in need thereof, the method comprising administering a fixed dose of the tau-binding antibody or antigen-binding fragment to the subject, wherein:
  • the subject has a body weight of 40 kg up to, but not including, 60 kg and the fixed dose is 4.5g to 5.5g of the tau-binding antibody or antigen-binding fragment;
  • the subject has a body weight of 60 kg to 100 kg and the fixed dose is 6.5g to 7.5g of the tau-binding antibody or antigen-binding fragment, wherein the tau-binding antibody or antigen-binding fragment thereof comprises: a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3; and a heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No.: 6.
  • FIG. 1 UP0047 - Dose proportionality of bepranemab exposure in serum (PK- PPS).
  • A Cmax;
  • B AUC.
  • AUC area under the concentration-time curve from time 0 to infinity;
  • AUC(O-t) area under the concentration-time curve from time 0 to time t;
  • CI confidence interval;
  • Cmax maximum observed concentration;
  • PK-PPS Pharmacokinetic-Per Protocol Set.
  • Regression line formula for AUC original values - linear scale
  • CI confidence interval
  • Cmax maximum observed concentration;
  • PK-PPS Pharmacokinetic-Per Protocol Set.
  • FIG. 1 UP0065 - Dose proportionality of bepranemab exposure in serum (PK-PPS).
  • A Cmax;
  • B AUC.
  • AUC area under the concentration-time curve from time 0 to infinity;
  • AUC(O-t) area under the concentration-time curve from time 0 to time t;
  • CI confidence interval;
  • Cmax maximum observed concentration;
  • PK PPS Pharmacokinetic-Per Protocol Set.
  • AUC dose proportionality in the exposure
  • Figure 9 Predicted bepranemab steady state average (Cavg) and maximal (Cmax) concentrations over a 40-100 kg body weight range, showing comparability in both parameters for fixed doses of 4.8 g (for 40- ⁇ 60 kg) and 7.2 g (for >60-100 kg) [red curve - in each graph the red curve is the one that starts second highest at the Y axis] versus a weight- adjusted dose of 90 mg/kg [blue curve - in each graph the blue curve is the one that lowest at the Y axis].
  • This invention pertains to methods of treating a tauopathy in which the administration of a tau-binding antibody is beneficial.
  • the present invention pertains to particularly effective doses and dosing regimens for treating tauopathies.
  • the present invention provides the methods themselves.
  • the present invention also provides tau binding antibodies and antigen-binding fragments thereof for use in such methods. It also provides use of tau binding antibodies and antigen-binding fragments thereof for the manufacture of a medicament for treating tauopathies.
  • the present invention is applicable to tauopathies in general, particular tauopathies of interest are Progressive Supranuclear Palsy (PSP) and Alzheimer’s Disease (AD).
  • PSP Progressive Supranuclear Palsy
  • AD Alzheimer’s Disease
  • the present application is based in part on the identification of particularly effective dose and dosing schedules for tau-binding antibodies or binding fragments thereof in the treatment of tauopathies.
  • the present section sets out examples of particular tau-binding antibodies and antigenbinding fragments thereof that may be used in the present invention.
  • Tau residue numbering in this text refers to Tau isoform 2 of SEQ ID No.: 11 (NCBI reference sequence: NP_005901.2).
  • the tau binding antibody or antigen-binding fragment thereof binds to the central region of the human tau protein.
  • the antibody or antigen-binding fragment thereof employed in the invention recognizes an epitope comprising at least the amino acids residues of S238, A239, S241, T245, A246 of SEQ ID No.: 11. This region is just before the first MTBR repeat region present in all 6 isoforms of Tau that may be found in the central nervous system.
  • the tau-binding antibody or binding fragment thereof binds to an epitope comprising the amino acid residues of S238, A239, S241, T245, A246, and one or more residues selected from S235, S237, K240, R242, L243, Q244, V248, and M250 of SEQ ID No.: 11.
  • the epitope bound by the tau-binding antibody or binding fragment thereof is determined by heteronuclear single quantum coherence nuclear magnetic resonance (HSQC NMR).
  • the antibody or antigen-binding fragment thereof is a monoclonal antibody or antigen-binding fragment thereof. In one particular embodiment the antibody or antigen-binding fragment thereof is a humanized monoclonal Tau-binding antibody or antigenbinding fragment thereof.
  • the tau-binding antibody or binding fragment thereof binds to both soluble human and paired helical filaments (PHF) of human tau.
  • WO 2017/005734 examples of antibodies and antigen-binding fragments thereof which may be employed in the present invention are described in WO 2017/005734.
  • WO 2017/005734 is incorporated by reference in its entirety. It is also incorporated by reference in relation to the tau binding antibodies and antigen-binding fragments thereof described.
  • Table 1 below sets out particular antibody sequences to be employed in the present invention as well as providing the amino acid sequence of human tau protein.
  • the tau-binding antibody or binding fragment thereof comprises a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3; and a heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No.: 6.
  • the tau-binding antibody or binding fragment thereof comprises a light chain variable region comprising SEQ ID No.: 7, and a heavy chain variable region comprising SEQ ID No.: 8.
  • the tau-binding antibody or binding fragment thereof comprises a light chain comprising SEQ ID No. : 9, and a heavy chain comprising SEQ ID No.: 10.
  • the antibody comprises two such heavy chains and two such light chains.
  • an antibody or antigen-binding fragment of the present invention may be provided in any suitable format.
  • an antibody or antigen-binding fragment thereof of the present invention may be an IgG class antibody or fragment thereof. In one embodiment, it may be an IgGl, IgG2, IgG3, or IgG4 isotype antibody and in particular IgGl.
