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WO2025170969A1 - Méthodes de traitement de l'amylose al - Google Patents

Méthodes de traitement de l'amylose al

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Publication number
WO2025170969A1
WO2025170969A1 PCT/US2025/014544 US2025014544W WO2025170969A1 WO 2025170969 A1 WO2025170969 A1 WO 2025170969A1 US 2025014544 W US2025014544 W US 2025014544W WO 2025170969 A1 WO2025170969 A1 WO 2025170969A1
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WO
WIPO (PCT)
Prior art keywords
slowing
decline
physical
points
antibody
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Pending
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PCT/US2025/014544
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English (en)
Inventor
Katherine Ingrid SPRINZ
Cheng-Yow Timothy LIN
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Prothena Biosciences Ltd
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Prothena Biosciences Ltd
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Publication of WO2025170969A1 publication Critical patent/WO2025170969A1/fr
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Classifications

    • 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
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/02—Detecting, measuring or recording for evaluating the cardiovascular system, e.g. pulse, heart rate, blood pressure or blood flow
    • A61B5/0205—Simultaneously evaluating both cardiovascular conditions and different types of body conditions, e.g. heart and respiratory condition
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/02—Detecting, measuring or recording for evaluating the cardiovascular system, e.g. pulse, heart rate, blood pressure or blood flow
    • A61B5/026—Measuring blood flow
    • A61B5/029—Measuring blood output from the heart, e.g. minute volume
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/103—Measuring devices for testing the shape, pattern, colour, size or movement of the body or parts thereof, for diagnostic purposes
    • A61B5/11—Measuring movement of the entire body or parts thereof, e.g. head or hand tremor or mobility of a limb
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/42—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins
    • C07K16/4283—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an allotypic or isotypic determinant on Ig
    • 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
    • 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
    • A61K2039/55—Medicinal preparations containing antigens or antibodies characterised by the host/recipient, e.g. newborn with maternal 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

Definitions

  • BACKGROUND Light chain (AL) amyloidosis is a rare, progressive, and typically fatal disease caused by circulating toxic light chain aggregates and insoluble amyloid that deposits in vital organs, leading to organ dysfunction and failure.
  • AL amyloidosis and cardiac involvement have high symptom burden and poor physical function, resulting in reduced health-related quality of life (HRQoL).
  • HRQoL health-related quality of life
  • treatment side effects also have negative impacts on patients’ lives.
  • the outcome of the disease for patients with AL amyloidosis can be predicted based on the Mayo four stage prognostic staging system discussed in Kumar et al., 2012 (Kumar et al., Revised Prognostic Staging System for Light Chain Amyloidosis Incorporating Cardiac Biomarkers and Serum Free Light Chain Measurements, J Clin Oncol.30:989-995 (2012)), with the outcome for Mayo Stage IV patients being quite dire.
  • Current treatment of patients with AL amyloidosis is aimed at reducing or eliminating the bone marrow disorder, i.e., the plasma cells that are responsible for producing the light chains, thereby limiting or halting the production of amyloid.
  • the most aggressive treatment Attorney Docket No.50887-0050WO1 options include stem cell transplant and high-dose chemotherapy for those patients who can tolerate it.
  • Other treatment regimens include combinations of drugs often used to treat hematological malignancies, such as melphalan, prednisone, dexamethasone and proteosome inhibitors such as bortezomib, in an attempt to reduce light chain production.
  • drugs often used to treat hematological malignancies, such as melphalan, prednisone, dexamethasone and proteosome inhibitors such as bortezomib, in an attempt to reduce light chain production.
  • the present disclosure provides a method of slowing a decline in social functioning in a subject having Mayo Stage IV AL amyloidosis, comprising administering to the subject an effective dosage of an antibody which competes for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin with 2A4 (ATCC Accession Number PTA-9662) or 7D8 (ATCC Accession Number PTA-9468), or competes for binding to kappa light chain immunoglobulin with 11-1F4 (ATCC Accession Number PTA-105).
  • the present disclosure provides a method of slowing a decline in Health-Related Quality of Life (HRQoL) in a subject having AL amyloidosis, comprising administering to the subject an effective dosage of an antibody which competes for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin with 2A4 (ATCC Accession Number PTA-9662) or 7D8 (ATCC Accession Number PTA-9468), or competes for binding to kappa light chain immunoglobulin with 11-1F4 (ATCC Accession Number PTA-105), wherein the slowing of the decline in HRQoL comprises a slowing of a decline in at least one of the following: physical functioning (PF), role physical (RP), bodily pain (BP), general health (GH), vitality (VT), social functioning (SF), role emotional (RE), mental health (MH), and mental component score (MCS).
  • PF physical functioning
  • RP role physical
  • BP bodily pain
  • GH general health
  • the slowing of the decline in HRQoL further comprises a slowing of a decline in physical component score (PCS).
  • PCS physical component score
  • the slowing of the decline in physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, mental health, mental component score and/or physical component score is assessed using the 36- Item Short Form Survey (SF-36) or the 36-Item Short Form Survey Version 2 (SF-36v2).
  • the present disclosure provides a method of treating Mayo Stage IV AL amyloidosis in a subject, comprising administering to the subject an effective dosage of Attorney Docket No.50887-0050WO1 an antibody which competes for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin with 2A4 (ATCC Accession Number PTA-9662) or 7D8 (ATCC Accession Number PTA-9468), or competes for binding to kappa light chain immunoglobulin with 11-1F4 (ATCC Accession Number PTA-105); wherein treating comprises a slowing of a decline in social functioning in the subject. In some embodiments, the method comprises a slowing of a decline in social functioning in the subject.
  • the slowing of the decline in social functioning is assessed using the SF-36 or the SF-36v2.
  • the slowing of the decline in social functioning comprises a higher score on a social functioning domain of an SF-36 or SF-36v2 relative to a different patient at the same time point who has not been administered the antibody.
  • the slowing of the decline in social functioning comprises a decrease of less than about 20 points on the social functioning domain of the SF-36v2 compared to baseline.
  • the slowing of the decline in social functioning comprises a decrease of less than about 10 points on the social functioning domain of the SF- 36v2 compared to baseline.
  • the light chain variable region comprises the amino acid sequence set forth as SEQ ID NO: 1 or 14, and the heavy chain variable region comprises the amino acid sequence set forth as SEQ ID NO: 2 or 15.
  • the antibody comprises a light chain comprising the amino acid sequence set forth as SEQ ID NO:10, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 11, 12 or 13.
  • the antibody comprises a light chain comprising the amino acid sequence set forth as SEQ ID NO:10, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO:12.
  • the antibody is a Fab, Fab’, F(ab’)2, F(ab)c, Dab, nanobody, or Fv.
  • the slowing of the decline in HRQoL includes a higher score on at least one of the following domains of an SF-36 or SF-36v2 relative to a different patient at the same time point who has not been administered the antibody: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, mental health, mental component score and/or physical component score.
  • the slowing of the decline in HRQoL is assessed by comparing a score on at least one of the following domains of an SF-36 or SF-36v2 to a baseline score: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, mental health, mental component score and/or physical component score.
  • the slowing of the decline in reported value for the role physical domain includes a decrease of less than about 5 points on the role physical domain of the SF-36v2 compared to baseline.
  • the method includes a slowing of a decline in a reported value for a bodily pain domain of the SF-36 or SF-36v2.
  • the reported value for the bodily pain domain is higher relative to a different patient at the same time point who has not been administered the antibody.
  • the slowing of the decline in reported value for the bodily pain domain includes a decrease of less than about 5 points on the bodily pain domain of the SF-36v2 compared to baseline.
  • the method includes a slowing of a decline in vitality in the subject. In some embodiments, the method includes a slowing of a decline in role emotional in the subject. In some embodiments, the method Attorney Docket No.50887-0050WO1 includes a slowing of a decline in mental health in the subject. In some embodiments, the method includes a slowing of a decline in mental component score in the subject. In some embodiments, the method includes a slowing of a decline in at least two of the following: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, mental health, and mental component score.
  • the method includes a slowing of a decline in at least three of the following: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, mental health, and mental component score.
