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WO2025149845A1 - Traitement de sujets atteints de polymyalgie rhumatismale auxquels a été adminsitré un stéroïde - Google Patents

Traitement de sujets atteints de polymyalgie rhumatismale auxquels a été adminsitré un stéroïde

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Publication number
WO2025149845A1
WO2025149845A1 PCT/IB2025/000012 IB2025000012W WO2025149845A1 WO 2025149845 A1 WO2025149845 A1 WO 2025149845A1 IB 2025000012 W IB2025000012 W IB 2025000012W WO 2025149845 A1 WO2025149845 A1 WO 2025149845A1
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Prior art keywords
steroid
therapy
administered
subject
antigen
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English (en)
Inventor
Stefano FIORE
Kerri FORD
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Sanofi Biotechnology SAS
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Sanofi Biotechnology SAS
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Publication of WO2025149845A1 publication Critical patent/WO2025149845A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • 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
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • 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
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule

Definitions

  • the subject had new-onset PMR when the steroid treatment began. In certain exemplary embodiments, the subject does not have giant cell arteritis or rheumatic arthritis.
  • the csIM therapy comprises methotrexate, azathioprine, sulfasalazine, hydroxychloroquine, or leflunomide.
  • the anti-IL6R antibody or antigen-binding fragment thereof comprises heavy chain complementarity determining region (HCDR) sequences of SEQ ID NOs: 3, 4 and 5, and comprises light chain complementarity determining region (LCDR) sequences of SEQ ID NOs: 6, 7 and 8.
  • the anti- IL6R antibody or antigen-binding fragment thereof comprises a heavy chain variable region sequence of SEQ ID NO: 1 and a light chain variable region sequence of SEQ ID NO: 2.
  • the anti-IL6R antibody or antigen-binding fragment thereof comprises a heavy chain comprising SEQ ID NO: 9 and a light chain comprising SEQ ID NO: 10.
  • the anti-IL6R antibody is sarilumab.
  • the determining is performed at about six months after start of the steroid treatment.
  • the dose of the steroid at about six months after the start of the steroid treatment is greater than or equal to about 7.5 mg/day.
  • the subject has new-onset PMR when steroid treatment began.
  • the subject does not have giant cell arteritis or rheumatic arthritis.
  • the steroid is tapered or discontinued beginning at about 26 weeks after the start of the steroid treatment.
  • the steroid is tapered in a manner such that the steroid is discontinued after the IL-6 inhibitory therapy is administered for a period of at least about 50 days.
  • the steroid is tapered in a manner such that the steroid is discontinued after the IL-6 inhibitory therapy is administered for a period of about 50 days to about 250 days.
  • the steroid is discontinued after the IL-6 inhibitory therapy is administered for a period of at least about 50 days.
  • the steroid is discontinued after the IL-6 inhibitory therapy is administered for a period of about 50 days to about 250 days.
  • the steroid comprises a corticosteroid.
  • the steroid comprises prednisone.
  • the PMR therapy comprising at least a steroid and no IL-6 inhibitory therapy essentially consists of or consists of a steroid.
  • the PMR therapy comprising at least a steroid and no IL-6 inhibitory therapy essentially consists of or consists of a steroid and a conventional synthetic immunomodulatory drug (csIM) therapy.
  • the csIM therapy is received within about six months of starting the steroid.
  • the csIM therapy comprises methotrexate (MTX), azathioprine, sulfasalazine, hydroxychloroquine, or leflunomide.
  • MTX methotrexate
  • azathioprine azathioprine
  • sulfasalazine hydroxychloroquine
  • leflunomide leflunomide
  • the IL-6 inhibitory therapy comprises an IL-6R antibody.
  • the IL-6 inhibitory therapy is further combined with a csIM therapy.
  • the csIM therapy comprises MTX, azathioprine, sulfasalazine, hydroxychloroquine, or leflunomide.
  • the IL-6 inhibitory therapy comprises an anti-IL6R antibody or antigen-binding fragment thereof.
  • the anti-IL6R antibody or antigen-binding fragment thereof is at a dose of about 150 mg.
  • the anti-IL6R antibody or antigen-binding fragment thereof is at a dose of about 200 mg.
  • the anti-IL6R antibody or antigen-binding fragment thereof is to be administered every other week (q2w).
  • the anti-IL6R antibody or antigen-fragment thereof comprises heavy chain complementarity determining region (HCDR) sequence of SEQ ID NOs: 3, 4 and 5, and comprises light chain complementarity determining region (LCDR) sequence of SEQ ID NOs: 6, 7 and 8.
  • HCDR heavy chain complementarity determining region
  • LCDR light chain complementarity determining region
  • the anti-IL6R antibody or antigen-binding fragment thereof comprises a heavy chain variable region sequence of SEQ ID NO: 1 and a light chain variable region sequence of SEQ ID NO: 2.
  • the anti-IL6R antibody or antigen-binding fragment thereof comprises a heavy chain comprising SEQ ID NO: 9 and a light chain comprising SEQ ID NO: 10.
  • the anti-IL6R antibody is sarilumab.
  • the subject is 50 years and older.
  • the anti-IL6R antibody or antigen-binding fragment thereof is administered as a pharmaceutical composition subcutaneously using a needle and syringe, a pen delivery device, or an autoinjector.
  • the anti-IL6R antibody or antigen binding fragment thereof is administered using a prefilled syringe containing about 175 mg/mL sarilumab.
  • administering of the IL-6 inhibitory therapy decreases a glucocorticoid toxicity index (GTI) score of the subject.
  • GTI glucocorticoid toxicity index
  • an IL-6 inhibitory therapy in the manufacture of a medicament for treatment of polymyalgia rheumatica (PMR) in a subject in in need thereof, wherein the subject is to be administered an IL-6 inhibitory therapy to a subject with PMR who is being treated with a PMR therapy comprising at least a steroid and no IL-6 inhibitory therapy, wherein a dose of the steroid administered to the subject at about six months after start of the treatment with the steroid is greater than or equal to about 5 mg per day; and tapering the dose of the steroid or discontinuing the steroid treatment.
  • PMR polymyalgia rheumatica
  • the steroid is discontinued after the IL-6 inhibitory therapy is administered for a period of at least about 50 days. In certain exemplary embodiments, the steroid is discontinued after the IL-6 inhibitory therapy is administered for a period of about 50 days to about 250 days.
  • the steroid comprises a corticosteroid. In certain exemplary embodiments, the steroid comprises prednisone.
  • the PMR therapy comprising at least a steroid and no IL-6 inhibitory therapy essentially consists of or consists of a steroid.
  • the PMR therapy comprising at least a steroid and no IL-6 inhibitory therapy essentially consists of or consists of a steroid and a conventional synthetic immunomodulatory drug (csIM) therapy.
  • the csIM therapy is received within about six months of starting the steroid.
  • the csIM therapy comprises methotrexate (MTX), azathioprine, sulfasalazine, hydroxychloroquine, or leflunomide.
  • the IL-6 inhibitory therapy is administered in combination with the csIM therapy to the subject.
  • the csIM therapy is selected from methotrexate, azathioprine, sulfasalazine, hydroxychloroquine, and leflunomide.
  • the IL-6 inhibitory therapy comprises an anti-anti- IL6R antibody or an antigen-binding fragment thereof.
  • the anti-IL6R antibody or antigen-binding fragment thereof is administered at a dose of about 150 mg to about 200 mg.
  • the anti-IL6R antibody or antigen-binding fragment thereof is administered at a dose of about 150 mg.
  • the anti-IL6R antibody or antigen-binding fragment thereof is administered at a dose of about 200 mg.
  • the anti-IL6R antibody or antigen-binding fragment thereof is administered every other week (q2w).
  • the anti-IL6R antibody or antigen-binding fragment thereof comprises heavy chain complementarity determining region (HCDR) sequences of SEQ ID NOs: 3, 4 and 5, and comprises light chain complementarity determining region (LCDR) sequences of SEQ ID NOs: 6, 7 and 8.
  • the anti- IL6R antibody or antigen-binding fragment thereof comprises a heavy chain variable region sequence of SEQ ID NO: 1 and a light chain variable region sequence of SEQ ID NO: 2.