  • an antibody of antigen-binding fragment thereof of the invention may be an IgA, IgE, IgD, or IgM class antibody. In a particular alternative embodiment, the antibody is a monoclonal IgG4 antibody.
  • the antibody employed is bepranemab.
  • bepranemab may be employed for any of the embodiments set out herein bepranemab.
  • Bioequivalents of bepranemab may also be employed.
  • Antibodies or antigen-binding fragments thereof that are able to crossblock any of the antibodies set out herein may be employed.
  • an antibody that is able to cross-block bepranemab is employed.
  • an antibody that is able to bind to substantially the same epitope of bepranemab is employed.
  • another name for bepranemab is UCB0107, and therefore these terms may be used interchangeably.
  • antibodies of the present disclosure refers to antibodies and antibody fragments. Wherever mention is made of an antibody an antibody fragment which is an antigen-binding fragment may be employed unless specifically stated otherwise.
  • antibodies of the present invention may comprise a complete antibody having full length heavy and light chains or be an antigen-binding fragment, for instance, a Fab, modified Fab, Fab’, modified Fab’, F(ab’)2, Fv, single domain antibody (e.g. VH or VL or VHH), scFv, bi, tri or tetra-valent antibody, Bis-scFv, diabody, triabody, tetrabody or epitope-binding fragments of any of the above (see for example Holliger and Hudson, 2005, Nature Biotech.
  • Multi-valent antibodies may comprise multiple specificities, e.g. bispecific or may be monospecific (see for example WO 92/22853, WO05/113605, W02009/040562 and W02010/035012).
  • the present invention is based on the identification of particularly effective dose of tau-binding antibody or antigen-binding fragment thereof for treating a tauopathy.
  • the doses are particularly effective for tau-binding antibodies or antigen-binding fragments thereof that bind the central region of tau protein, such as any of the antibodies and antigen- binding-fragments thereof disclosed in WO 2017/005732.
  • a dose is 30 mg/kg to 120 mg/kg of antibody or antigen-binding fragment thereof.
  • the dose is 30 mg/kg, 45 mg/kg, 60 mg/kg, 90 mg/kg or 120 mg/kg of antibody or antigen-binding fragment thereof. In one embodiment a dose is 45 mg/kg to 90 mg/kg. In a particular alternative embodiment of the invention a dose or doses of about 45 mg/kg or about 90 mg/kg of the tau-binding antibody or antigen-binding fragment thereof are employed. In an alternative embodiment of the invention a dose or doses of 45 mg/kg or 90 mg/kg of the tau- binding or antigen-binding fragment thereof are employed.
  • the dose is 40 mg/kg to 50 mg/kg. In another alternative embodiment, the dose is about 45 mg/kg.
  • Such doses may be administered to a patient with a tauopathy, such as any of those set out herein. In one embodiment, such doses are administered to a sufferer with AD. In another they are administered to a sufferer with PSP.
  • the dose is 85 mg/kg to 95 mg/kg. In another alternative embodiment, the dose is about 90 mg/kg.
  • Such doses may be administered to a patient with a tauopathy, such as any of those set out herein. In one embodiment, such doses are administered to a sufferer with AD. In another they are administered to a sufferer with PSP.
  • a fixed dose is given, rather than one based on mg/kg.
  • the fixed dose is from 3g to 10g.
  • the fixed dose is from 3g to 8g.
  • the fixed dose is from 4g to 8g.
  • a fixed dose is from 3g to 6g. In one embodiment it is from 3g to 5g. In another embodiment a fixed dose is from 5g to 9g. In one embodiment, it is from 6g to 8g.
  • a fixed dose of antibody or antigen-binding fragment thereof is administered, rather than based on a dosage calculated based on mg/kg and the exact bodyweight of the subject. In one embodiment, the dose given is based on what body weight range the subject falls in.
  • the subject has a body weight of 40 kg up to, but not including, 60kg and is given a fixed dose of 4.0g to 6.0g.
  • the fixed dose for that weight range is 4.5g to 5.5g.
  • the fixed dose for that weight range is 4.6g to 5.0g.
  • the fixed dose for that weight range is 4.7g to 4.9g.
  • the subject has a body weight of 40kg up to, but not including, 60kg and is given a fixed dose of 4.8g.
  • the subject has a body weight of 60kg up to 100kg and is given a fixed dose of 6.0g to 8.0g.
  • the fixed dose for that weight rage is 6.5g to 7.5g.
  • the fixed dose for that weight rage is 6.8g to 7.4g.
  • the fixed dose for that weight range is 7.0g to 7.4g.
  • the fixed dose for that weight range is 7.1g to 7.3g.
  • the subject has a body weight of 60kg up tolOOkg and is given a fixed dose of 7.5g.
  • a plurality of doses will be administered, for example at least 4 doses. In one alternative embodiment, at least 12 doses are administered. In a further embodiment, at least 20 doses are administered. In one embodiment from 4 to 30 doses are administered. In one embodiment, dosing is continued indefinitely.
  • tauopathies are neurodegenerative diseases of relatively slow progression, and the method of treating them according to the current invention is preferably able to slow progression of the symptoms, it is considered that a method according to the current invention will include administering the tau-binding antibody or binding fragment thereof to the human subject in need thereof for, at least 12 weeks, at least 24 weeks, at least 52 weeks, at least 68 weeks or at least 80 weeks, or until no longer clinically relevant. Given the nature of these diseases there is a potential requirement for life-time administration.
  • doses are administered at regular intervals, so that the intervals are the same or approximately the same each time.