  • the antibody includes a light chain variable region including three complementarity determining regions of 2A4, 7D8 or 11-1F4, and a heavy chain variable region including three complementarity determining regions of 2A4, 7D8 or 11-1F4, respectively.
  • the antibody is a humanized version of 2A4. In some embodiments, the antibody is a humanized or chimeric version of 11-1F4.
  • the antibody includes a light chain variable region including three complementarity determining regions set forth as SEQ ID NOs: 3, 4 and 5, or SEQ ID NOs: 16, 17, and 18, and a heavy chain variable region including three complementarity determining regions set forth as SEQ ID NOs: 6, 7 and 8, or SEQ ID NOs: 19, 20, and 21.
  • the light chain variable region includes the amino acid sequence set forth as SEQ ID NO: 1 or 14.
  • the heavy chain variable region includes the amino acid sequence set forth as SEQ ID NO: 2 or 15.
  • the light chain variable region includes the amino acid sequence set forth as SEQ ID NO: 1 or 14, and the heavy chain variable region includes the amino acid sequence set forth as SEQ ID NO: 2 or 15.
  • the antibody includes a light chain including the amino acid sequence set forth as SEQ ID NO:10, and a heavy chain including the amino acid sequence set forth as SEQ ID NO: 11, 12 or 13. In some embodiments, the antibody includes a light chain including the amino acid sequence set forth as SEQ ID NO:10, and a heavy chain including the amino acid sequence set forth as SEQ ID NO:12. In some embodiments, the antibody is a Fab, Fab’, F(ab’)2, F(ab)c, Dab, nanobody, or Fv. In some embodiments, the antibody is birtamimab.
  • the effective dosage of the antibody is administered from a pharmaceutical formulation including the antibody at a concentration within the range from about 1 mg/mL to about 100 mg/mL. In some embodiments, the dosage is from about 0.5 Attorney Docket No.50887-0050WO1 mg/kg to about 30 mg/kg and the antibody is administered intravenously or subcutaneously at a frequency of from about weekly to about quarterly. In some embodiments, the antibody is present at a concentration of about 50 mg/mL. In some embodiments, the dosage is administered intravenously following the transfer of an amount of the formulation required for the dosage from a vial to an intravenous bag containing a liquid. In some embodiments, the dosage is about 24 mg/kg and the antibody is administered intravenously every 28 days.
  • Figure 1 shows the change from baseline to month 9 in reported values for the eight domains of the SF-36v2 questionnaire for Mayo Stage IV patients treated with birtamimab plus standard of care compared to placebo plus standard of care and demonstrates a slowing of decline in reported values for social functioning, role physical, and bodily pain domains.
  • the present disclosure provides methods of slowing a decline in Health-Related Quality of Life (HRQoL) in a subject having AL amyloidosis, including administering to the subject an effective dosage of an antibody which competes for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin with 2A4 (ATCC Accession Number PTA-9662) or 7D8 (ATCC Accession Number PTA-9468), or competes for binding to kappa light chain immunoglobulin with 11-1F4 (ATCC Accession Number PTA-105), where the slowing of the decline in HRQoL includes a slowing of a decline in at least one of the following: physical functioning (PF), role physical (RP), bodily pain (BP), general health (GH), vitality (VT), social functioning (SF), role emotional (RE), mental health (MH), and mental component score (MCS).
  • PF physical functioning
  • RP role physical
  • BP bodily pain
  • GH general health
  • VT vitality
  • this disclosure provides methods of treating AL amyloidosis in a subject, including administering to the subject an effective dosage of an antibody which competes for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin with 2A4 (ATCC Accession Number PTA-9662) or 7D8 (ATCC Accession Number PTA-9468), or competes for binding to kappa light chain immunoglobulin with 11- 1F4 (ATCC Accession Number PTA-105); where treating includes a slowing of a decline in HRQoL including a slowing of a decline in at least one of the following: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, mental health, and mental component score.
  • the present disclosure also provides methods for reducing a decline in life quality for Mayo Stage IV AL amyloidosis, as demonstrated by a slowing of a decline in reported values (e.g., on an SF-36 and/or SF-36v2 questionnaire) relative to Health Related Quality of Life (“HRQoL”).
  • HRQoL Health Related Quality of Life
  • the present disclosure provides methods of slowing of a decline in reported value for at least one of the following domains: social function, physical functioning, role physical, bodily pain, general health perceptions, vitality, role-emotional, mental health, and mental component score in patients with Mayo Stage IV AL amyloidosis.
  • the present disclosure provides methods of slowing of a decline in reported value for a social function domain in patients with Mayo Stage IV AL amyloidosis.
  • the disclosure further provides treating certain AL amyloidosis patients namely patients with Mayo Stage IV AL amyloidosis, wherein treating comprises a slowing of a decline in reported value for a social function domain.
  • the slowing of the decline in HRQoL comprises an increase in a reported domain value of at least about 5 points (e.g., at least about 6 points, at least about 7 points, at least about 8 points, or at least about 9 points) relative to a different patient at the same time point who has not been administered the antibody; wherein the domain value is at least one of the following: a physical functioning value, a role physical value, a bodily pain value, a general health value, a vitality value, a social functioning value, a role emotional value, a mental health value, and/or a mental component score value.
  • the slowing of the decline in HRQoL comprises an increase in a reported domain value of at least about 10 points (e.g., at least about 11 points, at least about 12 points, at least about 13 points, or at least about 14 points) relative to a different patient at the same time point who has not been administered the antibody; wherein the domain value is at least one of the following: a physical functioning Attorney Docket No.50887-0050WO1 value, a role physical value, a bodily pain value, a general health value, a vitality value, a social functioning value, a role emotional value, a mental health value, and/or a mental component score value.
  • a physical functioning Attorney Docket No.50887-0050WO1 value e.g., a role physical value, a bodily pain value, a general health value, a vitality value, a social functioning value, a role emotional value, a mental health value, and/or a mental component score value.
  • the slowing of the decline in HRQoL comprises an increase in a reported domain value of about 5 points to about 15 points (e.g., about 6 points to about 15 points, about 7 points to about 15 points, about 8 points to about 15 points, about, or 9 points to about 15 points) relative to a different patient at the same time point who has not been administered the antibody; wherein the domain value is at least one of the following: a physical functioning value, a role physical value, a bodily pain value, a general health value, a vitality value, a social functioning value, a role emotional value, a mental health value, and/or a mental component score value.
  • the slowing of the decline in HRQoL comprises an increase in a reported domain value of about 10 points to about 15 points (e.g., about 11 points to about 15 points, about 12 points to about 15 points, about 11 points to about 14 points, about, or 12 points to about 14 points) relative to a different patient at the same time point who has not been administered the antibody; wherein the domain value is at least one of the following: a physical functioning value, a role physical value, a bodily pain value, a general health value, a vitality value, a social functioning value, a role emotional value, a mental health value, and/or a mental component score value.
  • the present disclosure provides a method of treating Mayo Stage IV AL amyloidosis in a subject, comprising administering to the subject an effective dosage of an antibody which competes for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin with 2A4 (ATCC Accession Number PTA-9662) or 7D8 (ATCC Accession Number PTA-9468), or competes for binding to kappa light chain immunoglobulin with 11-1F4 (ATCC Accession Number PTA-105); wherein treating comprises a slowing of a decline in social functioning in the subject.
  • this disclosure provides methods of treating AL amyloidosis in a subject, including administering to the subject an effective dosage of an antibody which competes for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin with 2A4 (ATCC Accession Number PTA-9662) or 7D8 (ATCC Accession Number PTA-9468), or competes for binding to kappa light chain immunoglobulin with 11- 1F4 (ATCC Accession Number PTA-105); where treating includes a slowing of a decline in HRQoL including a slowing of a decline in at least one of the following: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, mental health, and mental component score.