  • the anti-IL6R antibody or antigen-binding fragment thereof comprises a heavy chain comprising SEQ ID NO: 9 and a light chain comprising SEQ ID NO: 10.
  • the anti-IL6R antibody is sarilumab.
  • the anti-IL6R antibody or antigen-binding fragment thereof is administered subcutaneously.
  • the anti-IL6R antibody or antigen-binding fragment thereof is administered as a pharmaceutical composition subcutaneously using a needle and syringe, a pen delivery device, or an autoinjector.
  • the anti-IL6R antibody or antigen binding fragment thereof is administered using a prefilled syringe containing about 175 mg/mL sarilumab.
  • the administering the IL-6 inhibitory therapy improves at least one symptom of PMR in the subject.
  • the administering the IL-6 inhibitory therapy decreases a glucocorticoid toxicity index (GTI) score of the subject.
  • GTI glucocorticoid toxicity index
  • the selecting the subject In certain exemplary embodiments, the selection is performed at about six months after start of the steroid treatment. In certain exemplary embodiments, the selection is performed after about six months after start of the steroid treatment.
  • the dose of the steroid at about six months after the start of the steroid treatment is greater than about 5 mg per day. In certain exemplary embodiments, the dose of the steroid at about six months after the start of the steroid treatment is greater than or equal to about 7.5 mg/day.
  • the steroid is discontinued after the IL-6 inhibitory therapy is administered for a period of about 50 days to about 250 days.
  • the steroid comprises a corticosteroid.
  • the steroid comprises prednisone.
  • the PMR therapy comprising at least a steroid and no IL-6 inhibitory therapy essentially consists of or consists of a steroid.
  • the PMR therapy comprising at least a steroid and no IL-6 inhibitory therapy essentially consists of or consists of a steroid and a conventional synthetic immunomodulatory drug (csIM) therapy.
  • the csIM therapy is received within about six months of starting the steroid.
  • the csIM therapy comprises methotrexate (MTX), azathioprine, sulfasalazine, hydroxychloroquine, or leflunomide.
  • the IL-6 inhibitory therapy is administered in combination with the csIM therapy to the subject.
  • the csIM therapy is selected from methotrexate, azathioprine, sulfasalazine, hydroxychloroquine, and leflunomide.
  • the IL-6 inhibitory therapy comprises an anti-anti- IL6R antibody or an antigen-binding fragment thereof.
  • the anti-IL6R antibody or antigen-binding fragment thereof is administered at a dose of about 150 mg to about 200 mg.
  • the anti-IL6R antibody or antigen-binding fragment thereof is administered at a dose of about 150 mg.
  • the anti-IL6R antibody or antigen-binding fragment thereof is administered at a dose of about 200 mg.
  • the anti-IL6R antibody or antigen-binding fragment thereof is administered every other week (q2w).
  • the anti-IL6R antibody or antigen-binding fragment thereof comprises heavy chain complementarity determining region (HCDR) sequences of SEQ ID NOs: 3, 4 and 5, and comprises light chain complementarity determining region (LCDR) sequences of SEQ ID NOs: 6, 7 and 8.
  • the anti- IL6R antibody or antigen-binding fragment thereof comprises a heavy chain variable region sequence of SEQ ID NO: 1 and a light chain variable region sequence of SEQ ID NO: 2.
  • the anti-IL6R antibody or antigen-binding fragment thereof comprises a heavy chain comprising SEQ ID NO: 9 and a light chain comprising SEQ ID NO: 10.
  • the anti-IL6R antibody is sarilumab.
  • the subject is 50 years and older.
  • the subject is further characterized by Charlson comorbidity index score and is seronegative for rheumatoid arthritis of FIG. 4, or has diabetes, myocardial infection, stroke, percutaneous coronary intervention and cardiac artery bypass surgery, hypertension, unstable angina, cardiac dysrhythmia, heart failure, osteoporosis or osteopenia, osteonecrosis, glaucoma, steroid myopathy psychiatric conditions or combinations thereof.
  • the anti-IL6R antibody or antigen-binding fragment thereof is administered subcutaneously.
  • the anti-IL6R antibody or antigen-binding fragment thereof is administered as a pharmaceutical composition subcutaneously using a needle and syringe, a pen delivery device, or an autoinjector.
  • the anti-IL6R antibody or antigen binding fragment thereof is administered using a pre filled syringe containing about 175 mg/mL sarilumab.
  • FIG. 1A-FIG. IB graphically represent the mean and median glucocorticoid dose at six months by glucocorticoid status at one year.
  • the mean daily glucocorticoid dose is from month 5 to month 7, with the P value determined by T-test, Wilcoxon signed-rank test, Chi- squared test, and Fisher’s exact test.
  • FIG. 4 is a table depicting the key demographic and clinical characteristics at six months by glucocorticoid status at one year.
  • a Region reason for enrolling in Medicare, baseline diagnosis of asthma, atopic dermatitis COPD, Crohn’s disease, psoriasis, ulcerative colitis, baseline HCRU (inpatient days, emergency room visits, outpatient office visits, unique prescription medications filled) were also analyzed and were not significant.
  • b T-test was used to compare normally distributed continuous variables, Wilcoxon signed-rank test for non- normally distributed continuous variables, chi-squared test for categorical variables and Fisher's exact test to compare categorical variables for small sample size.
  • the present disclosure provides methods and compositions for treating polymyalgia rheumatica (PMR).
  • PMR polymyalgia rheumatica
  • Polymyalgia rheumatica is a chronic, inflammatory disorder almost exclusively occurring in people over 50 years old.
  • Polymyalgia rheumatica presents with pain and stiffness of the shoulders and possibly the hip, elevated inflammatory makers (although occasionally normal), and a characteristic dramatic response to corticosteroids.
  • administering typically refers to the administration of a composition to a subject to achieve delivery of an agent that is, or is included in, a composition to a target site or a site to be treated.
  • routes may, in appropriate circumstances, be utilized for administration to a subject, for example a human.
  • administration may be parenteral or subcutaneous.
  • administration may involve only a single dose.
  • administration may involve application of a fixed number of doses.
  • administration may involve dosing that is intermittent (e.g., a plurality of doses separated in time) and/or periodic (e.g., individual doses separated by a common period) dosing. In some embodiments, administration may involve continuous dosing (e.g., perfusion) for at least a selected period.
  • csIM conventional synthetic immunomodulatory drug
  • sDMARD synthetic disease-modifying antirheumatic drug
  • an IL-6 inhibitory therapy is a therapy that partially or completely blocks an IL-6-associated pathway.
  • an IL-6 inhibitory therapy is an antibody.
  • Suitable IL-6 antibodies include, but are not limited to, sarilumab, tocilizumab, satralizumab, olokizumab, siltuximab, clazakizumab, sirukumab, vobarilizumab, gerilimzumab, clazakizumab, ziltivekimab, olokizumab, and levilimab.
  • new onset when used in the context of PMR, means a newly developed or recent appearance or beginning of one or more signs and symptoms of PMR. For example, in some embodiments, a subject does not have a prior history of PMR before the treatment of the subject.
  • PMR flare refers to an increase in one or more PMR symptoms.
  • the signs and symptoms include (i) shoulder pain associated with inflammatory stiffness, (ii) hip girdle pain associated with inflammatory stiffness, (iii) morning stiffness for more than 45 minutes, (iv) elevated C-reactive protein (CRP) levels, (v) elevated erythrocyte sedimentation rate (ESR), and any combination thereof.
  • the terms “treat,” and “treating,” mean to: (1) partially or completely alleviate one or more symptoms or features of a disease, disorder, and/or condition; or (2) ameliorate, relieve, inhibit, prevent, delay onset of, reduce the severity of, and/or reduce the incidence of one or more symptoms or features of a disease, disorder, and/or condition, e.g., PMR, either on a temporary or permanent basis.
  • Subjects diagnosed with PMR are based on the classification criteria for the diagnosis of PMR described in the European League against Rheumatism and the American College of Rheumatology (Dasgupta B, et al. 2012 provisional classification criteria for polymyalgia rheumatica: a European League against Rheumatism/American College of Rheumatology collaborative initiative. Annals of the Rheumatic Diseases 2012; 71 :484-492, incorporated by reference herein in its entirety). Criteria for classification include a patient who is 50 years old or older presenting with bilateral shoulder pain (not better explained by an alternative diagnosis) and elevated C-reactive protein (CRP) levels and/or elevated erythrocyte sedimentation rate (ESR).