  • doses are administered at intervals of 3 to 5 weeks.
  • doses are administered about monthly.
  • doses may be administered about every 4 weeks.
  • the tau-binding antibody is administered once every 4 +/- 1 weeks, or alternatively once every 21 to 35 days.
  • the tau-binding antibody or antigen-binding fragment thereof may be administered by any suitable route to the patient.
  • routes include intravenous, subcutaneous or intramuscular administration of the tau-binding antibody or antibody fragment to the individual in need thereof.
  • the route of administration is intravenous.
  • the administration is via intravenous injection.
  • the administration is via intravenous infusion.
  • the administration is subcutaneous.
  • Subcutaneous administration is advantageous because the patient may self-administer a therapeutic substance, e.g., a tau-binding antibody or antibody fragment thereof, which is convenient for both the patient and the health care provider.
  • the present invention provides a tau-binding antibody or antigenbinding fragment thereof for use in a method of treating a tauopathy in a human subject in need thereof, the method comprising administering to the human subject at least one dose of 30 mg/kg to 120 mg/kg of the tau-binding antibody or binding fragment thereof.
  • the tauopathy is AD. In another particular embodiment it is PSP.
  • the present invention provides a tau-binding antibody or antigenbinding fragment thereof for use in a method of treating a tauopathy in a human subject in need thereof, the method comprising administering to the human subject at least one dose of 30 mg/kg to 120 mg/kg of the tau-binding antibody or binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises: a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3; and a heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No.: 6.
  • the antibody is bepranemab.
  • the tauopathy is AD. In another particular embodiment it is PSP.
  • the present invention provides a tau-binding antibody or antigenbinding fragment thereof for use in a method of treating a tauopathy in a human subject in need thereof, the method comprising administering to the human subject a plurality of doses of 30 mg/kg to 120 mg/kg of the tau-binding antibody or binding fragment thereof, wherein the doses are administered 3 weeks to 5 weeks apart.
  • the antibody or antigenbinding fragment thereof comprises: a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3; and a heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No.: 6.
  • the antibody is bepranemab.
  • the tauopathy is AD. In one particular embodiment, it is PSP.
  • the present invention provides a tau-binding antibody or antigenbinding fragment thereof for use in a method of treating a tauopathy in a human subject in need thereof, the method comprising administering to the human subject a plurality of doses of 40 mg/kg to 50 mg/kg of the tau-binding antibody or binding fragment thereof, wherein the doses are administered 3 weeks to 5 weeks apart. In one particular embodiment, the doses are 4 weeks apart. In a preferred embodiment, the dose is about 45 mg/kg.
  • the antibody or antigen-binding fragment thereof comprises: a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3; and a heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No.: 6.
  • the antibody is bepranemab.
  • the tauopathy is AD. In one particular embodiment, it is PSP.
  • the present invention provides a tau-binding antibody or antigenbinding fragment thereof for use in a method of treating a tauopathy in a human subject in need thereof, the method comprising administering to the human subj ect a plurality of doses of 85 mg/kg to 95 mg/kg of the tau-binding antibody or binding fragment thereof, wherein the doses are administered 3 weeks to 5 weeks apart. In one embodiment, they are 4 weeks apart. In a particular embodiment, the dose is about 90 mg/kg.
  • the antibody or antigenbinding fragment thereof comprises: a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3; and a heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No.: 6.
  • the antibody is bepranemab.
  • the tauopathy is AD. In one particular embodiment, it is PSP.
  • the present invention provides a tau-binding antibody or antigenbinding fragment thereof for use in a method of treating PSP in a human subject in need thereof, the method comprising administering to the human subject a plurality of doses of 85 mg/kg to 95 mg/kg of the tau-binding antibody or binding fragment thereof, wherein the doses are administered 3 weeks to 5 weeks apart. In a particular embodiment, the dose is about 90 mg/kg.
  • the antibody or antigen-binding fragment thereof comprises: a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3; and a heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No.: 6.
  • the antibody is bepranemab.
  • the present invention provides a tau-binding antibody or antigenbinding fragment thereof for use in a method of treating AD in a human subject in need thereof, the method comprising administering to the human subject a plurality of doses of 40 mg/kg to 50 mg/kg of the tau-binding antibody or binding fragment thereof, wherein the doses are administered 3 weeks to 5 weeks apart. In a particular embodiment, the dose is about 45 mg/kg.
  • the antibody or antigen-binding fragment thereof comprises: a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3; and a heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No.: 6.
  • the antibody is bepranemab.
  • at least 10 doses are administered.
  • at least 20 doses are administered.
  • the present invention provides a tau-binding antibody or antigenbinding fragment thereof for use in a method of treating AD in a human subject in need thereof, the method comprising administering to the human subject a plurality of doses of 85 mg/kg to 95 mg/kg of the tau-binding antibody or antigen-binding fragment thereof, wherein the doses are administered 3 to 5 weeks apart. In a particular embodiment, the dose is about 90 mg/kg.
  • the antibody or antigen-binding fragment thereof comprises: a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3; and a heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No.: 6.
  • the antibody is bepranemab.
  • at least 10 doses are administered.
  • at least 20 doses are administered.
  • the administration is intravenous. In one more particular embodiment, it is via intravenous infusion. In another, it is via subcutaneous injection.
  • the doses are administered about once a month or once every 4 weeks.
  • Illustrative fixed dose regimens for subjects with body weight 40kg up to, but not including 60 kg the present invention provides a tau-binding antibody or antigenbinding fragment thereof for use in a method of treating a tauopathy in a human subject in need thereof, the method comprising administering to the human subject having a body weight of 40kg up to, but not including 60 kg at least one dose of 4.0g to 5.5g of the tau-binding antibody or binding fragment thereof.