  • This disclosure further provides methods of slowing a decline in Health-Related Quality of Life (HRQoL) in a subject having AL amyloidosis with cardiac involvement, including administering to the subject an effective dosage of an antibody which competes for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin with 2A4 (ATCC Accession Number PTA-9662) or 7D8 (ATCC Accession Number PTA- 9468), or competes for binding to kappa light chain immunoglobulin with 11-1F4 (ATCC Accession Number PTA-105), where the slowing of the decline in HRQoL includes a Attorney Docket No.50887-0050WO1 slowing of a decline in at least one of the following: physical functioning (PF), role physical (RP), bodily pain (BP), general health (GH), vitality (VT), social functioning (SF), role emotional (RE), mental health (MH), and mental component score (MCS).
  • PF physical functioning
  • RP role physical
  • this disclosure provides methods of treating AL amyloidosis with cardiac involvement in a subject, including administering to the subject an effective dosage of an antibody which competes for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin with 2A4 (ATCC Accession Number PTA-9662) or 7D8 (ATCC Accession Number PTA-9468), or competes for binding to kappa light chain immunoglobulin with 11-1F4 (ATCC Accession Number PTA-105); where treating includes a slowing of a decline in HRQoL including a slowing of a decline in at least one of the following: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, mental health, and mental component score.
  • the slowing the decline in social functioning comprises a decrease of about 1 point to about 15 points (e.g., 1 point to about 12 points, 1 point to about 10 points, 1 point to about 8 points) on the social functioning domain compared to baseline. In some embodiments, the slowing the decline in social functioning comprises a decrease of about 3 points to about 15 points (e.g., 3 points to about 12 points, 3 points to about 10 points, 3 points to about 8 points) on the social functioning domain compared to baseline. In some embodiments, the slowing the decline in social functioning comprises a decrease of about 5 points to about 15 points (e.g., 5 points to about 12 points, 5 points to about 10 points, 5 points to about 8 points) on the social functioning domain compared to baseline.
  • the slowing the decline in social functioning comprises a decrease of about 4 points to about 8 points on the social functioning domain compared to baseline. In some embodiments, the slowing the decline in social functioning comprises a decrease of about 5 points to about 7 points on the social functioning domain compared to baseline. In some embodiments, the slowing the decline in social functioning comprises a decrease of about 3 points, about 4 points, about 5 points, about 6 points, about 7 points, about 8 points, about 9 points, or about 10 points on the social functioning domain compared to baseline.
  • the slowing the decline in social functioning comprises a higher score on a social functioning domain of an SF-36 or SF-36v2 relative to a different patient having Mayo Stage IV AL amyloidosis at the same time point who has not been administered the antibody.
  • the slowing of the decline in social functioning comprises a higher score on a social functioning domain of an SF-36 relative to a different patient at the same time point who has not been administered the antibody.
  • the slowing of the decline in social functioning comprises a higher score on a social functioning domain of an SF-36v2 relative to a different patient at the same time point who has not been administered the antibody.
  • the slowing of the decline in social functioning comprises a increase of about 20 points to about 25 points (e.g., 21 points to about 24 points, 22 points to about 24 points, 21 points to about 23 points, or 22 points to about 23 points) on the social functioning domain relative to a different patient at the same time point who has not been administered the antibody.
  • the slowing of the decline in social functioning comprises a increase of about 18 points, about 19 points, about 20 points, about 21 points, about 22 points, about 23 points, about 24 points, about 25 points, about 26 points, or about 27 points on the social functioning domain relative to a different patient at the same time point who has not been administered the antibody.
  • the slowing of the decline in social functioning comprises an increase of about 23 points on the social functioning domain relative to a different patient at the same time point who has not been administered the antibody. In some embodiments, the slowing of the decline in social functioning is assessed after at least about 6 months (e.g., at least about 7 months or at least about 8 months) following a first administration of the antibody. In some embodiments, the slowing of the decline in social functioning is assessed after at least about 9 months (e.g., at least about 10 months or at least about 11 months) following a first administration of the antibody.
  • the slowing of the decline in social functioning is assessed after about 12 months (e.g., about 13 months, about 14 months, or about 15 months) following a first administration of the antibody.
  • the method further comprises assessing the HRQoL in the subject in at least one of the following domains (e.g., using the SF-36 or the SF-36v2) is assessed: role physical, bodily pain, general health, vitality, social functioning, role emotional, mental health, mental component score and/or physical component score.
  • the method comprises a slowing of a decline in bodily pain in the subject, and the first and second HRQoL values comprise a first bodily pain value and a second bodily pain value, respectively.
  • the method comprises a slowing of a decline in general health in the subject, and the first and second HRQoL values comprise a first general health value and a second general health value, respectively.
  • the method comprises a slowing of a decline in vitality in the subject, and the first and second HRQoL values comprise a first vitality value and a second vitality value, respectively.
  • the first value comprises a first score on a domain of the SF-36 or the SF-36v2 and the second value comprises a second score on a domain of the SF-36 or Attorney Docket No.50887-0050WO1 the SF-36v2.
  • the first value comprises a first score on a domain of the SF-36 and the second value comprises a second score on a domain of the SF-36.
  • the first value comprises a first score on a domain of the SF-36v2 and the second value comprises a second score on a domain of the SF-36v2.
  • the domain is at least one of the following: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, mental health, and mental component score.
  • the first HRQoL value is a baseline HRQoL value.
  • the first HRQoL value comprises a at least one of the following a baseline physical functioning value, a baseline role physical value, a baseline bodily pain value, a baseline general health value, a baseline vitality value, a baseline social functioning value, a baseline role emotional value, a baseline mental health value, and a baseline mental component score value.
  • the present disclosure provides a method of slowing a decline in social functioning in a subject having AL (including Mayo Stage IV AL amyloidosis or AL amyloidosis with cardiac involvement) amyloidosis, the method comprising: (d) assessing social functioning in the subject thereby obtaining a first social functioning value; (e) administering to the subject an effective dosage of an antibody, wherein the antibody competes for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin with 2A4 (ATCC Accession Number PTA-9662) or 7D8 (ATCC Accession Number PTA-9468), or competes for Attorney Docket No.50887-0050WO1 binding to kappa light chain immunoglobulin with 11-1F4 (ATCC Accession Number PTA-105); and (f) assessing social functioning in the subject thereby obtaining a second social functioning value.
  • AL Mayo Stage IV AL amyloidosis or AL amyloidosis with cardiac involvement
  • the second score on the social functioning domain is less than about 20 points (e.g., less than about 19 points, less than about 18 points, less than about 17 points, or less than about 16 points) lower than the first score on the social functioning domain. In some embodiments, the second score on the social functioning domain is less than about 15 points (e.g., less than about 14 points, less than about 13 points, less than about 12 points, or less than about 11 points) lower than the first score on the social functioning domain. In some embodiments, the second score on the social functioning domain is less than about 10 points (e.g., less than about 9 points, less than about 8 points, less than about 7 points, or less than about 6 points) lower than the first score on the social functioning domain.
  • the second score on the social functioning domain is about 3 points, about 4 points, about 5 points, about 6 points, about 7 points, about 8 points, about 9 points, or about 10 points lower than the first score on the social functioning domain.
  • the second social function value is assessed after at least about 6 months (e.g., at least about 7 months or at least about 8 months) following a first administration of the antibody.
  • the second social function value is assessed after at least about 9 months (e.g., at least about 10 months or at least about 11 months) following a first administration of the antibody.
  • the second social function value is assessed after at least about 12 months (e.g., at least about 13 months, at least about 14 months, or at least about 15 months) following a first administration of the antibody. In some embodiments, the second social function value is assessed after about 6 months (e.g., about 7 months or about 8 months) following a first administration of the antibody. In some embodiments, the second social function value is assessed after about 9 months (e.g., about 10 months or about 11 months) following a first administration of the antibody. In some embodiments, the second social function value is assessed after about 12 months (e.g., about 13 months, about 14 months, or about 15 months) following a first administration of the antibody.
  • the method further comprises a slowing of a decline in at least one value for the following domains of the SF-36 or SF-36v2: physical functioning, role physical, bodily pain, general health perceptions, vitality, role-emotional, mental health, physical component score, and mental component score.
  • the method further comprises a slowing of a decline in at least one value for the following domains of the SF-36 or SF-36v2: physical functioning, role physical, bodily pain, role-emotional, mental health, physical component score, and mental component score.