  • CRP C-reactive protein
  • Additional criteria include the presence of morning stiffness for more than 45 minutes, and the presentation of new symptoms involving the hip (e.g., pain, tenderness, and limited movement). Additional classification criteria can include the lack of peripheral synovitis, lack of positive rheumatoid arthritis (RA) serology (rheumatoid factor (RF), anti-citrullinated protein antibody (ACPA), or both), and absence of peripheral joint pain. Additional classification criteria can include musculoskeletal ultrasound findings of bilateral shoulder abnormalities (subacromial bursitis / bicipital tenosynovitis / glenohumeral effusion) or abnormalities in one shoulder and hip (hip effusion, trochanteric bursitis).
  • Classification criteria for the diagnosis of polymyalgia rheumatica are also described in the European League against Rheumatism and the American College of Rheumatology, Dasgupta B, et al. 2012 provisional classification criteria for polymyalgia rheumatica: a European League against Rheumatism/ American College of Rheumatology collaborative initiative. Annals of the Rheumatic Diseases 2012; 71 :484-492, incorporated herein in their entireties). Criteria for classification may include a patient who is 50 years old or older presenting with bilateral shoulder pain (not better explained by an alternative diagnosis) and elevated C-reactive protein (CRP) levels and/or elevated erythrocyte sedimentation rate (ESR).
  • CRP C-reactive protein
  • Additional criteria may include the presence of morning stiffness for more than 45 minutes, and the presentation of new symptoms involving the hip (e.g., pain, tenderness, and limited movement).
  • American College of Rheumatology criteria for rheumatic diseases including polymyalgia rheumatica can be found at www.rheumatology.org/Practice-Quality/Clinical-Support/Criteria/ACR-Endorsed-Criteria, incorporated herein in its entirety).
  • Sarilumab (SAR153191), also designated as REGN88, is a recombinant IgGl kappa monoclonal antibody of fully human sequence directed against the alpha subunit of the IL-6 receptor complex (IL-6Ra). Sarilumab blocks the binding of IL-6 and interrupts the cytokine-mediated signaling cascade. Sarilumab is also known by the tradename KEVZARA®. [00116] Tocilizumab (TCZ) is a humanized anti-interleukin-6 (IL-6) receptor monoclonal antibody that binds to the membrane -bound and soluble IL-6 receptors, inhibiting IL-6 signaling. Tocilizumab is also known by the tradename ACTEMRA®.
  • Satralizumab is a recombinant humanized monoclonal antibody targeted against human interleukin-6 (IL-6) receptors. Satralizumab is also known by the tradename ENSPRYNG®.
  • Levilimab is a fully human monoclonal antibody that binds to interleukin-6 receptor.
  • Levilimab is also known by new the tradename ILSIRA®.
  • Siltuximab is a chimeric, human-murine immunoglobulin monoclonal antibody that binds to and neutralizes human IL-6 directly, thereby decreasing levels of unbound IL-6 and preventing binding to its receptor. Siltuximab is also known as SYLVANT®.
  • Clazakizumab is a humanized monoclonal antibody that binds interleukin-6.
  • the administration of the IL-6 inhibitory therapy decreases the cumulative amount of the steroid received by the subject (as measured over a period of time after the administration of the IL-6 inhibitory therapy).
  • a period of time may be about 2 months, about 4 months, about 5 months, or about 6 months after the administration of the IL-6 inhibitory therapy.
  • such a period of time may be about 2 months to 6 months or about 2 months to 4 months.
  • a subject who is receiving at least the steroid treatment is recommended for a different PMR therapy comprising: (a) administering an IL-6 inhibitory therapy and (b) tapering the dose of the steroid or discontinuing the steroid treatment.
  • PMR-associated ClinRO measure includes physician global assessment of disease activity-visual analog scale (MD-VAS).
  • An “improvement in a PMR-associated ClinRO measure” means a decrease from baseline of MD-VAS score.
  • baseline means the numerical value of the ClinRO measure for a patient prior to or at the time of administration of a pharmaceutical composition comprising an IL-6R antagonist.
  • a PMR-associated parameter is quantified at baseline and at a time point after administration of the pharmaceutical composition described herein.
  • a PMR-associated parameter may be measured at day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, day 10, day 11, day 12, day 14, or at week 3, week 4, week 5, week 6, week 7, week 8, week 9, week 10, week 11, week 12, week 13, week 14, week 15, week 16, week 17, week 18, week 19, week 20, week 21, week 22, week 23, week 24, week 32, week 40, week 52, or longer, after the initial treatment with the pharmaceutical composition.
  • Information that is acquired indirectly can be provided in the form of a report, e.g., supplied in paper or electronic form, such as from an online database or application (an “App”).
  • the report or information can be provided by, for example, a healthcare institution, such as a hospital or clinic; or a healthcare provider, such as a doctor or nurse.
  • Therapeutic methods are provided that result in an increase in FACIT-Fatigue score from baseline.
  • administration of an IL-6R antagonist to a subject in need thereof causes an increase in FACIT-Fatigue score from baseline of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50.
  • PtGA is a single question with a score of 0 to 100 that focuses on overall health or disease activity from the patient perspective. A higher score represents a higher level of disease activity or a worse global health.
  • VAS Pain Visual Analog Scale
  • Pain VAS is a unidimensional, patient reported measure of pain intensity (See Delgado et al. “Validation of digital visual analog scale pain scoring with a traditional paper-based visual analog scale in adults” Journal of the American Academy of Orthopaedic Surgeons, Mar;2(3)). Pain VAS score ranges from 0 to 100 and a higher score indicates greater pain intensity.
  • Therapeutic methods are provided that result in a decrease in Pain VAS score from baseline.
  • administration of an IL-6R antagonist to a subject in need thereof causes a decrease in Pain VAS score from baseline of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,
  • PMR-AS PMR Activity Score
  • Therapeutic methods are provided that result in a decrease in GTI-CWS or GTI-AIS score from baseline.
  • administration of an IE-6R antagonist to a subject in need thereof causes a decrease in GTI-CWS or GTI-AIS score from baseline of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,
  • the cumulative corticosteroid dose is a measure of a patient’s exposure to corticosteroids over a period of time, such as about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,
  • the methods described herein comprise administering a therapeutically effective amount of an anti-IL-6R antibody to a subject.
  • therapeutically effective amount means a dose of the therapeutic that results in treatment of polymyalgia rheumatica.
  • “treating” refers to causing a detectable improvement in one or more symptoms associated with polymyalgia rheumatica or causing a biological effect (e.g., a decrease in the level of a particular biomarker) that is correlated with the underlying pathologic mechanism(s) giving rise to the condition or symptom(s).
  • a detectable “improvement” can also be detected using at least one test, score or metric described herein.
  • the improvement is detected by a reduction in a symptom of PMR selected from the group consisting of: morning stiffness, pain in the neck, pain in the shoulder, pain in the hip girdles, limited range of motion of the shoulders, limited range of motion in the hip girdles, constitutional symptoms (e.g., fatigue, weight loss and low grade fever), and other features judged by the clinician-investigator to be consistent with a PMR flare.
  • a treatment has not been effective when a dose of anti-IL-6R antibody does not result in a detectable improvement in one or more parameters or symptoms associated with PMR or which does not cause a biological effect that is correlated with the underlying pathologic mechanism(s) giving rise to the condition or symptom(s) of PMR.
  • an IL-6R antibody is administered subcutaneously.
  • the IL-6R antibody is sarilumab.
  • a csIM e.g., MTX
  • a combination of the IL-6R antibody and csIM is administered.
  • a therapeutically effective amount of anti-IL-6R antibody that is administered to the subject will vary depending upon the age and the size (e.g., body weight or body surface area) of the subject as well as the route of administration and other factors well known to those of ordinary skill in the art.
  • compositions provided herein e.g., encapsulation in liposomes, microparticles, microcapsules, receptor mediated endocytosis.
  • Methods of introduction include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes.
  • the composition may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc), and may be administered together with other biologically active agents. Administration can be systemic or local.