  • the tauopathy is AD.
  • it is PSP.
  • the dose is 4.5g to 5.0g.
  • the dose is 4.8g.
  • the present invention provides a tau-binding antibody or antigenbinding fragment thereof for use in a method of treating a tauopathy in a human subject in need thereof having a body weight of 40kg up to, but not including 60 kg, the method comprising administering to the human subject at least one dose of 4.5g to 5.5g of the tau-binding antibody or binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises: a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No. : 2, and a CDR3 selected from SEQ ID No.
  • the antibody is bepranemab.
  • the tauopathy is AD. In another particular embodiment it is PSP.
  • the dose is 4.5g to 5.0g. In one embodiment, the dose is 4.8g.
  • the present invention provides a tau-binding antibody or antigenbinding fragment thereof for use in a method of treating a tauopathy in a human subject in need thereof having a body weight of 40kg up to, but not including 60 kg, the method comprising administering to the human subject a plurality of doses of 4.5g to 5.5g of the tau-binding antibody or binding fragment thereof, wherein the doses are administered 3 weeks to 5 weeks apart.
  • the antibody or antigen-binding fragment thereof comprises: a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3; and a heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No.: 6.
  • the antibody is bepranemab.
  • the tauopathy is AD. In one particular embodiment, it is PSP.
  • the dose is 4.5g to 5.0g. In one embodiment, the dose is 4.8g.
  • the present invention provides a tau-binding antibody or antigenbinding fragment thereof for use in a method of treating a tauopathy in a human subject in need thereof, the method comprising administering to the human subject having a body weight of 40kg up to, but not including 60 kg a plurality of doses of 4.5g to 5.0g of the tau-binding antibody or binding fragment thereof, wherein the doses are administered 3 weeks to 5 weeks apart. In one particular embodiment, the doses are 4 weeks apart. In a preferred embodiment, the dose is about 4.6g to 4.9 g.
  • the antibody or antigen-binding fragment thereof comprises: a light chain variable region comprising a CDR1 selected from SEQ ID No.
  • the antibody is bepranemab.
  • the tauopathy is AD. In one particular embodiment, it is PSP. In one embodiment, the dose is 4.8g.
  • the administration is intravenous. In one more particular embodiment, it is via intravenous infusion. In another, it is via subcutaneous injection.
  • the doses are administered about once a month or once every 4 weeks.
  • the present invention provides a tau-binding antibody or antigenbinding fragment thereof for use in a method of treating a tauopathy in a human subject in need thereof, the method comprising administering to the human subject having a body weight of 60kg up to 100 kg at least one dose of 6.5g to 7.5g of the tau-binding antibody or binding fragment thereof.
  • the tauopathy is AD.
  • it is PSP.
  • the dose is 7.0 to 7.5g.
  • the dose is 7.2g.
  • the present invention provides a tau-binding antibody or antigenbinding fragment thereof for use in a method of treating a tauopathy in a human subject in need thereof having a body weight of 60kg up to 100 kg, the method comprising administering to the human subject at least one dose of 6.5g to 7.5g of the tau-binding antibody or binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises: a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3; and a heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No.: 6.
  • the antibody is bepranemab.
  • the tauopathy is AD.
  • it it is PSP.
  • the dose is 7.0 to 7.5g.
  • the dose is 7.0 to 7.5g.
  • the present invention provides a tau-binding antibody or antigenbinding fragment thereof for use in a method of treating a tauopathy in a human subject in need thereof having a body weight of 60kg up to 100kg, the method comprising administering to the human subject a plurality of doses of 6.5g to 7.5g of the tau-binding antibody or binding fragment thereof, wherein the doses are administered 3 weeks to 5 weeks apart.
  • the antibody or antigen-binding fragment thereof comprises: a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3; and a heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No.: 6.
  • the antibody is bepranemab.
  • the tauopathy is AD.
  • it it is PSP.
  • it is PSP.
  • the dose is 7.0 to 7.5g. In one embodiment, the dose is 7.2g.
  • the present invention provides a tau-binding antibody or antigenbinding fragment thereof for use in a method of treating a tauopathy in a human subject in need thereof, the method comprising administering to the human subject having a body weight of 60kg up to 100 kg a plurality of doses of 6.5g to 7.5g of the tau-binding antibody or binding fragment thereof, wherein the doses are administered 3 weeks to 5 weeks apart. In one particular embodiment, the doses are 4 weeks apart. In a preferred embodiment, the dose is about 45 mg/kg.
  • the antibody or antigen-binding fragment thereof comprises: a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3; and a heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No.: 6.
  • the antibody is bepranemab.
  • the tauopathy is AD.
  • it it is PSP.
  • it is PSP.
  • the dose is 7.0 to 7.5g. In one embodiment, the dose is 7.2g.
  • the administration is intravenous. In one more particular embodiment, it is via intravenous infusion. In another, it is via subcutaneous injection.
  • the doses are administered about once a month or once every 4 weeks.
  • a subject alters body weight they will be moved to the appropriate fixed dose for the weight range they fall in, so either that for 40kg up to, but not including 60kg, or that for 60kg up to 100kg.
  • the present disclosure sets out a tau-binding antibody or antigen-binding fragment thereof for use in various methods of treatment.
  • the present invention also provides the methods themselves. It also provides for the use of a tau-binding antibody or antigen-binding fragment thereof in the manufacture of a medicament for treating a tauopathy as set out.