  • the method further comprises a slowing of a decline in at least one value for the following domains of the SF-36 or SF-36v2: physical functioning, role physical, bodily pain, physical component score, and mental component score. In some embodiments, the method further comprises a slowing of a decline in at least one value for the following domains of the SF-36 or SF-36v2: role physical, bodily pain, and physical component score.
  • the present disclosure provides a method of slowing a decline in a reported value for at least one of the following domains in a subject having AL amyloidosis(including Mayo Stage IV AL amyloidosis or AL amyloidosis with cardiac involvement): physical functioning, role physical, bodily pain, general health perceptions, vitality, role-emotional, mental health, physical component score, and mental component score (e.g., reported value of one or more domain of the SF-36 or SF-36v2); the method comprising administering to the subject an effective dosage of an antibody which competes for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin with 2A4 (ATCC Accession Number PTA-9662) or 7D8 (ATCC Accession Number PTA-9468), or competes for binding to kappa light chain immunoglobulin with 11- 1F4 (ATCC Accession Number PTA-105
  • the present disclosure provides a method of treating AL amyloidosis (including Mayo Stage IV AL amyloidosis or AL amyloidosis with cardiac involvement) in a subject, comprising administering to the subject an effective dosage of an antibody which competes for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin with 2A4 (ATCC Accession Number PTA-9662) or 7D8 (ATCC Accession Number PTA-9468), or competes for binding to kappa light chain immunoglobulin with 11-1F4 (ATCC Accession Number PTA-105); wherein treating comprises a slowing of a decline in a reported value for at least one of the following domains in the subject: physical functioning, role physical, bodily pain, general health perceptions, vitality, role-emotional, mental health, physical component score, and mental component score (e.g., reported value of one or more domain of the SF-36 or SF-36v2).
  • AL amyloidosis including May
  • the method further comprises a slowing of a decline in role physical and/or bodily pain domains of the SF-36 or SF-36v2. In some embodiments, the method further comprises a slowing of a decline in role physical and/or bodily pain domains of the SF-36. In some embodiments, the method further comprises a slowing of a decline in role physical and/or bodily pain domains of the SF-36v2. In some embodiments, the method further comprises a slowing of a decline in role physical and/or bodily pain domains of the SF-36v2 compared to baseline.
  • the reported value for the role physical domain is higher relative to a different patient at the same time point who has not been administered the antibody.
  • the present disclosure provides a method of slowing a decline in role physical (e.g., reported value of role physical domain) in a subject having AL Attorney Docket No.50887-0050WO1 amyloidosis (including Mayo Stage IV AL amyloidosis or AL amyloidosis with cardiac involvement), comprising administering to the subject an effective dosage of an antibody which competes for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin with 2A4 (ATCC Accession Number PTA-9662) or 7D8 (ATCC Accession Number PTA-9468), or competes for binding to kappa light chain immunoglobulin with 11-1F4 (ATCC Accession Number PTA-105).
  • the present disclosure provides a method of treating AL amyloidosis (including Mayo Stage IV AL amyloidosis or AL amyloidosis with cardiac involvement) in a subject, comprising administering to the subject an effective dosage of an antibody which competes for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin with 2A4 (ATCC Accession Number PTA-9662) or 7D8 (ATCC Accession Number PTA-9468), or competes for binding to kappa light chain immunoglobulin with 11-1F4 (ATCC Accession Number PTA-105); wherein treating comprises a slowing of a decline in role physical (e.g., reported value of role physical domain) in the subject.
  • AL amyloidosis including Mayo Stage IV AL amyloidosis or AL amyloidosis with cardiac involvement
  • an antibody which competes for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin with 2A4
  • the slowing of the decline in reported value for the role physical domain comprises a decrease of less than about 10 points (e.g., less than about 9 points, less than about 8 points, less than about 7 points, or less than about 6 points) on the role physical domain (e.g., of the SF-36 or SF-36v2) compared to baseline. In some embodiments, the slowing of the decline in reported value for the role physical domain comprises a decrease of less than about 5 points (e.g., less than about 4 points, less than about 3 points, or less than about 2 points) on the role physical domain compared to baseline.
  • the slowing of the decline in reported value for the role physical domain comprises a decrease of about 1 point to about 5 points (e.g., about 1 point to about 4 points, about 1 point to about 3 points, or about 1 point to about 2 points) on the role physical domain (e.g., of the SF-36 or SF-36v2) compared to baseline.
  • the slowing of the decline in reported value for the role physical domain comprises a decrease of about 2 points to about 3 points on the role physical domain compared to baseline.
  • the slowing of the decline in reported value for the role physical domain comprises a decrease of about 1 point, about 2 points, about 3 points, about 4 points, or about 5 points on the role physical domain compared to baseline.
  • the slowing of the decline in reported value for the role physical domain comprises a decrease of about 2 points on the role physical domain compared to baseline.
  • Attorney Docket No.50887-0050WO1 the slowing of the decline in reported value for the role physical domain comprises an increase of at least about 1 point (e.g., at least about 2 points, at least about 3 points, or at least about 4 points) on the role physical domain relative to a different patient at the same time point who has not been administered the antibody.
  • the slowing of the decline in reported value for the role physical domain comprises an increase of at least about 5 points (e.g., at least about 6 points, at least about 7 points, at least about 8 points, or at least about 9 points) on the role physical domain relative to a different patient at the same time point who has not been administered the antibody. In some embodiments, the slowing of the decline in reported value for the role physical domain comprises an increase of at least about 10 points (e.g., at least about 11 points, at least about 12 points, at least about 13 points, or at least about 14 points) on the role physical domain relative to a different patient at the same time point who has not been administered the antibody.
  • the slowing of the decline in reported value for the role physical domain comprises an increase of about 11 points to about 12 points on the role physical domain relative to a different patient at the same time point who has not been administered the antibody. In some embodiments, the slowing of the decline in reported value for the role physical domain comprises an increase of about 8 points, about 9 points, about 10 points, about 11 points, about 12 points, about 13 points, or about 14 points on the role physical domain relative to a different patient at the same time point who has not been administered the antibody.
  • the slowing of the decline in reported value for the role physical domain comprises an increase of about 11 points on the role physical domain Attorney Docket No.50887-0050WO1 relative to a different patient at the same time point who has not been administered the antibody.
  • the method further comprises a slowing of the decline in bodily pain of the SF-36 or SF-36v2.
  • the method further comprises a slowing of the decline in a bodily pain domain of the SF-36.
  • the method further comprises a slowing of the decline in a bodily pain domain of the SF-36v2.
  • the reported value for the bodily pain domain is lower than baseline.
  • the slowing of the decline in bodily pain comprises a decrease of less than about 10 points (e.g., less than about 9 points, less than about 8 points, less than about 7 points, or less than about 6 points) on the bodily pain domain compared to baseline. In some embodiments, the slowing of the decline in bodily pain comprises a decrease of less than about 5 points (e.g., less than about 4 points, less than about 3 points, or less than about 2 points) on the bodily pain domain compared to baseline.
  • the slowing of the decline in bodily pain comprises a decrease of about 1 point to about 10 points (e.g., 1 point to about 9 points, 1 point to about 8 points, 1 point to about 6 points, 1 point to about 5 points, or 1 point to about 4 points) on the bodily pain domain compared to baseline.
  • the slowing of the decline in bodily pain comprises a decrease of about 2 points to about 8 points (e.g., 2 points to about 7 points, 2 points to about 6 points, 2 points to about 5 points, 2 points to about 4 points, or 2 points to about 3 points) on the bodily pain domain compared to baseline.
  • the slowing of the decline in bodily pain comprises a decrease of about 2 points to about 4 points on the bodily pain domain compared to baseline. In some embodiments, the slowing of the decline in bodily pain comprises a decrease of about 1 point, about 2 points, about 3 points, about 4 points, about 5 points, about 6 points, about 7 points, at least 8 points, at least 9 points, or at least 10 points on the bodily pain domain compared to baseline. In some embodiments, the slowing of the decline in bodily pain domain comprises a decrease of about 3 points on the bodily pain domain compared to baseline.