  • the IL-6R antibody can be administered subcutaneously.
  • the pharmaceutical composition can also be delivered in a vesicle, such as a liposome.
  • the pharmaceutical composition can be delivered in a controlled release system, for example, with the use of a pump or polymeric materials.
  • a controlled release system can be placed in proximity of the composition’s target, thus requiring only a fraction of the systemic dose.
  • the injectable preparations may include dosage forms for intravenous, subcutaneous, intracutaneous, and intramuscular injections, local injection, drip infusions, etc. These injectable preparations may be prepared by methods publicly known.
  • the injectable preparations may be prepared, e.g., by dissolving, suspending or emulsifying the antibody or its salt described above in a sterile aqueous medium or an oily medium conventionally used for injections.
  • a sterile aqueous medium or an oily medium conventionally used for injections.
  • the aqueous medium for injections there are, for example, physiological saline, an isotonic solution containing glucose and other auxiliary agents, etc., which may be used in combination with an appropriate solubilizing agent such as an alcohol (e.g., ethanol), a polyalcohol (e.g., propylene glycol, polyethylene glycol), a nonionic surfactant [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], etc).
  • an alcohol e.g., ethanol
  • a polyalcohol e.g., propylene glycol, polyethylene glyco
  • the antibody is typically formulated as described herein and in international publication number WO2011/085158, incorporated herein by reference in its entirety.
  • the antibody is administered as an aqueous buffered solution at about pH 6.0 containing, about 21 mM histidine, about 45 mM arginine, about 0.2% (w/v) polysorbate 20, about 5% (w/v) sucrose, and between about 100 mg/mL and about 200 mg/mL of the antibody.
  • the antibody is administered as an aqueous buffered solution at about pH 6.0 containing, about 21 mM histidine, about 45 mM arginine, about 0.2% (w/v) polysorbate 20, about 5% (w/v) sucrose, and at least about 130 mg/mL of the antibody.
  • the antibody is administered as an aqueous buffered solution at about pH 6.0 containing, about 21 mM histidine, about 45 mM arginine, about 0.2% (w/v) polysorbate 20, about 5% (w/v) sucrose, and about 131.6 mg/mL of the antibody.
  • the antibody is administered as an aqueous buffered solution at about pH 6.0 containing, about 21 mM histidine, about 45 mM arginine, about 0.2% (w/v) polysorbate 20, about 5% (w/v) sucrose; and about 175 mg/mL of the antibody.
  • the antibody is administered as an aqueous buffered solution at pH 6.0 containing,
  • the antibody is administered as an aqueous buffered solution at pH 6.0 containing,
  • the anti-IL-6R antibody (or pharmaceutical formulation comprising the antibody) can be administered to the patient using any acceptable device or mechanism.
  • the administration can be accomplished using a syringe and needle or with a reusable pen and/or autoinjector delivery device.
  • the methods of the present disclosure include the use of numerous reusable pen and/or autoinjector delivery devices to administer an anti-IL-6R antibody (or pharmaceutical formulation comprising the antibody).
  • Examples of disposable pen and/or autoinjector delivery devices having applications in subcutaneous delivery of a pharmaceutical composition of the present disclosure include, but are not limited to the SOLOSTAR® pen (Sanofi-Aventis), the FLEXPEN® (Novo Nordisk), and the KWIKPEN® (Eli Lilly), the SURECLICK® Autoinjector (Amgen, Thousand Oaks, CA), the PENLET® (Haselmeier, Stuttgart, Germany), the EPIPEN® (Dey, L.P.)., and the HUMIRA® Pen (AbbVie Inc., North Chicago, IL), to name only a few.
  • SOLOSTAR® pen Sanofi-Aventis
  • the FLEXPEN® Novo Nordisk
  • KWIKPEN® Eli Lilly
  • SURECLICK® Autoinjector Amgen, Thousand Oaks, CA
  • the PENLET® Heaselmeier, Stuttgart, Germany
  • EPIPEN® Dey, L.P.
  • HUMIRA® Pen AbbVi
  • the antibody is administered with a prefilled syringe.
  • the antibody is administered with a prefilled syringe containing a safety system.
  • the safety system prevents an accidental needle-stick injury.
  • the antibody is administered with a prefilled syringe containing an ERIS safety system (West Pharmaceutical Services Inc).
  • microinfusor means a subcutaneous delivery device designed to slowly administer large volumes (e.g., up to about 2.5 mL or more) of a therapeutic formulation over a prolonged period of time (e.g., about 10, 15, 20, 25, 30 or more minutes). Microinfusors are particularly useful for the delivery of large doses of therapeutic proteins contained within high concentration (e.g., about 100, 125, 150, 175, 200 mg/mL or more) and/or viscous solutions.
  • high concentration e.g., about 100, 125, 150, 175, 200 mg/mL or more
  • an inadequate response to prior treatment refers to subjects whose pain is not well controlled after receiving the prior treatment at the maximum tolerated typical dose.
  • an inadequate response to prior treatment refers to subjects who have moderate or high disease activity and features of poor prognosis despite prior treatment.
  • an inadequate response to prior treatment refers to subjects with a pain symptom (e.g., any symptom listed herein) that has not improved or that has worsened despite prior treatment.
  • the amount of IL-6R antagonist (e.g., anti-IL-6R antibody) administered to a subject according to the methods described herein is, generally, a therapeutically effective amount.
  • therapeutically effective amount means an amount of IL-6R antagonist that results in improvement in one or more PMR-associated PRO measures or ClinRO measures (as defined elsewhere herein).
  • a “therapeutically effective amount” also includes an amount of IL-6R antagonist that inhibits, prevents, lessens, or delays the progression of PMR in a subject.
  • a therapeutically effective amount of anti-IL-6R antibody reduces the dose of corticosteroid (e.g., prednisone) administered to a subject.
  • a therapeutically effective amount can be from about 0.05 mg to about 700 mg, e.g., about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 3.0 mg, about 5.0 mg, about 7.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about
  • a subject is an adult, and the IL-6R antagonist is administered at an initial dose of about 400 mg and one or more secondary doses or maintenance doses of about 200 mg, and the secondary doses are administered every other week (q2w).
  • the initial dose comprises about 300 mg of the IL-6R antagonist, and the one or more subsequent doses comprise about 300 mg of the IL-6R antagonist administered every other week.
  • an IL-6R antagonist is administered at a concentration of 150 mg/mL using a prefilled device.
  • a 150 mg/mL IL-6R antagonist solution in a pre-filled device is used to deliver about 300 mg IL-6R antagonist in a 2 mL injection.
  • an IL-6R antagonist is administered at a concentration of 175 mg/mL using a prefilled device.
  • a 175 mg/mL IL-6R antagonist solution in a pre-filled device is used to deliver about 200 mg IL-6R antagonist in a 1.14 mL injection.
  • the method is used to treat PMR (or one or more symptoms of PMR) in a subject that has had an inadequate response to a background therapy, in particular to steroids such as corticosteroids.
  • the method leads to treatment of PMR (or one or more symptoms of PMR) with a reduced need or without the need for corticosteroid background therapy.
  • the corticosteroid background therapy is administered at a dosage of about greater than 5.0 mg/day, 7.5 mg/day, about 10 mg/day, about 12.5 mg/day, about 15 mg/day, about 20 mg/day, about 25 mg/day, about 30 mg/day, about 35 mg/day, about 40 mg/day, about 45 mg/day, about 50 mg/day, about 55 mg/day, about 60 mg/day, about 65 mg/day, about 70 mg/day, about 75 mg/day, or about 80 mg/day.
  • the corticosteroid background therapy is administered at a dosage of about greater than 5 mg/day.
  • the dose of the background therapy is tapered with treatment with the IL-6R inhibitory therapies or csIM.
  • Polymyalgia rheumatica patients attempting to taper the daily dosage of corticosteroid treatment to lower dosages of corticosteroid can experience at least one episode of flare, e.g., reducing the dose such that the patient no longer experiences shoulder pain, hip girdle pain, or both, along with inflammatory stiffness lasting more than a certain period of time (e.g., 45 minutes) in the morning.
  • Treatment with an IL-6R antibody or antibody fragment, as described herein can lessen the episodes of flare as a subject’s daily dosage of corticosteroid treatment is tapered, or decreased, over time.