  • a tau-binding antibody or antigen-binding fragment thereof for use a method of treatment, or use in the manufacture of a medicament is set out, the equivalent other format is also provided.
  • the tau-binding antibody or antibody fragment of the invention can be incorporated into pharmaceutical composition.
  • a pharmaceutical composition comprising the antibody or antigenbinding fragment thereof may be provided or employed.
  • the pharmaceutical composition comprises the tau-binding antibody or antibody fragment of the invention and/or a pharmaceutically acceptable carrier and/or other active ingredient such as galantamine, rivastigmine, or donepezil.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible and are suitable for administration to a subject for the methods described herein.
  • pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof.
  • isotonic agents for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition.
  • compositions of this invention may be in a variety of forms. These include, for example, liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, powders and liposomes. The preferred form depends on the intended mode of administration and therapeutic application. Typical preferred compositions are in the form of injectable or infusible solutions, such as compositions similar to those used for passive immunization of humans with other antibodies.
  • the formulation is specific for one of the administration routes set out herein, for instance compositions suitable for administration to a subject intravenously, subcutaneously or intramuscularly may be provided.
  • a pharmaceutical composition comprising the tau-binding antibody or antigen-binding fragment according to any of the embodiments of the invention and a pharmaceutically acceptable carrier wherein the composition is prepared for intravenous, subcutaneous or intramuscular administration to the individual in need thereof.
  • composition is part of a kit with instructions for use, including instructions and optionally a device for intravenous, subcutaneous or intramuscular administration to the individual in need thereof.
  • instructions set out a dosage and/or regimen as disclosed herein.
  • the present invention may be used to treat tauopathies in general.
  • tauopathies to be treated are Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration and Alzheimer’s disease (AD).
  • PSP Progressive Supranuclear Palsy
  • AD Alzheimer’s disease
  • the tauopathy is PSP or AD.
  • PSP Progressive supranuclear palsy
  • pathological tau which spreads through the brain, causing neurodegeneration and resultant brain atrophy
  • Pathology in PSP begins with tau accumulation in subcortical and brainstem nuclei, the globus pallidus and striatum, regions associated with symptoms such as postural instability, sleep disorders, ocular motor dysfunction, and Parkinsonism.
  • tau accumulation in cortical areas including the frontal, parietal, and temporal lobes, which are associated with symptoms such as cognitive impairment and behavioural alterations, apraxia, and impaired language function, respectively (Coughlin et al. Parkinsonism Relat Disord 2020; 73: 105-16).
  • symptoms such as cognitive impairment and behavioural alterations, apraxia, and impaired language function, respectively.
  • PSP RS Richardson syndrome
  • PSP P PSP predominant parkinsonism
  • PGP PGF PSP progressive gait freezing
  • the tauopathy is selected from PSP RS, PSP P and PSP PGF.
  • PSP RS Planar ophthalmoplegia
  • Disease progression is rapid and relentless, with increased physical disability; on average, PSP RS advances from symptom onset to death in 7 years, with a dependency on care developing within 3-4 years from presentation (Williams et al Brain 2005; 128: 1247-58; Hoglinger et al Mov Disord 2017; 32: 853-64).
  • the average age at death in people with PSP-RS is earlier at 72.1 years, compared with 75.5 years in people with PSP P.
  • a treatment of the invention results in a slowing of disease progression as measured by adequate rating tools recommended by the regulatory agencies.
  • PSP Rating Scale is a prospectively validated physician-rated measure of disease severity for PSP, measured by 28 items within 6 categories: daily activities, mentation, bulbar, ocular motor, limb motor, and gait/midline exam. The rater assigns 0-2 or 0-4 points for each item, yielding a total PSPRS score from 0-100. Higher PSPRS scores indicate higher degrees of disease severity, with higher functional impairment. Previous studies that utilized the PSPRS as a primary endpoint indicate annual increases in the total PSPRS score between 10 and 12. A reduction of progression in PSP by -40% is considered clinically meaningful (Donker Kaat et al. Parkinsonism Relat Disord 2018; 56: 98- 101).
  • the present invention results in a slowing of disease progression as measured by the PSP-Rating Scale, wherein said reduction of disease progression is obtained for at least one of the indices selected from the PSP-Rating Scale.
  • said reduction of disease progression is at least 20%, at least 25%, at least 30%, at least 35% or at least 40% according to the PSP-Rating Scale.
  • CAFS Combined Assessment of Function and Survival
  • ALS amyotrophic lateral sclerosis
  • CAFS would rank patient clinical outcomes based on survival time and change in the PSP-Rating Scale. Consequently, in a further embodiment the subject treated achieves a reduction in disease progression according to the Combined Assessment of Function and Survival with respect to PSP.
  • the Schwab and England ADL (Activities of Daily Living) scale (also known as SEADL scale) is a method of assessing the capabilities of people with impaired mobility.
  • the scale uses percentages to represent how much effort and dependence on other people need to complete daily chores. The rating may be given by a professional or by the person being tested.
  • PSP Activity of Daily Living
  • the subject treated achieves a slowing of disease progression as measured by the SEADL scale.
  • one of the features of PSP is progressive brain atrophy. Therefore, in a further alternative embodiment, the subject treated achieves a reduction in the progression of brain atrophy. Measurement of brain atrophy is performed routinely by a person of ordinary skill in the art with available techniques in a neurology unit, such as for example by Volumetric MRI or Computed Tomography (CT) scan. In a further alternative embodiment, the subject treated achieves a reduction in the progression of brain atrophy as measured by Volumetric MRI. Alternatively, in another particular embodiment the treated subject achieved a reduction in the progression of brain atrophy as measured by CT scan.