  • the slowing of the decline in reported value for the bodily pain domain comprises an increase of at least about 1 point (e.g., at least about 2 points, at least about 3 points, or at least about 4 points) on the bodily pain domain relative to a different patient at the same time point who has not been administered the antibody. In some embodiments, the slowing of the decline in reported value for the bodily pain domain comprises an increase of at least about 5 points (e.g., at least about 6 points, at least about 7 points, at least about 8 points, or at least about 9 points) on the bodily pain domain relative to a different patient at the same time point who has not been administered the antibody.
  • the slowing of the decline in reported value for the bodily pain domain comprises an increase of at least about 10 points (e.g., at least about 11 points, at least about 12 points, at least about 13 points, or at least about 14 points) on the bodily pain domain relative to a different patient at the same time point who has not been administered the antibody. In some embodiments, the slowing of the decline in reported value for the bodily pain domain comprises an increase of at least about 15 points (e.g., at least about 16 points, at least about 17 points, at least about 18 points, or at least about 19 points) on the bodily pain domain relative to a different patient at the same time point who has not been administered the antibody.
  • the slowing of the decline in reported value for the bodily pain domain comprises an increase of about 15 points to about 18 points (e.g., about 15 points to about 17 points, about 15 points to about 16 points, about 16 points to about 18 points, or about 16 points to about 17 points) on the bodily pain domain relative to a different patient at the same time point who has not been administered the antibody.
  • the slowing of the decline in reported value for the bodily pain domain comprises an increase of about 12 points, about 13 points, about 14 points, about 15 points, about 16 points, about 17 points, about 18 points, about 19 points, or about 20 points on the bodily pain domain relative to a different patient at the same time point who has not been administered the antibody.
  • the present disclosure provides a method of treating AL amyloidosis (including Mayo Stage IV AL amyloidosis or AL amyloidosis with cardiac involvement) in a subject, comprising administering to the subject an effective dosage of an antibody which competes for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin with 2A4 (ATCC Accession Number PTA-9662) or 7D8 (ATCC Accession Number PTA-9468), or competes for binding to kappa light chain immunoglobulin with 11-1F4 (ATCC Accession Number PTA-105); wherein treating comprises a slowing of a decline in physical functioning (e.g., reported value of physical functioning domain) in the subject.
  • AL amyloidosis including Mayo Stage IV AL amyloidosis or AL amyloidosis with cardiac involvement
  • an antibody which competes for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin with 2A4
  • the present disclosure provides a method of slowing a decline in vitality (e.g., reported value of vitality domain) in a subject having AL amyloidosis (including Mayo Stage IV AL amyloidosis or AL amyloidosis with cardiac involvement), comprising administering to the subject an effective dosage of an antibody which competes for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin with 2A4 (ATCC Accession Number PTA-9662) or 7D8 (ATCC Accession Number PTA-9468), or competes for binding to kappa light chain immunoglobulin with 11- 1F4 (ATCC Accession Number PTA-105).
  • AL amyloidosis including Mayo Stage IV AL amyloidosis or AL amyloidosis with cardiac involvement
  • the present disclosure provides a method of treating AL amyloidosis (including Mayo Stage IV AL amyloidosis or AL amyloidosis with cardiac involvement) in a subject, comprising administering to the subject an effective dosage of an antibody which competes for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin with 2A4 (ATCC Accession Number PTA-9662) or 7D8 (ATCC Accession Number PTA-9468), or competes for binding to kappa light chain immunoglobulin with 11-1F4 (ATCC Accession Number PTA-105); wherein treating comprises a slowing of a decline in vitality (e.g., reported value of vitality domain) in the subject.
  • an antibody which competes for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin with 2A4 (ATCC Accession Number PTA-9662) or 7D8 (ATCC Accession Number PTA-9468), or competes for binding
  • the present disclosure provides a method of treating AL amyloidosis (including Mayo Stage IV AL amyloidosis or AL amyloidosis with cardiac involvement) in a subject, comprising administering to the subject an effective dosage of an antibody which competes for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin with 2A4 (ATCC Accession Number PTA-9662) or 7D8 (ATCC Attorney Docket No.50887-0050WO1 Accession Number PTA-9468), or competes for binding to kappa light chain immunoglobulin with 11-1F4 (ATCC Accession Number PTA-105); wherein treating comprises a slowing of a decline in mental component score (e.g., reported value of mental component score domain) in the subject.
  • AL amyloidosis including Mayo Stage IV AL amyloidosis or AL amyloidosis with cardiac involvement
  • an antibody which competes for binding to human amyloid A peptide or human k
  • the method comprises a slowing of the decline in value for any of the following domains of the SF-36 compared to baseline: physical functioning, role physical, bodily pain, general health perceptions, vitality, role-emotional, mental health, physical component score, and/or mental component score.
  • the method comprises a slowing of a decline in value for any of the following domains of the SF-36v2 compared to baseline: physical functioning, role physical, bodily pain, general health perceptions, vitality, role-emotional, mental health, physical component score, and/or mental component score.
  • the slowing of the decline in reported value for any of the following domains: physical functioning, role physical, bodily pain, general health perceptions, vitality, role-emotional, mental health, physical component score, and/or mental component score comprises a decrease of less than about 5 points (e.g., less than about 4 points, less than about 3 points, less than about 2 points, or less than about 1 point) on the domain compared to baseline.
  • the slowing of the decline in in reported value for any of the following domains: physical functioning, role physical, bodily pain, general health perceptions, vitality, role-emotional, mental health, physical component score, and/or mental component score comprises a decrease of about 5 points to about 15 points (e.g., 5 points to about 12 points, 5 points to about 10 points, 5 points to about 8 points) on the domain compared to baseline.
  • the slowing of the decline in in reported value for any of the following domains: physical functioning, role physical, bodily pain, general health perceptions, vitality, role-emotional, mental health, physical component score, and/or mental component score comprises a decrease of about 4 points to about 8 points on the domain compared to baseline.
  • the slowing of the decline in reported value for any of the following domains: physical functioning, role physical, bodily pain, general health perceptions, vitality, role-emotional, mental health, physical component score, and/or mental component score comprises an increase of at least about 1 point (e.g., at least about 2 points, at least about 3 points, or at least about 4 points) on the domain (e.g., of the SF-36 or SF- 36v2) relative to a different patient at the same time point who has not been administered the antibody.
  • the slowing of the decline in reported value for any of the following domains: physical functioning, role physical, bodily pain, general health perceptions, vitality, role-emotional, mental health, physical component score, and/or mental Attorney Docket No.50887-0050WO1 component score comprises an increase of at least about 20 points (e.g., at least about 21 points, at least about 22 points, or at least about 23 points) on the domain relative to a different patient at the same time point who has not been administered the antibody.
  • the slowing of the decline in reported value for any of the following domains: physical functioning, role physical, bodily pain, general health perceptions, vitality, role-emotional, mental health, physical component score, and/or mental component score comprises a increase of about 5 points to about 15 points (e.g., 5 points to about 14 points, 5 points to about 12 points, 5 points to about 10 points, 6 points to about 14 points, 6 points to about 12 points, 6 points to about 10 points, or 6 points to about 8 points) on the domain relative to a different patient at the same time point who has not been administered the antibody.
  • the slowing of the decline in reported value for any of the following domains: physical functioning, role physical, bodily pain, general health perceptions, vitality, role-emotional, mental health, physical component score, and/or mental component score comprises an increase of about 1 point, about 2 points, about 3 points, about 4 points, about 5 points, about 6 points, about 7 points, about 8 points, about 9 points, about 10 points, about 11 points, about 12 points, about 13 points, about 14 points, about 15 points, about 16 points, or about 17 points, about 18 points, about 19 points, about 20 points, about 21 points, about 22 points, about 23 points, about 24 points, or about 25 points, on the domain relative to a different patient at the same time point who has not been administered the antibody.
  • the slowing of the decline in reported value for any of the following domains: physical functioning, role physical, bodily pain, general health perceptions, vitality, role-emotional, mental health, Attorney Docket No.50887-0050WO1 physical component score, and/or mental component score is assessed after about 9 months (e.g., about 10 months or about 11 months) following a first administration of the antibody.