  • the corticosteroid background therapy can be tapered from about greater than or equal to 7.5 mg/day to about 1 mg/day. In certain embodiments, corticosteroid background therapy can be tapered from about less than 7.5 mg/day daily, less than 6.0 mg/day, less than 5 mg/day, less than 4 mg/day, 3 mg/day, 2 mg/day, 1 mg/day. In some embodiments, the taper is from 7.5 mg/day to 5.0 mg/day, 6 mg/day to 3 mg/day, 4 mg/day to2 mg/day, 3 mg/day tol mg/day or 1 mg/day to 5 mg/day.
  • the steroid is tapered or discontinued beginning about 24 weeks, about 25 weeks, about 26 weeks, 30 weeks, 40 weeks or up to 1 year.
  • the taper begins from about 24 to about 30 weeks, about 26 weeks to about 36 weeks, about 30 weeks to about 40 weeks, 40 weeks to about 52 weeks.
  • the steroid is tapered in a manner such that the steroid is discontinued after the IL-6 inhibitory therapy (e.g., an anti-IL-6R antibody or antigen-binding fragment thereof) is administered for a period of at least about 50 days, at least about 60 days, at least about 70 days, at least about 80 days, at least about 90 days, at least about 100 days, at least about 125 days, at least about 150 days.
  • the IL-6 inhibitory therapy e.g., an anti-IL-6R antibody or antigen-binding fragment thereof
  • the steroid is tapered in a manner such that the steroid is discontinued after the IL-6 inhibitory therapy (e.g., an anti-IL-6R antibody or antigen-binding fragment thereof) is administered for a period of about 25 days to about 300 days.
  • the IL-6 inhibitory therapy e.g., an anti-IL-6R antibody or antigen-binding fragment thereof
  • the steroid is tapered in a manner such that the steroid is discontinued after the IL-6 inhibitory therapy (e.g., an anti-IL-6R antibody or antigen-binding fragment thereof) is administered for a period of about about 50 days to about 250 days, about 50 days to about 300 days, about 50 days to about 350 days, at least about 50 days to 150 days, of at least about 50 days to 100 days, of at least about 50 days to 80 days, of at least about 50 days to 70 days, or of at least about 50 days to 60 day.
  • the IL-6 inhibitory therapy e.g., an anti-IL-6R antibody or antigen-binding fragment thereof
  • the steroid is discontinued after the IL-6 inhibitory therapy (e.g., an anti-IL-6R antibody or antigen-binding fragment thereof) is administered for a period of at least about 50 days, at least about 60 days, at least about 70 days, at least about 80 days, at least about 90 days, at least about 100 days, at least about 125 days, at least about 150 days.
  • the IL-6 inhibitory therapy e.g., an anti-IL-6R antibody or antigen-binding fragment thereof
  • the steroid is discontinued after the IL-6 inhibitory therapy (e.g., an anti-IL-6R antibody or antigen-binding fragment thereof) is administered for a period of about 25 days to about 300 days.
  • the steroid is tapered in a manner such that the steroid is discontinued after the IL-6 inhibitory therapy (e.g., an anti-IL-6R antibody or antigen-binding fragment thereof) is administered for a period of about 50 days to about 250 days, about 50 days to about 300 days, about 50 days to about 350 days, at least about 50 days to 150 days, of at least about 50 days to 100 days, of at least about 50 days to 80 days, of at least about 50 days to 70 days, or of at least about 50 days to 60 day.
  • the steroid being administered to a PMR subject in need thereof is tapered to a dose of less than or equal to about 2.5 mg/day (prednisone equivalent dose), less than or equal to about 2 mg/day (prednisone equivalent dose), less than or equal to about 1.5 mg/day (prednisone equivalent dose), less than or equal to about 1 mg/day (prednisone equivalent dose), or less than or equal to about 0.5 mg/day (prednisone equivalent dose), after the IL-6 inhibitory therapy (e.g., an anti-IL-6R antibody or antigen-binding fragment thereof) is administered for a period of time.
  • the IL-6 inhibitory therapy e.g., an anti-IL-6R antibody or antigen-binding fragment thereof
  • the additional therapeutic agent may be, e.g., another IL-6R antagonist, an IL-6 antagonist, a steroid, etc.
  • the additional therapeutic is a corticosteroid.
  • the additional therapeutic is prednisone.
  • an additional therapeutic agent administered in combination with the IL-6R antagonist is a vaccine.
  • the vaccine is a viral vaccine or a bacterial vaccine.
  • the vaccine is a live (e.g., live-attenuated) viral vaccine or a live (e.g., live-attenuated) bacterial vaccine.
  • Suitable vaccines include, but are not limited to adenovirus, anthrax (e.g., AVA vaccine (BioThrax)), cholera (e.g., Vaxchora), diphtheria (e.g., DTaP (Daptacel, Infanrix), Td (Tenivac, generic), DT (generic), Tdap (Adacel, Boostrix), DTaP-IPV (Kinrix, Quadracel), DTaP-HepB-IPV (Pediarix), DTaP-IPV/Hib (Pentacel)), hepatitis A (e.g., HepA (Havrix, Vaqta), HepA-HepB (Twinrix)), hepatitis B (e.g., HepB (Engerix-B, Recombivax HB, Heplisav-B), DTaP-HepB-IPV (Pediari
  • Suitable vaccines are also listed at the US Centers for Disease Control vaccine list, incorporated herein in its entirety for all purposes (cdc.gov/vaccines/vpd/vaccines-list.html).
  • the vaccine is for tetanus, diphtheria, pertussis and/or seasonal tri valent/ quadri valent influenza vaccine.
  • the vaccine is an inactivated vaccine, a recombinant vaccine, a conjugate vaccine, a subunit vaccine, a polysaccharide vaccine, or a toxoid vaccine.
  • the vaccine is a yellow fever vaccine.
  • the subject treated with the vaccine is concurrently treated for PMR with an IL-6R antagonist.
  • treatment with an IL-6R antagonist is suspended or terminated prior to treatment with the vaccine.
  • treatment with the IL-6R antagonist is suspended about 1 to about 9 (e.g., about 1, about 1%, about 2, about 2%, about 3, about 3%, about 4, about 4%, about 5, about 5%, about 6, about 6%, about 7, about YU, about 8, about 8%, about 9, or more) weeks prior to administration of the vaccine.
  • treatment with the IL-6R antagonist is resumed subsequent to treatment with the vaccine.
  • treatment with the IL-6R antagonist is resumed about 1 to about 14 (e.g., about 1, about 1%, about 2, about 2%, about 3, about 3%, about 4, about 4%, about 5, about 5%, about 6, about 6%, about 7, about 7%, about 8, about 8%, about 9, about 9%, about 10, about 10%, about 11, about 11%, about 12, about 12%, about 13, about 13%, about 14, about 14%, or more) weeks subsequent to administration of the vaccine.
  • treatment with the IL-6R antagonist is resumed 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, 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 76, about 77, about 78, about 79, about 80, about 81, about 82, about 83, about
  • the effectiveness of the IL-6R antagonist is not decreased by administration in combination with the vaccine, or by subsequent administration of the vaccine.
  • the effectiveness of the vaccine is not decreased by administration in combination with the IL-6R antagonist, or by previous and/or subsequent administration of the IL-6R antagonist.
  • the subject develops seroprotective neutralization titers to the vaccine when the vaccine is co-administered with the IL-6R antagonist.
  • a subject is administered a vaccine described herein, wherein before, during, or after administration of the vaccine, the subject is administered at least one dose of IL-6R antagonist.
  • multiple doses of an IL-6R antagonist may be administered to a subject over a defined time course.
  • Such methods comprise sequentially administering to a subject multiple doses of an IL-6R antagonist.
  • “sequentially administering” means that each dose of IL-6R antagonist is administered to the subject at a different point in time, e.g., on different days separated by a predetermined interval (e.g., hours, days, weeks, or months).