  • CT scan Computed Tomography
  • the tauopathy is Alzheimer’s disease.
  • three stages of Alzheimer’s disease are recognized: early stage or mild AD, middle stage or moderate AD and late stage or severe AD, according to the severity of symptoms. Therefore, in a particular embodiment of the method of the invention the tauopathy is early AD (prodromal and mild). In another it is moderate AD. In another it is severe AD. In one embodiment, the invention slows or stops progression from one of those forms of AD to a more severe form.
  • Alzheimer’s disease is considered a secondary tauopathy, where the degree of tau accumulation in the brain appears to correlate with cognitive decline, highlighting the relevance of tau in this disease.
  • Cognitive decline in Alzheimer’s disease may be determined according to a number of established rating tools including the Clinical Dementia Rating, Alzheimer’s disease assessment scale-cognitive subscale, Amsterdam-Instrument Activities of Daily Living Questionnaire, Repeatable Battery for the Assessment of Neuropsychological Status, Alzheimer’s disease Cooperative Study-Activities of Daily Living, Mini-Mental State Examination, Alzheimer’s disease Composite Score, or Integrated Alzheimer’s disease Rating Scale. Accordingly, in one embodiment, the invention results in a slowing of disease progression according to any one of the above tools. These tools are used to both help diagnose the disease but also to monitor disease progression.
  • the global CDR score is established by clinical scoring rules and has values of 0 (no dementia), 0.5, (questionable dementia), 1 (mild dementia), 2 (moderate dementia), and 3 (severe dementia).
  • the CDR-SB (CDR Sum of Boxes) is obtained by adding the ratings in each of the 6 categories and ranges from 0 to 18 with higher scores indicative of greater impairment; it typically provides more information in cases of mild dementia than the global CDR score.
  • the CDR/CDR- SB is administered to the patient and informant separately by a trained rater and takes approximately 40 to 75 minutes.
  • the Alzheimer’s Disease Assessment Scale-Cognitive Subscale or ADAS-Cogl4 is a composite scale (neuropsychological test battery and clinician reported outcome) that evaluates memory, orientation, attention, reasoning, language, and constructional praxis. Higher scores indicate greater impairment, with a minimum of 0 and a maximum of 90.
  • the ADAS Cogl4 is administered to the patient by a trained rater and takes approximately 30-45 minutes.
  • the Amsterdam-Instrumental Activities of Daily Living Questionnaire or A-iADL is an adaptive and computerized observer-reported outcome measure designed to assess impairments in instrumental activities of daily living (iADL) in early dementia.
  • the questionnaire is administered to an informant such as a relative or friend, with every effort made to use the same informant for a particular study participant throughout the study.
  • the questionnaire consists of 70 items in 7 categories, which takes approximately 20 to 25 minutes to complete.
  • the A-iADL assesses impairments in a broad range of daily activities including household activities, household appliances, finances, work, computer, appliances, leisure activities.
  • the scoring range is 20 to 80 using an item response theory algorithm, with higher scores indicating better functioning.
  • the A- iADL will be administered by a trained rater.
  • the Repeatable Battery for the Assessment of Neuropsychological Status or RBANS is a neuropsychological test battery that was developed for screening dementia.
  • the RBANS consists of 12 subtests, which give 5 Index scores, one for each of the five domains tested, and a Total Scale Score:
  • Index scores have a mean of 100 and a standard deviation (SD) of 15, all of which are corrected for age and education.
  • RBANS is administered to the patient by a trained rater and takes approximately 30 to 45 minutes to administer.
  • the Alzheimer’s Disease Cooperative Study-Activities of Daily Living is an observer (informant)-reported outcome measure that assesses impairments in basic activities of daily living (bADLs) and iADLs.
  • the ADCS ADL is a 23-item scale that includes 6 bADL items and 17 iADL items (the 17 items used in Integrated Alzheimer’s Disease Rating Scale [iADRS]) that score from 0 to 78, with a lower score indicating greater severity.
  • the ADCS-ADL is administered by a trained rater and takes approximately 30 to 45 minutes to complete.
  • the Mini -Mental State Examination or MMSE is an 11 -item neuropsychological test that is used to assess cognitive status in adults, and can be used to screen for cognitive impairment and to estimate severity of cognitive impairment. It assesses orientation, memory, attention, ability to name, ability to follow verbal and written commands, ability to write a sentence and to copy a drawing.
  • the MMSE is administered by a trained rater and takes approximately 10 to 15 minutes to complete. The score ranges from 0 to 30. Lower scores are indicative of poorer cognitive performance.
  • ADCOMS Alzheimer’s Disease Composite Score
  • the ADCOMS is a composite score that includes 2 MMSE items, 6 CDR-SB items, and 4 ADAS Cogl4 subscales and is considered to be more sensitive to change and treatment effects than individual study instruments. There is no action for the site/Investigator to perform to achieve collection of the ADCOMS.
  • the ADAS-Cogl4 may be combined with the ADCS-ADL score to form the iADRS or Integrated Alzheimer’s Disease Rating Scale.
  • the iADRS is a linear combination of the ADAS- Cogl4 and the instrumental items of the ADCS-ADL.
  • iADRS [-1(ADAS-Cogl4) + 90] + iADL
  • the total range of the iADRS is 0 to 146, with lower scores indicating worse performance.
  • the iADRS has been shown to be composed of 2 principal components, cognition, and instrumental function. It has been shown to be more responsive to disease progression in MCI and AD than previous versions of the ADAS-Cog, or the ADAS Cogl4 alone. There is no action for the site/Investigator to perform to achieve collection of the iADRS.