  • treatment with an antibody disclosed herein results in an increase of a subject’s score on the SF-36 and/or SF36v2, of at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, at least 30, at least 31, at least 32, at least 33, at least 34, at least 35, at least 36, at least 37, at least 38, at least 39, at least 40, at least 41, at least 42, at least 43, at least 44, at least 45, at least 46, at least 47, at least 48, at least 49, at least 50, at least 51, at least 52, at least 53, at least 54, at least 55, at least 56, at least 57, at least 58, at least 59, at least 60, at least 61,
  • treatment with an antibody disclosed herein results in an increase of a subject’s SF-36 or SF36v2, of about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, Attorney Docket No.50887-0050WO1 about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, about 75, about
  • the response of patients with AL amyloidosis to treatment can be monitored by assessing cardiac markers, such as NT-proBNP and/or troponin-T, serum creatine, and/or alkaline phosphatase; by performing serum free light chain (SFLC) assays, quantitative immunoglobulin assays, Attorney Docket No.50887-0050WO1 biopsies, serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP), serum, urine immunofixation electrophoresis (IFE), and/or organ imaging techniques.
  • An exemplary complete response (CR) can be determined from response criteria including negative IFE of serum and urine, normal ⁇ ration and/or ⁇ 5 % plasma cells in bone marrow.
  • An exemplary very good partial response can be determined from a dFLC of ⁇ 40 mg/L.
  • An exemplary partial response (PR) can be determined from a dFLC decrease of ⁇ 50%.
  • a response to treatment can be determined, for example, from a ⁇ 50% reduction (e.g., > 0.5g/24 hours) in 24 hour urine protein excretion in the absence of either a reduction in eGFR of ⁇ 25% or an increase in serum creatine of ⁇ 0.5 mg/dL.
  • a response to treatment can be determined, for example, from a ⁇ 50% reduction in initially elevated alkaline phosphatase or a ⁇ 2 cm reduction in liver size on CT scan or MRI.
  • the birtamimab formulation transferred to the intravenous bag was first reconstituted from a lyophilized formulation to a formulation having a pH of about 6.5 and comprising about 50 mg/ml birtamimab, about 25 mM histidine buffer, about 230 mM trehalose and about 0.2 g/L polysorbate 20.
  • the desired dosage can be administered subcutaneously without dilution from a vial containing any of the formulations disclosed herein.
  • the antibody is administered to the patient for at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, or for a longer period of time.
  • the subject has been previously determined diagnosed, identified, or selected as having decreased score for at least one (e.g., at least two, at least three, or at least four) of the following domains: social functioning, physical functioning, role physical, bodily pain, general health perceptions, vitality, role-emotional, mental health, physical component score, and/or mental component score (e.g., as compared to a subject of similar age and not having AL amyloidosis or any neurological disorder or compared to a prior measurement taken from the same subject).
  • subjects may be selected for treatment based on their reported value for a social functioning score (e.g., as measured by the SF-36 or SF- 36v2).
  • the subject has been previously determined diagnosed, identified, or selected Attorney Docket No.50887-0050WO1 as having decreased general health perceptions score (e.g., as compared to a subject of similar age and not having AL amyloidosis or any neurological disorder or compared to a prior measurement taken from the same subject).
  • subjects may be selected for treatment based on their reported value for a vitality score (e.g., as measured by the SF-36 or SF-36v2).
  • subject has been determined, diagnosed, identified, or selected for treatment as having baseline role physical score (e.g., as measured using the SF-36 or SF- 36v2) of about 20 to about 50 (e.g., about 25 to about 50, about 30 to about 50, about 35 to about 50, or about 40 to about 50).
  • baseline role physical score e.g., as measured using the SF-36 or SF- 36v2
  • the subject has been determined, diagnosed, identified, or selected for treatment as having baseline role physical score of about 20 to about 40 (e.g., about 25 to about 40, about 30 to about 40, or about 35 to about 40).
  • Such patients may, or may not, have experienced cardiac and/or renal improvement as a result of such treatment.
  • the methods of the disclosure include administering to a patient an antibody that specifically bind to immunoglobulin light chain.
  • examples include antibodies that compete with 11-1F4 for binding to immunoglobulin light chain, and antibodies that compete with 2A4 or 7D8 for binding to human amyloid A peptide, or specifically bind to the same epitope as 11-1F4 (U.S. Patent No.8,105,594), 2A4 or 7D8 (U.S. Patent No.7,928,203).
  • the antibody is a humanized version of 2A4.
  • the light chain variable region comprises the amino acid sequence set forth as SEQ ID NO: 1.
  • the heavy chain variable region comprises the amino acid sequence set forth as SEQ ID NO: 2.
  • the antibody comprises light chain and heavy chain variable regions of a murine, chimeric, or humanized 2A4 antibody, or of a murine, chimeric, or humanized 7D8 antibody, as described in U.S. Patent No.7,928,203 and PCT International Publication No. WO 2009/086539, each of which is incorporated herein by reference in its entirety, and the light chain and heavy chain variable region sequences described in the referenced patent and publication are specifically incorporated by reference herein.
  • Antibodies used in the disclosed formulations also include modified forms of murine, chimeric or humanized 2A4 antibodies, or murine, chimeric or humanized 7D8 antibodies, which have increased in vivo half-lives relative to the corresponding unmodified antibodies.
  • modified forms may be prepared, for example, by glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, linkage to a cellular ligand or other protein, etc.
  • representative methods for antibody half-life extension are described in PCT International Publication No. WO 02/060919.
  • polysorbate 20 is present at a concentration within the range of about from about 0.005% to about 0.05% by weight, for example, 0.005%, 0.01%, 0.015%, 0.02%, 0.025%, 0.03%, 0.035%, 0.04%, 0.045%, or 0.05%.
  • polysorbate 20 is present at a concentration within the range of about from about 0.05 g/L, 0.1 g/L, 0.15 g/L, 0.2 g/L, 0.25 g/L, 0.3 g/L, 0.35 g/L, 0.4 g/L, 0.45 g/L, or 0.5 g/L.
  • Some formulations include polysorbate 20 at a concentration of 0.2 g/L. Some formulations are characterized by a pH within the range of about 6-7, for example, a pH of 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, or 7.0. Some formulations have a pH of about 6.5. Some formulations are characterized by an osmolality of about 300 mOsm/kg. A bulking agent may also be included some formulations. Typically, the formulations are sterile, for example, as accomplished by sterile filtration using a 0.2 ⁇ m or a 0.22 ⁇ m filter. The formulations disclosed herein are also generally stable upon freezing and thawing.
  • formulations disclosed herein may further comprise other excipients, such as saccharides, polyols, and amino acids (e.g., arginine, lysine, and methionine).
  • excipients such as saccharides, polyols, and amino acids (e.g., arginine, lysine, and methionine).
  • the present disclosure also provides formulations substantially free of surfactant, inorganic salts, additional sugars, and/or other excipients, i.e., less than about less than 0.0005%, less than 0.0003%, or less than 0.0001% of such compounds.
  • An exemplary formulation comprises an antibody comprising a light chain comprising an amino acid sequence set forth as SEQ ID NO: 10 and a heavy chain comprising an amino acid sequence set forth as any one of SEQ ID NOs: 11, 12, or 13, which is present at a concentration of about 50 mg/mL, a histidine buffer present at a concentration of about 25 mM, trehalose present at a concentration of about 230 mM, polysorbate 20 present at a concentration of about 0.2 g/L, and a pH of about 6.5.
  • Some formulations comprise an antibody comprising a light chain comprising an amino acid sequence set forth as SEQ ID NO: 10 and a heavy chain comprising an amino acid sequence set forth as SEQ ID NO: 12, which is present at a concentration of about 50 mg/mL, a histidine buffer present at a concentration of about 25 mM, trehalose present at a concentration of about 230 mM, polysorbate 20 present at a concentration of about 0.2 g/L, and a pH of about 6.5.