  • Methods comprising administering to a subject a pharmaceutical composition comprising an IL-6R antagonist at a dosing frequency of about four times a week, twice a week, once a week (ql w), once every two weeks (every two weeks is used interchangeably with every other week, bi-weekly or q2w), once every three weeks (tri-weekly or q3w), once every four weeks (monthly or q4w), once every five weeks (q5w), once every six weeks (q6w), once every seven weeks (q7w), once every eight weeks (q8w), once every nine weeks (q9w), once every ten weeks (qlOw), once every eleven weeks (ql Iw), once every twelve weeks (ql2w), or less frequently so long as a therapeutic response is achieved, are provided.
  • a pharmaceutical composition comprising an anti-IL-6R antibody once a week dosing of an amount of about 150 mg or about 200 mg can be employed. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-6R antibody, once every two weeks dosing (every two weeks is used interchangeably with every other week, bi-weekly or q2w) of an amount of about 150 mg, or about 200 mg can be employed. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-6R antibody, once every three weeks dosing of an amount of about 150 mg or about 200 mg can be employed.
  • a pharmaceutical composition comprising an anti-IL-6R antibody once every four weeks dosing (monthly dosing) of an amount of about 150 mg or about 200 mg can be employed. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-6R antibody, once every five weeks dosing of an amount of about 150 mg or about 200 mg can be employed. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-6R antibody, once every six weeks dosing of an amount of about 150 mg or about 200 mg can be employed. In certain exemplary embodiments, the route of administration is subcutaneous.
  • week refers to a period of (n x 7 days) ⁇ 3 days, e.g., (n x 7 days) ⁇ 2 days, (n x 7 days) ⁇ 1 day, or (n x 7 days), wherein “n” designates the number of weeks, e.g., 1, 2, 3, 4, 5, 6, 8, 12 or more.
  • one or more initial doses/loading doses of 150 mg or 200 mg of IL-6R antagonist may be administered followed by secondary doses/maintenance doses of about 150 mg or about 200 mg, respectively.
  • a loading dose may be split, e.g., two or more doses administered at different time points, e.g., two loading doses wherein a second loading dose is administered two weeks after a first loading dose.
  • Methods comprising sequential administration of an IL-6R antagonist and a second therapeutic agent, to a patient to treat PMR or an associated condition are provided.
  • the methods comprise administering one or more doses of an IL-6R antagonist followed by one or more doses (e.g., 2, 3, 4, 5, 6, 7, 8, or more) of a second therapeutic agent.
  • one or more doses of about 150 mg to about 200 mg of the IL-6R antagonist may be administered after which one or more doses (e.g., 2, 3, 4, 5, 6, 7, 8, or more) of a second therapeutic agent (e.g., a corticosteroid) may be administered to treat, alleviate, reduce or ameliorate one or more symptoms of PMR.
  • a second therapeutic agent e.g., a corticosteroid
  • the IL-6R antagonist is administered at one or more doses (e.g., 2, 3, 4, 5, 6, 7, 8, or more) resulting in an improvement in one or more PMR-associated parameters followed by the administration of a second therapeutic agent to prevent recurrence of at least one symptom of PMR.
  • doses e.g., 2, 3, 4, 5, 6, 7, 8, or more
  • a second therapeutic agent is administered at a separate dosage at a similar or different frequency relative to the IL-6R antagonist.
  • the second therapeutic agent is administered before, after or concurrently with the IL-6R antagonist.
  • the IL-6R antagonist is administered every other week for 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks, 26 weeks, 28 weeks, 30 weeks, 32 weeks, 34 weeks, 36 weeks, 38 weeks, 40 weeks, 42 weeks, 44 weeks, 46 weeks, 48 weeks or more.
  • the IL-6R antagonist is administered for at least 14 weeks.
  • the IL-6R antagonist is administered for at least 52 weeks.
  • a “subject in need thereof’ may be a subject who, prior to receiving an IL-6R antagonist, a csIM or combination thereof, has been prescribed or is currently taking a steroid.
  • the subject may be a subject who, prior to receiving an IL-6R antagonist a csIM or combination thereof, has been prescribed or is currently taking a corticosteroid.
  • the subject is currently taking prednisone or a prednisone equivalent dose.
  • the amount of the corticosteroid is gradually decreased prior to or after the start of IL-6R antagonist, a csIM or combination thereof.
  • a “subject in need thereof’ has a diagnosis of PMR refractory to steroids prior to receiving the IL-6R antagonist.
  • the PMR signs and symptoms of the subject persist despite treatment with steroids.
  • a “subject in need thereof’ has a diagnosis of PMR refractory to corticosteroids (e.g., prednisone) prior to receiving the IL-6R antagonist.
  • the PMR symptoms of the subject persist despite treatment with corticosteroids (e.g., prednisone).
  • a pharmacodynamic PMR-associated parameter is quantified at baseline and at a time point after administration of the pharmaceutical composition.
  • a pharmacodynamic PMR-associated parameter may be measured at about day 1, about day 2, about day 3, day 4, about day 5, about day 6, about day 7, about day 8, about day 9, about day 10, about day 11, about day 12, about day 14, or at about week 3, about week 4, about week 5, about week 6, about week 7, about week 8, about week 9, about week 10, about week 11, about week 12, about week 13, about week 14, about week 15, about week 16, about week 17, about week 18, about week 19, about week 20, about week 21, about week 22, about week 23, about week 24, or longer, after the initial treatment with the pharmaceutical composition.
  • administering causes a change, such as a decrease or increase, in expression of a particular biomarker.
  • PMR-associated biomarkers include, but are not limited to total IL-6, IL6R, and C-reactive protein (CRP).
  • administration of an IL-6R antagonist to a PMR patient can cause a decrease in IL-6, IL6R, or C-reactive protein (CRP) levels. The decrease can be detected at about week 1, about week 2, about week 3, about week 4, about week 5, or longer following administration of the IL-6R antagonist.
  • Biomarker expression can be assayed by methods known in the art.
  • RNA levels can be measured by ELISA (Enzyme Linked Immunosorbent Assay).
  • RNA levels can be measured, for example, by reverse transcription coupled to polymerase chain reaction (RT-PCR).
  • Biomarker expression as discussed above, can be assayed by detection of protein or RNA in serum.
  • the serum samples can also be used to monitor additional protein or RNA biomarkers related to response to treatment with an IL-6R antagonist or IL-6 signaling.
  • RNA samples are used to determine RNA levels (non-genetic analysis), e.g., RNA levels of biomarkers; and in other embodiments, RNA samples are used for transcriptome sequencing (e.g., genetic analysis).
  • the present disclosure includes methods that comprise administering to a subject an antibody, or an antigen-binding fragment thereof, that binds specifically to hIL-6R.
  • hIL-6R means a human cytokine receptor that specifically binds human interleukin-6 (IL-6).
  • the antibody that is administered to the patient binds specifically to the extracellular domain of hIL-6R.
  • antibody refers to immunoglobulin molecules comprising four polypeptide chains, two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, as well as multimers thereof (e.g., IgM).
  • Each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region.
  • the heavy chain constant region comprises three domains, CHI, CH2 and CH3.
  • Each light chain comprises a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region.
  • the light chain constant region comprises one domain (CLI).
  • VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR).
  • CDRs complementarity determining regions
  • FR framework regions
  • Each VH and VL is composed of three CDRs and four FRs, arranged from amino -terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • the FRs of the antibody (or antigen-binding portion thereof) may be identical to the human germline sequences or may be naturally or artificially modified.
  • An amino acid consensus sequence may be defined based on a side-by-side analysis of two or more CDRs.
  • antibody also includes antigen-binding fragments of full antibody molecules.
  • antigen-binding portion of an antibody, “antigen-binding fragment” of an antibody, and the like, as used herein, include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex.
  • Antigen-binding fragments of an antibody may be derived, e.g., from full antibody molecules using any suitable standard techniques such as proteolytic digestion or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding antibody variable and optionally constant domains.
  • DNA is known and/or is readily available from, e.g., commercial sources, DNA libraries (including, e.g., phage-antibody libraries), or can be synthesized.
  • the DNA may be sequenced and manipulated chemically or by using molecular biology techniques, for example, to arrange one or more variable and/or constant domains into a suitable configuration, or to introduce codons, create cysteine residues, modify, add or delete amino acids, etc.
  • Non- limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of the amino acid residues that mimic the hypervariable region of an antibody (e.g., an isolated complementarity determining region (CDR) such as a CDR3 peptide), or a constrained FR3-CDR3-FR4 peptide.