  • Mitochondrial impairment can also be a feature of taupoathies.
  • treatment with an antibody or antigen-binding fragment thereof of the present invention may help restore mitochondrial function in a tauopathy.
  • mitochondrial membrane potential may be affected, and treatment with an antibody or antigen-binding fragment thereof may help restore mitochondrial membrane potential to, or towards, normal levels.
  • the subject to be treated is one that displays mitochondrial dysfunction.
  • the subject may be one who displays altered mitochondrial membrane potential.
  • the subject displays lowered membrane potential.
  • the subject displays raised membrane potential and in particular displays such raised membrane potential and has a 10+16 MAPT mutation.
  • such a subject may display excess 4R tau protein isoforms.
  • the subject has a P301L mutation and in particular may display hyperpolarised mitochondrial membranes.
  • employing the invention may mean that mitochondrial membrane potential may return, or at least be closer to, normal.
  • the term “obtained” is considered to be a preferred embodiment of the term “obtainable”. If hereinafter e.g. an antibody is defined to be obtainable from a specific source, this is also to be understood to disclose an antibody which is obtained from this source.
  • treatment refers to obtaining a desired pharmacologic and/or physiologic effect.
  • the effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of slowing the progression or, obtaining a partial or complete cure for a disease and/or adverse effect attributable to the disease.
  • Treatment thus covers any treatment of a disease in a human subject, and includes: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., causing regression of the disease.
  • the present disclosure sets out various approaches for assessing tauopathy patients, including in particular for assessing PSP and AD.
  • tau-binding antibody or antigen-binding fragment thereof for use according to [1] or [2], wherein the dose or doses are each 40 mg/kg to 50 mg/kg of the tau-binding antibody or antigen-binding fragment thereof and are optionally about 45 mg/kg of the antibody or antigenbinding fragment thereof.
  • tau-binding antibody or antigen-binding fragment thereof for the use according to any one of [1] to [3], wherein the dose or doses are each 85 mg/kg to 95 mg/kg of the tau-binding antibody or antigen- binding fragment thereof and are optionally about 90 mg/kg of the antibody or antigen-binding fragment thereof.
  • tau-binding antibody or antigen-binding fragment thereof for use according to any one of [1] to [6], wherein the tau-binding antibody or antigen-binding fragment thereof is administered to the human subject in need thereof for at least 12 weeks, at least 24 weeks, at least 52 weeks, at least 68 weeks or at least 80 weeks.
  • tau-binding antibody or antigen-binding fragment thereof according to any one of [1] to [7], wherein the tau-binding antibody or antigen-binding fragment thereof binds to an epitope comprising the amino acid residues of S238, A239, S241, T245, A246, of SEQ ID No.: 11, optionally wherein the epitope further comprises one or more residues selected from S235, S237, K240, R242, L243, Q244, V248, and M250 of SEQ ID No.: 11.
  • tau-binding antibody or antigen-binding fragment thereof for use according to any one of [1] to [8], wherein the tau-binding antibody or anti gen -binding fragment thereof binds to both soluble human and paired helical filaments (PHF) of human tau.
  • PHF paired helical filaments
  • tau-binding antibody or antigen -binding fragment thereof for use according to any one of [1] to [9], wherein the tau-binding antibody or antigen-binding fragment thereof comprises a light chain variable region comprising SEQ ID No.: 7, and a heavy chain variable region comprising SEQ ID No.: 8.
  • tau-binding antibody or antigen -binding fragment thereof for use according to any one of [1] to [10], wherein the tau-binding antibody or antigen-binding fragment thereof comprises a light chain comprising SEQ ID No.: 9, and a heavy chain comprising SEQ ID No.: 10.
  • the tau-binding antibody or antigen -binding fragment thereof for use according to any one of [1] to [11], wherein the tau-binding antibody or antigen-binding fragment thereof is a monoclonal humanized antibody.
  • tau-binding antibody or antigen-binding fragment thereof for use to any one of [1] to [12], wherein the tau-binding antibody or antigen-binding fragment thereof is administered intravenously.
  • tau-binding antibody or antigen -binding fragment thereof for use according to any one of [1] to [13], wherein the tauopathy is selected from progressive supranuclear palsy (PSP), corticobasal degeneration and Alzheimer’s disease (AD).
  • PSP progressive supranuclear palsy
  • AD Alzheimer’s disease
  • tau-binding antibody or antigen-binding fragment thereof for use according to any one of [1] to [14], wherein the tauopathy is Alzheimer’s disease (AD), optionally wherein the subject treated achieves a slowing of disease progression as measured by Clinical Dementia Rating score, Clinical Dementia Rating Memory Box, the delayed recall domain of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), or mini-mental state examination (MMSE)
  • AD Alzheimer’s disease
  • RBANS Clinical Dementia Rating Memory Box
  • MMSE mini-mental state examination
  • tau-binding antibody or antigen -binding fragment thereof for use according to any one of [1] to [15], wherein the tauopathy is progressive supranuclear palsy (PSP), optionally wherein the method achieves a slowing of disease progression as measured by the PSP-Rating Scale.
  • PSP progressive supranuclear palsy
  • tau-binding antibody or antigen-binding fragment thereof in the manufacture of a medicament for the treatment of a tauopathy, wherein at least one dose of 30 mg/kg to 120 mg/kg of the tau-binding antibody or binding fragment thereof is administered to a human subject in need thereof, wherein the tau-binding antibody or binding fragment thereof comprises: a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3; and a heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No.: 6.