  • Some formulations comprise birtamimab, which is present at a concentration of about 50 mg/mL, a histidine buffer present at a concentration of about 25 mM, trehalose present at a concentration of about 230 mM, polysorbate 20 present at a concentration of about 0.2 g/L, and a pH of about 6.5.
  • the methods disclosed herein involve pharmaceutical products comprising lyophilized antibody drug substance and instructions for reconstitution and use.
  • a representative pharmaceutical product can comprise: (a) a vial comprising about 100 mg antibody in powder form; (b) instructions for reconstitution of the antibody; and (c) instructions for preparing the reconstituted antibody for infusion, wherein (i) the antibody comprises a light chain comprising an amino acid sequence set forth as SEQ ID NO: 10 and a heavy chain comprising an amino acid sequence set forth as any one of SEQ ID NOs: 12-15; and (ii) the reconstitution instructions require reconstitution with water for injection to an extractable volume of 10 mL.
  • Example 1 Phase 2b Clinical Assessment of NEOD001, also known as birtamimab (Humanized 2A4) A Phase 2b global, multi-center, randomized, double-blind, placebo-controlled clinical study of NEOD001 vs.
  • Example 2 Phase 3 Clinical Assessment of NEOD001 A Phase 3 global, multi-center, randomized, double-blind, placebo-controlled clinical study of NEOD001 vs. placebo was conducted in newly diagnosed, treatment-na ⁇ ve patients with AL amyloidosis and cardiac dysfunction, with both arms of the study receiving standard of care (VITAL Study; The VITAL Amyloidosis Study, a Global Phase 3, Efficacy and Safety Study of NEOD001 in Patients With AL Amyloidosis (VITAL), ClinicalTrials.gov Identifier: NCT02312206). The study enrolled 260 patients (see Table 1). Table 1.
  • NEOD001 placebo-based chemotherapy
  • Placebo was administered as a 250 mL bag of normal saline once every 28 days.
  • the primary outcome measures were time to composite of all-cause mortality or cardiac hospitalization. Secondary outcome measures included NT-proBNP best response, time to cardiac mortality or cardiac hospitalization, change in the 6 minute walk test, change in the Short Form-36 questionnaire, change in the Kansas City Cardiomyopathy questionnaire, renal best response as assessed using Palladini et al, 2014 criteria and hepatic best response as assessed using Comenzo et al, 2012 criteria.
  • Example 3 Improvements in Health-Related Quality of Life Metrics for Stage IV AL Amyloidosis Patients – Surprising Results in Certain Patients from the VITAL Study Patients with AL amyloidosis have reduced HRQoL, particularly those with advanced cardiac involvement who have a high symptom burden and poor physical function.
  • we Attorney Docket No.50887-0050WO1 assessed longitudinal HRQoL changes in the VITAL trial among patients with Mayo Stage IV (MSIV) AL amyloidosis.
  • VITAL newly diagnosed treatment-na ⁇ ve patients received birtamimab in combination with standard of care or placebo with standard of care.
  • Short Form-36 questionnaire, version 2 (SF-36v2) was completed at baseline and months 3, 6, and 9 (i.e., after 3, 6, and 9 months of treatment. Lower scores on the SF-36v2 and domains and component scores therein indicate worse HRQoL.
  • a mixed model for repeated measures was used to estimate least squares mean (LSM), standard error (SE), and 95% CI for each treatment group and LSM difference between groups.
  • LSM least squares mean
  • SE standard error
  • 95% CI 95% CI for each treatment group and LSM difference between groups.
  • LSM least squares mean
  • SE standard error
  • 95% CI 95% CI for each treatment group and LSM difference between groups.
  • Tables 2A-2C provide values for HRQoL values reported by the Mayo Stage IV Amyloidosis patients at baseline, month 3, month 6, and month 9.
  • n 7 5 7 0 0 0 7 H a e e c 30 . 3 a 8 . l , 7 . 7 . 5 , 0 . 0 . 4 , 5 . 0 . N 3 3 5 2 3 3 2 5 1 0 5 0 3 02 3 5 2 1 7 6 . . 5 y ( 3 ( 6 6 ( 5 ( d m ) P . 0 u 7 . 0 2 .
  • the MMRM included fixed effects for treatment group, categorical time point (all postbaseline visits), treatment group by visit interaction, IWRS stratification factors (Renal Stage: I, II/III and baseline 6MWT distance: ⁇ 300 meters, ⁇ 300 meters), the associated baseline value as a covariate, and an unstructured covariance structure to model the within- subject errors.
  • Secondary objectives are to evaluate birtamimab plus standard of care on the following: (1) change from baseline to month 9 in health related quality of life using the SF-36v2, including but not limited to, the social functioning, role physical, and bodily pain domains; and (2) change from baseline to month 9 in the 6 Minute Walk Test (6MWT) distance (meters).
  • 6MWT 6 Minute Walk Test
  • Newly diagnosed Mayo Stage IV subjects with AL amyloidosis receive birtamimab plus local standard of care chemotherapy.
  • the initial first-line chemotherapy regimen must include bortezomib. Subjects remain on study until study completion, which occurs when approximately 16 primary endpoint events (all-cause mortality) have been reached or 62 subjects have completed 9 months of treatment.
  • ETD Early Treatment Discontinuation
  • Subject screening will occur during the 28 days prior to the first administration of study drug on Month 1-Day 1. The screening period may be extended upon approval by the Medical Monitor. Screening assessments are listed in Table 3, herein. Two screening 6MWTs are required before the first administration of study drug.
  • the first screening 6MWT is required to be performed between Days -28 and 5, at least 4 days prior to the second Screening 6MWT, which should be performed within 2 days prior to Month 1 Day 1.
  • the postbaseline 6MWTs may be performed on the same day as study drug administration and must be completed prior to study drug infusion. If all eligibility requirements are met, Month 1-Day 1 assessments are completed, and treatment is initiated. Each visit is denoted by its “month” and “day” such that the first study drug infusion day is denoted as Month 1-Day 1; subsequent months use sequential numbers (e.g., the second dose is administered on Month 2-Day 1). “Cycle” is reserved to denote administration of chemotherapy.
  • ⁇ Is over 75 years of age with concurrent monoclonal gammopathy. ⁇ Has a history of familial amyloidosis and has concurrent monoclonal gammopathy. OR ⁇ If the subject meets any of the above 3 conditions and has echocardiographic evidence of amyloidosis, biopsy-proven amyloidosis with a monoclonal gammopathy and no tissue is available for mass spectrometry or immunoelectron microscopy, the subject must have gene sequencing consistent with transthyretin (TTR) wild type (e.g., no TTR mutation present) AND must score 0 in technetium-99m-3,3-diphosphono-1,2 propanodicarboxylic acid (99mTc DPD; Rapezzi 2011), hydroxymethylenediphosphonate (99mTc HMDP; Galat 2015), or pyrophosphate (99mTc PYP; Bokhari 2013) scintigraphy.
  • TTR transthyretin
  • AST Aspartate aminotransferase
  • SGOT Aspartate aminotransferase
  • ALT Alanine aminotransferase
  • SGPT Serum glutamic pyruvic transaminase
  • ALP Alkaline phosphatase
  • eGFR Estimated glomerular filtration rate
  • Non-AL amyloidosis 2.
  • NT-proBNP > 8,500 pg/mL.
  • IMWG International Myeloma Working Group
  • Subject is eligible for and plans to undergo ASCT or organ transplant during the study. 5.
  • Symptomatic orthostatic hypotension that in the medical judgment of the Investigator would interfere with subject’s ability to safely receive treatment or complete study assessments. 6.
  • ECG evidence of acute ischemia within 6 months prior to the Month 1-Day 1 Visit. 7. Severe valvular stenosis (e.g., aortic or mitral stenosis with a valve area ⁇ 1.0 cm2) or severe congenital heart disease. 8. ECG evidence of acute ischemia or active conduction system abnormalities with the exception of any of the following: ⁇ First degree AV-block. ⁇ Second degree AV-block Type 1 (Mobitz Type 1 / Wenckebach type). ⁇ Right or left bundle branch block.