  • CDR complementarity determining region
  • engineered molecules such as domain-specific antibodies, single domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g., monovalent nanobodies, and bivalent nanobodies), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also encompassed within the expression “antigen-binding fragment,” as used herein.
  • SMIPs small modular immunopharmaceuticals
  • An antigen-binding fragment of an antibody will typically comprise at least one variable domain.
  • the variable domain may be of any size or amino acid composition and will generally comprise at least one CDR which is adjacent to or in frame with one or more framework sequences.
  • the VH and VL domains may be situated relative to one another in any suitable arrangement.
  • the variable region may be dimeric and contain VH-VH, VH-VL or VL-VL dimers.
  • the antigen-binding fragment of an antibody may contain a monomeric VH or VL domain.
  • an antigen-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain.
  • variable and constant domains that may be found within an antigen-binding fragment of an antibody include: (I) VH-CHI ; (ii) VH-CH2; (iii) VH-Cn3; (iv) VH-CH1 -C H 2; (V) VH-C H 1 -C H 2-CH3; (vi) VH-C H 2-C H 3; (vii) VH-C L ; (viii) VL-C H 1 ; (ix) VL-CH2; (X) VL-CH3 ; (xi) VL-CH1 -CH2; (xii) VL-CH1 -CH2-CH3; (xiii) VL-CH2-CH3; and (xiv) VL-CL.
  • An exemplary bi-specific antibody format that can be used in the context certain embodiments involves the use of a first immunoglobulin (Ig) CH3 domain and a second Ig CH3 domain, wherein the first and second Ig CH3 domains differ from one another by at least one amino acid, and wherein at least one amino acid difference reduces binding of the bispecific antibody to Protein A as compared to a bi-specific antibody lacking the amino acid difference.
  • the first Ig CH3 domain binds Protein A and the second Ig CH3 domain contains a mutation that reduces or abolishes Protein A binding such as an H95R modification (by IMGT exon numbering; H435R by EU numbering).
  • the present disclosure includes antibodies, and antigen-binding fragments thereof, which are derived from any of the amino acid sequences disclosed herein, wherein one or more amino acids within one or more framework and/or CDR regions are back-mutated to the corresponding germline residue(s) or to a conservative amino acid substitution (natural or non-natural) of the corresponding germline residue(s) (such sequence changes are referred to herein as “germline back-mutations”).
  • germline back-mutations such sequence changes are referred to herein as “germline back-mutations”.
  • antibodies and antigen-binding fragments that contain one or more germline back-mutations can be easily tested for one or more desired property such as, improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic biological properties (as the case may be), reduced immunogenicity, etc.
  • Antibodies and antigen-binding fragments obtained in this general manner are encompassed within the present disclosure.
  • the constant region of an antibody is important in the ability of an antibody to fix complement and mediate cell-dependent cytotoxicity.
  • the isotype of an antibody may be selected on the basis of whether it is desirable for the antibody to mediate cytotoxicity.
  • human antibody is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences.
  • the human antibodies featured in the disclosure may in various embodiments nonetheless include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs and in some embodiments CDR3.
  • the term “human antibody,” as used herein is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.
  • recombinant human antibody is intended to include all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described further below), antibodies isolated from a recombinant, combinatorial human antibody library (described further below), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes or antibodies prepared, expressed, created or isolated by any other means that involves splicing of human immunoglobulin gene sequences to other DNA sequences.
  • recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences.
  • such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo.
  • an immunoglobulin molecule comprises a stable four chain construct of approximately 150-160 kDa in which the dimers are held together by an interchain heavy chain disulfide bond.
  • the dimers are not linked via inter-chain disulfide bonds and a molecule of about 75-80 kDa is formed composed of a covalently coupled light and heavy chain (half-antibody). In certain embodiments, these forms have been extremely difficult to separate, even after affinity purification.
  • the frequency of appearance of the second form in various intact IgG isotypes is due to, but not limited to, structural differences associated with the hinge region isotype of the antibody.
  • a single amino acid substitution in the hinge region of the human IgG4 hinge can significantly reduce the appearance of the second form to levels typically observed using a human IgGl hinge.
  • the instant disclosure encompasses in various embodiments antibodies having one or more mutations in the hinge, CH2 or CH3 region which may be desirable, for example, in production, to improve the yield of the desired antibody form.
  • an “isolated antibody,” as used herein, means an antibody that has been identified and separated and/or recovered from at least one component of its natural environment. For example, an antibody that has been separated or removed from at least one component of an organism, or from a tissue or cell in which the antibody naturally exists or is naturally produced, is an “isolated antibody”.
  • the isolated antibody also includes an antibody in situ within a recombinant cell.
  • isolated antibodies are antibodies that have been subjected to at least one purification or isolation step.
  • an isolated antibody may be substantially free of other cellular material and/or chemicals.
  • the term “specifically binds,” or the like, means that an antibody or antigen-binding fragment thereof forms a complex with an antigen that is relatively stable under physiologic conditions.
  • Methods for determining whether an antibody specifically binds to an antigen are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like.
  • an antibody that “specifically binds” IL-6R includes antibodies that bind IL-6R (e.g., human IL-6R) or portion thereof with a KD of less than about 1000 nM, less than about 500 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM or about 0.5 nM, as measured in a surface plasmon resonance assay.
  • IL-6R e.g., human IL-6R
  • the antibody binds IL-6R (e.g., human IL-6Ra) with a KD of from about 0.1 nM to about 1000 nM or from about 1 nM to about 100 nM. In some embodiments, the antibody binds IL-6R (e.g., human IL-6Ra) with a KD of from about 1 pM to about 100 pM or from about 40 pM to about 60 pM. Specific binding can also be characterized by a dissociation constant of at least about 1x1 O’ 6 M or smaller. In other embodiments, the dissociation constant is at least about I xlO’ 7 M, 1 x 10’ 8 M, or lx IO’ 9 M.
  • An isolated antibody that specifically binds human IL-6R may, however, have cross-reactivity to other antigens, such as IL-6R molecules from other (non-human) species.
  • surface plasmon resonance refers to an optical phenomenon that allows for the analysis of real-time interactions by detection of alterations in protein concentrations within a biosensor matrix, for example using the BIACORE® system (Biacore Life Sciences division of GE Healthcare, Piscataway, NJ).
  • epitope refers to an antigenic determinant that interacts with a specific antigen binding site in the variable region of an antibody molecule known as a paratope.
  • a single antigen may have more than one epitope.
  • different antibodies may bind to different areas on an antigen and may have different biological effects.
  • Epitopes may be either conformational or linear.
  • a conformational epitope is produced by spatially juxtaposed amino acids from different segments of the linear polypeptide chain.
  • a linear epitope is one produced by adjacent amino acid residues in a polypeptide chain.
  • an epitope may include moieties of saccharides, phosphoryl groups, or sulfonyl groups on the antigen.
  • the anti-IL-6R antibodies useful for the methods described herein may in various embodiments include one or more amino acid substitutions, insertions and/or deletions in the framework and/or CDR regions of the heavy and light chain variable domains as compared to the corresponding germline sequences from which the antibodies were derived. Such mutations can be readily ascertained by comparing the amino acid sequences disclosed herein to germline sequences available from, for example, public antibody sequence databases.
  • the present disclosure includes in various embodiments methods involving the use of antibodies, and antigen-binding fragments thereof, which are derived from any of the amino acid sequences disclosed herein, wherein one or more amino acids within one or more framework and/or CDR regions are mutated to the corresponding residue(s) of the germline sequence from which the antibody was derived, or to the corresponding residue(s) of another human germline sequence, or to a conservative amino acid substitution of the corresponding germline residue(s) (such sequence changes are referred to herein collectively as “germline mutations”).
  • Numerous antibodies and antigen-binding fragments may be constructed which comprise one or more individual germline mutations or combinations thereof.
  • all of the framework and/or CDR residues within the VH and/or VL domains are mutated back to the residues found in the original germline sequence from which the antibody was derived.
  • only certain residues are mutated back to the original germline sequence, e.g., only the mutated residues found within the first 8 amino acids of FR1 or within the last 8 amino acids of FR4, or only the mutated residues found within CDR1, CDR2 or CDR3.