  • a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3
  • a heavy chain variable region comprising a CDR1 selected
  • UP0047 was a Phase 1, first-in-human, placebo-controlled, participant-blind, investigator blind, single-dose, dose-escalation study of intravenous (iv) bepranemab in healthy participants (NCT03464227). The study was conducted in Germany. The present Example describes a further study in healthy patients, UP0065. The primary objective of UP0065 was to assess the safety, tolerability and serum PK of a single-dose of bepranemab in healthy Japanese study participants, in order to determine whether these differed from the safety, tolerability and PK assessments in Caucasian participants in UP0047. An exploratory objective of the study was to assess the incidence and emergence of AD As in serum (immunogenicity).
  • PSP003 is a randomised, double-blind, placebo-controlled, phase lb study designed to primarily assess the safety and tolerability of bepranemab in 25 study participants with PSP (NCT04185415). The study was conducted in a hospital setting across 13 centres in Belgium, Spain, Germany, and the UK. Study participants received either intravenous (iv) 90 mg/kg bepranemab or a matching volume of placebo at each infusion time point, once every four weeks over a 52-week treatment period, for a maximum of 13 infusions per study participant.
  • iv intravenous
  • Blood and CSF samples were collected to measure concentrations of bepranemab, antidrug antibodies and for biomarker research (Figure 3). Lumbar punctures were performed before dosing. CSF sampling was carried out at baseline and day 7 (with a 14-day window in between); each CSF sample was split into aliquots for PK analyses, biomarker analyses, quality control, and biorepository samples (if consent was provided). Blood samples for coagulation parameters and platelets counts were taken and the results were evaluated before the lumbar puncture. Blood draws were performed via venipuncture and the sample divided into two aliquots for PK analyses. Postdose PK samples were only collected for the first two infusions; for all subsequent infusions only trough samples were taken.
  • PSPRS Progressive Supranuclear Palsy rating scale
  • Serial structure brain MRIs were performed to detect eventual emergent alterations in brain structure at timepoints specified in Figure 3. At any time during the study, additional brain MRIs or MRI sequences may have been performed in any study participant if deemed appropriate by the Investigator/local radiologist.
  • Figures 4 and 5 summarise the treatment-emergent adverse events (TEAEs) from baseline to last visit and most frequent TEAEs observed in PSP003.
  • bepranemab-tau refers to those species of tau present in the CSF containing the epitopes for both bepranemab and the detection antibody.
  • the baseline (pre-dose) value of free bepranemab-tau species was taken as the 100% value, and this was used to assess the reduction of measured tau species.
  • the term ‘free’ indicates tau species that have not been bound by bepranemab and are still detectable in the assay. Hence, before bepranemab treatment, all bepranemab-tau species are free and after treatment, only a proportion will remain free, depending on the administered dose of bepranemab.
  • the concentrations of free bepranemab-tau in CSF changed from baseline to week 1 as follows: four participants (26.7%) had 25-100% of baseline free tau, nine participants (60.0%) had 10-25% of baseline free tau, and two participants (13.3%) had 0-10% of baseline free tau.
  • *CI is based on the assumption that the data is normally distributed.
  • AH0003 (NCT04867616) is a global, multicenter, patient-blind, investigator-blind, placebo-controlled, parallel-group study, investigating the efficacy, safety, and tolerability of bepranemab (administered intravenously, every 4 weeks) versus placebo in patients with prodromal (40%) or mild (60%) AD over an 80-week treatment period, followed by an optional 48-week open-label extension (OLE).
  • the primary objective is the change from baseline to Week 80 in the Clinical Dementia Rating (CDR) Scale Sum of Boxes total score.
  • CDR Clinical Dementia Rating
  • PK pharmacokinetics
  • PET tau positron emission tomography
  • ADAS-Cogl4 14-item Alzheimer’s Disease Assessment Scale-Cognitive Subscale
  • MMSE Mini -Mental State Examination
  • the OLE will assess the long-term safety and tolerability of bepranemab. Approximately 150 patients per arm will be enrolled across 3 study arms (45 mg/kg and 90 mg/kg bepranemab, and placebo; randomized 1 :1 : 1).
  • Eligible patients will meet the National Institute of Aging- Alzheimer’ s Association (NIA- AA) 2018 Stage 3 or 4 definitions of prodromal or mild AD, respectively.
  • Patients will have a global CDR score indicative of prodromal AD (0.5) or mild AD (0.5 or 1.0) and a CDR-Memory Box score >0.5 at screening and baseline.
  • Patients will have a score of ⁇ 85 for the delayed recall domain of the Repeatable Battery for the Assessment of Neuropsychological Status, MMSE >20 at screening and must meet the NIA-AA 2018 definition of cerebral beta-amyloid (AP) accumulation, by either a positive centrally read PET scan or a positive cerebrospinal fluid pTau!81/Api-42 ratio.
  • Example 4 Body weight-tiered fixed dosing based on modeling & simulation
  • a population pharmacokinetic (PopPK) model was developed based on data from study UP0047 (with i.v. bepranemab doses of 0.3-120 mg/kg were administered), which characterized the dependency of bepranemab clearance and distribution volume.
  • PopPK population pharmacokinetic

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Abstract

La présente invention concerne un anticorps de liaison à la protéine tau ou un fragment de liaison à l'antigène de celui-ci destiné à être utilisé dans une méthode de traitement d'une tauopathie chez un sujet humain en ayant besoin, l'anticorps ou le fragment de liaison à l'antigène de celui-ci étant administré selon un schéma posologique particulier.
PCT/EP2025/057692 2024-03-21 2025-03-20 Traitement de tauopathies avec des anticorps se liant à la protéine tau Pending WO2025196217A1 (fr)

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