  • Atrial fibrillation with a controlled ventricular rate (uncontrolled [>110 bpm] ventricular rate is not allowed [determined by an average of three beats in Lead II or three representative beats if Lead II is not representative of the overall EKG]).
  • Attorney Docket No.50887-0050WO1 9.
  • Subject is receiving oral or IV antibiotics, antifungals or antivirals within 1 week of Month 1-Day 1 with the exception of prophylactic oral agents.
  • birtamimab such as histidine/L histidine hydrochloride monohydrate, trehalose dehydrate, or polysorbate 20 or history of Grade ⁇ 3 infusion-related AEs or hypersensitivity to another monoclonal antibody, or known hypersensitivity to diphenhydramine (or an equivalent H1 antihistamine) or acetaminophen (or its equivalent, paracetamol).
  • Study drug consists of birtamimab (24 mg/kg) supplied as a sterile, lyophilized dosage form in a 20/25 mL vial containing 500 mg birtamimab. Each vial is reconstituted with 9.6 mL sterile water for injection (WFI) to a concentration of 50 mg/mL resulting in a buffered, isotonic, preservative-free solution. Study drug is administered once every 28 days as an initial 120 ( ⁇ 10)-minute IV infusion. If the subject tolerates the initial infusion, subsequent infusions may be administered over 60 ( ⁇ 10) minutes.
  • WFI sterile water for injection
  • the length of the infusion may be extended over a longer period of time if and when it is clinically indicated. A minimum of 21 days between doses is required.
  • Premedication All subjects are premedicated for each dose of study drug with 25 mg diphenhydramine (or an equivalent dose of a H1 antihistamine) and 650 mg acetaminophen (or an equivalent paracetamol dose) within 30-90 minutes prior to study drug administration.
  • Standard of Care Chemotherapy All subjects receive concomitant standard of care chemotherapy, which must include bortezomib administered subcutaneously on a weekly basis for the initial, first-line chemotherapy regimen. Subsequent chemotherapy regimens may be prescribed as per standard of care at the Investigator’s discretion. Antiviral prophylaxis is required.
  • the Intent-to-Treat (ITT) Population includes all subjects with Mayo Stage IV AL amyloidosis who receive any amount of study drug.
  • the ITT Population is the primary population used for efficacy and safety analyses. Efficacy Analyses. Primary Analysis - The primary endpoint is time to all-cause mortality. For all-cause mortality, all deaths occurring after the first infusion of study drug (Study Day 1) through the study’s last subject last visit (LSLV) are included. Using an exponential survival model, the estimated survival percentage at 9 months is estimated. Using an exact binomial test, the estimated survival percentage is compared to the historical control value of 49%.
  • the 28-day Screening period may be extended upon approval by the Medical Monitor. Individual test results that do not meet eligibility requirements may be repeated, with the exception of 6MWT; full rescreening is allowed once per subject.
  • Cycle 2-Days 8 and 22 and Cycle 3-Days 8, 15 and 22 bortezomib-containing chemotherapy should be administered by the Investigator at the study site if subject had significant toxicity; otherwise, it may be administered by local physician at Investigator’s discretion.
  • Results from mass spectrometry tissue typing, immunoelectron microscopy, gene sequencing, and/or 99mTc scintigraphy must be obtained prior to randomization to assess eligibility for subjects identified in Inclusion Criterion #5. 6.
  • the SF-36v2 (Appendix 4) is to be administered, the SF-36v2 needs to be administered prior to the performance of any other study assessments on that day. 7. If an echocardiogram has been conducted within 90 days prior to Screening Day -28, it does not need to be repeated during Screening and the previous result can be used for eligibility. After Screening, perform echocardiograms every 6 months within 10 days prior to Day 1; repeat at EOT/ETD if not performed within 60 days prior to visit.
  • ECG to be performed in triplicate as follows: Month 1-Day 1: within 30 minutes before dosing and 1 hour ( ⁇ 15 min) post-EOI; All Other Visits (Months 1, 2, 3 and every 3 months starting at Month 6): within 30 minutes before dosing or any time on non-infusion days. Medications given for prophylaxis chemotherapy-induced side effects should not be administered prior to completion of the post infusion ECG. 9.
  • Complete PE includes height (Screening only), weight, and examination of the following: general appearance; head, ears, eyes, nose, and throat; neck; skin; cardiovascular Attorney Docket No.50887-0050WO1 system; respiratory system; gastrointestinal system; and nervous system. Assess macroglossia, submandibular nodes/fullness, adenopathy, ecchymoses, liver/spleen size (palpable +/-), ascites (+/-), and edema (which should be quantified on a scale of 0-4). 10.
  • Symptom-directed PE should be as clinically indicated and also include weight, and assessment of macroglossia, submandibular nodes/fullness, adenopathy, ecchymoses, liver/spleen size (palpable +/-), ascites (+/-), and edema (which should be quantified on a scale of 0-4).
  • Local laboratory results for hematology and chemistry will be used for subject management and should be reviewed for safety assessment prior to administration of chemotherapy but will not be collected in the electronic case report forms or the clinical database. 12. Perform only if subject returns to study site for this visit.
  • 14. Obtain local urine pregnancy test prior to study drug administration. 15.
  • the postbaseline 6MWT may be administered on the same calendar day that study drug is administered (i.e., Months 3, 6, 9, etc.) as long as the NT- proBNP sample is drawn before conducting the 6MWT and the 6MWT is completed before initiation of the study drug infusion.
  • Collect BP and HR pre- and post-6MWT administration 20.
  • the first Screening 6MWT must be performed between Days -28 and -5, at least 4 days prior to the second Screening 6MWT, which should be performed within 2 days prior to the Month 1-Day 1 visit (i.e., on Day -2 or Day -1).
  • Attorney Docket No.50887-0050WO1 21.
  • Archive serum samples will only be collected from those subjects who have consented to the collection and archiving of their samples for future correlative testing. 22. All subjects are to receive 25 mg diphenhydramine (or an equivalent dose of a H1 antihistamine) and 650 mg acetaminophen (or an equivalent paracetamol dose) within 3090 minutes prior to the start of infusion.
  • First-line chemotherapy must be a bortezomib-containing regimen, with bortezomib administered weekly, SC, according to the approved prescribing information and local institutional practices. Antiviral prophylaxis is required. When chemotherapy is administered on same day as study drug, the chemotherapy must be administered AFTER the post-study drug infusion observation period. Number of first-line chemotherapy cycles and subsequent chemotherapy regimens will be administered per standard of care at the Investigator’s discretion. 26.
  • Cycle 2-Days 8 and 22, and Cycle 3-Days 8, 15, and 22 chemotherapy may be administered by local physician with a Homecare visit by a Prothena-sponsored healthcare professional to the subject within 1 day prior to or pre-dose on the day of each bortezomib administration to obtain vital signs, blood samples for central laboratory testing, and bioanalytical samples (if applicable).

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Abstract

L'invention concerne des formulations d'anticorps et des méthodes utiles pour le traitement de patients atteints d'amylose AL.
PCT/US2025/014544 2024-02-06 2025-02-05 Méthodes de traitement de l'amylose al Pending WO2025170969A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200308260A1 (en) * 2019-03-05 2020-10-01 Prothena Biosciences Limited Methods of treating al amyloidosis
WO2023137342A2 (fr) * 2022-01-11 2023-07-20 Prothena Biosciences Limited Procédés de traitement de l'amyloïdose al

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200308260A1 (en) * 2019-03-05 2020-10-01 Prothena Biosciences Limited Methods of treating al amyloidosis
WO2023137342A2 (fr) * 2022-01-11 2023-07-20 Prothena Biosciences Limited Procédés de traitement de l'amyloïdose al

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
NUVOLONE MARIO, NEVONE ALICE, MERLINI GIAMPAOLO: "Targeting Amyloid Fibrils by Passive Immunotherapy in Systemic Amyloidosis", BIODRUGS, ADIS INTERNATIONAL LTD., NZ, vol. 36, no. 5, 1 September 2022 (2022-09-01), NZ , pages 591 - 608, XP093346375, ISSN: 1173-8804, DOI: 10.1007/s40259-022-00550-w *

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