  • one or more of the framework and/or CDR residue(s) are mutated to the corresponding residue(s) of a different germline sequence (i.e., a germline sequence that is different from the germline sequence from which the antibody was originally derived).
  • the antibodies may contain any combination of two or more germline mutations within the framework and/or CDR regions, e.g., wherein certain individual residues are mutated to the corresponding residue of a certain germline sequence while certain other residues that differ from the original germline sequence are maintained or are mutated to the corresponding residue of a different germline sequence.
  • antibodies and antigen-binding fragments that contain one or more germline mutations can be easily tested for one or more desired property such as, improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic biological properties (as the case may be), reduced immunogenicity, etc.
  • desired property such as, improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic biological properties (as the case may be), reduced immunogenicity, etc.
  • the use of antibodies and antigen-binding fragments obtained in this general manner are encompassed within the present disclosure.
  • the present disclosure also includes methods involving the use of anti-IL-6R antibodies comprising variants of any of the HCVR, LCVR, and/or CDR amino acid sequences disclosed herein having one or more conservative substitutions.
  • the present disclosure includes the use of anti-IL-6R antibodies having HCVR, LCVR, and/or CDR amino acid sequences with, e.g., 10 or fewer, 8 or fewer, 6 or fewer, 4 or fewer, etc. conservative amino acid substitutions relative to any of the HCVR, LCVR, and/or CDR amino acid sequences disclosed herein.
  • the anti-IL-6R antibody or antigen-binding fragment thereof comprises the heavy chain complementarity determining regions (HCDRs) of a HCVR comprising the amino acid sequence of SEQ ID NO: 1 and the light chain complementarity determining regions (LCDRs) of a LCVR comprising the amino acid sequence of SEQ ID NO: 2.
  • HCDRs heavy chain complementarity determining regions
  • LCDRs light chain complementarity determining regions
  • the anti-IL-6R antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.
  • the extracellular domain of hIL-6R comprises the amino acid sequence of SEQ ID NO: 11.
  • the methods of the present disclosure comprise the use of the anti-IL-6R antibody referred to and known in the art as sarilumab, or a bioequivalent thereof.
  • amino acid sequence of SEQ ID NO: 11 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • sequence identity of the disclosed sequences herein is at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, and up to 100%.
  • a polynucleotide or polypeptide has a certain percent “sequence identity” to another polynucleotide or polypeptide, meaning that, when aligned, that percentage of bases or amino acids are the same, and in the same relative position, when comparing the two sequences. Sequence identity can be determined in a number of different manners.
  • sequences can be aligned using various methods and computer programs (e.g., BEAST, T-COFFEE, MUSCEE, MAFFT, etc.), available over the world wide web at sites including ncbi.nlm.nili.gov/BLAST, ebi.ac.uk/Tools/msa/tcoffee/, ebi.ac.uk/Tools/msa/muscle/, mafft.cbrc.jp/alignment/software/. See, e.g., Altschul et al. (1990), J. Mol. Bioi. 215:403-10.
  • Sequence similarity for polypeptides is typically measured using sequence analysis software. Protein analysis software matches similar sequences using measures of similarity assigned to various substitutions, deletions and other modifications, including conservative amino acid substitutions.
  • GCG software contains programs such as Gap and Bestfit which can be used with default parameters to determine sequence homology or sequence identity between closely related polypeptides, such as homologous polypeptides from different species of organisms or between a wild type protein and a mutein thereof. See, e.g., GCG Version 6.1. Polypeptide sequences also can be compared using FASTA using default or recommended parameters, a program in GCG Version 6.1.
  • FASTA e.g., FASTA2 and FASTA3
  • FASTA2 and FASTA3 provides alignments and percent sequence identity of the regions of the best overlap between the query and search sequences (Pearson (2000) supra).
  • Another preferred algorithm when comparing a sequence of the invention to a database containing many sequences from different organisms is the computer program BLAST, especially blastp or tblastn, using default parameters. See, e.g., Altschul et al. (1990) J. Mol. Biol. 215: 403 410 and Altschul et al. (1997) Nucleic Acids Res. 25:3389 402.
  • the sequence identity to SEQ ID NO:1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, is at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, and up to 100%.
  • the anti-IL-6R antibody, or antigen-binding fragment thereof in various embodiments comprises a heavy chain variable region (HCVR), light chain variable region (LCVR), and/or complementarity determining regions (CDRs) comprising any of the amino acid sequences of the anti-IL-6R antibodies described in U.S. Patent No.
  • the hybridoma cell line producing tocilizumab has been internationally deposited at International Patent Organism Depository (AIST Tsukuba Central 6, 1-1, Higashi 1-chome, Tsukuba-shi, Ibaraki Pref.) based on Budapest Treaty as FERM BP-2998 on Jul. 12, 1989.
  • the anti-IL-6R antibody or antigen-binding fragment thereof comprises the heavy chain complementarity determining regions (HCDRs) and or the light chain complementarity determining regions (LCDRs) of a HCVR comprising the amino acid sequence of SEQ ID NO : 13 and the light chain complementarity determining regions (LCDRs) of a LCVR comprising the amino acid sequence of SEQ ID NO: 12.
  • the anti-IL-6R antibody or antigen-binding fragment thereof comprises three HCDRs (i.e., HCDR1, HCDR2 and HCDR3) and three LCDRs (i.e., LCDR1, LCDR2 and LCDR3), wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 17; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 18; the HCDR3 comprises the amino acid sequence of SEQ ID NO: 19; the LCDR1 comprises the amino acid sequence of SEQ ID NO: 14; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 15; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 16.
  • the anti-IL-6R antibody or antigen-binding fragment thereof comprises an heavy chain comprising the amino acid sequence of SEQ ID NO: 13 and an light chain comprising the amino acid sequence of SEQ ID NO: 12.
  • the anti-IL-6R antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence of the heavy chain of TCZ and a light chain comprising the amino acid sequence of the light chain of TCZ.
  • the extracellular domain of hIL-6R comprises the amino acid sequence of the extracellular domain of TCZ.
  • the methods of the present disclosure comprise the use of the anti-IL-6R antibody referred to and known in the art as tocilizumab, or a bioequivalent thereof.
  • amino acid sequence of SEQ ID NO: 13 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • amino acid sequence of SEQ ID NO: 14 is RASQDISSYLN.
  • amino acid sequence of SEQ ID NO: 15 is YTSRLHS.
  • the amino acid sequence of SEQ ID NO: 16 is QQGNTLPYT.
  • the amino acid sequence of SEQ ID NO: 17 is SDHAWS.
  • amino acid sequence of SEQ ID NO: 18 is YISYSGITTYNPSLK.
  • amino acid sequence of SEQ ID NO: 19 is SLARTTAMDY.
  • bioequivalent refers to a molecule having similar bioavailability (rate and extent of availability) after administration at the same molar dose and under similar conditions (e.g., same route of administration), such that the effect, with respect to both efficacy and safety, can be expected to be essentially same as the comparator molecule.
  • Two pharmaceutical compositions comprising an anti-IL-6R antibody are bioequivalent if they are pharmaceutically equivalent, meaning they contain the same amount of active ingredient (e.g., IL-6R antibody), in the same dosage form, for the same route of administration and meeting the same or comparable standards.
  • Bio equivalence can be determined, for example, by an in vivo study comparing a pharmacokinetic parameter for the two compositions.
  • Parameters commonly used in bioequivalence studies include peak plasma concentration (Cmax) and area under the plasma drug concentration time curve (AUC).
  • the disclosure in certain embodiments relates to methods comprising administering to the subject an antibody which comprises the heavy chain variable region comprising sequence SEQ ID NO : 1 and the light chain variable region comprising sequence SEQ ID NO: 2.

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Abstract

La présente invention concerne des procédés et des compositions pour traiter la polymyalgie rhumatismale (PMR) chez des sujets qui ont été préalablement traités avec un stéroïde. L'invention concerne également des méthodes de traitement de tels sujets avec une thérapie inhibitrice de l'interleukine-6.
PCT/IB2025/000012 2024-01-12 2025-01-10 Traitement de sujets atteints de polymyalgie rhumatismale auxquels a été adminsitré un stéroïde Pending WO2025149845A1 (fr)

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