WO2019027828A1 - Schéma posologique d'anticorps anti-il-17 - Google Patents

Schéma posologique d'anticorps anti-il-17 Download PDF

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Publication number
WO2019027828A1
WO2019027828A1 PCT/US2018/044064 US2018044064W WO2019027828A1 WO 2019027828 A1 WO2019027828 A1 WO 2019027828A1 US 2018044064 W US2018044064 W US 2018044064W WO 2019027828 A1 WO2019027828 A1 WO 2019027828A1
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antibody
pharmaceutical formulation
administering
subcutaneous
seq
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PCT/US2018/044064
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English (en)
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Olawale Olukayode OSUNTOKUN
Paula Kay POLZER
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Eli Lilly And Company
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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
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244—Interleukins [IL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the present invention relates to the field of medicine. More particularly, the present invention relates to a dose regimen of pharmaceutical formulations of an anti-IL- 17 antibody which is expected to be useful in treating Psoriasis (Ps), Ankylosing
  • AS Spondilitis
  • PA Psoriatic Arthritis
  • RA Rheumatoid Arthritis
  • MM Multiple Myeloma
  • Ixekizumab is an anti-IL-17 antibody, approved by the United States Food and Drug Administration, for the treatment of moderate-to-severe Ps and marketed under the tradename Taltz ® .
  • up to 90% of patients based on PASI 75 assesment; up to 83%) under sPGA 0,1 assessment
  • sufficient improvement in Ps was not obtained under current treatment dose regimens.
  • Anti-IL-17 antibodies including ixekizumab, are disclosed in U.S. Patent Number 7,838,638 as useful for the treatment of autoimmune disorders including Ps, AS, PA, RA and MM.
  • U.S. Patent Number 9,376,491 dislcoses specific pharmaceutical formulations of anti-IL-17 antibodies including ixekizumab useful for the treatment of autoimmune disorders including Ps, AS, PA, RA and MM.
  • ixekizumab was approved by the U.S. Food and Drug Administration with a dose regiment of: an initial dose of 160mg (two 80 mg injections) at Day 0, followed by an 80 mg dose at each of Weeks 2, 4, 6, 8, 10, and 12, then an 80 mg dose every 4 weeks.
  • the present invention provides a dose regimen for administering an anti-IL-17 antibody, or a pharmaceutical formulation thereof, to a patient, comprising: administering subcutaneous an initial dose of about 160 mg of the anti-IL-17 antibody or pharmaceutical formulation thereof (e.g., a pharmaceutical formulation comprising about 160 mg of the anti-IL-17 antibody or two doses of a pharmaceutical formulation each comprising about 80 mg of the anti-IL-17 antibody); administering subcutaneously a second dose of about 80 mg of the anti-IL-17 antibody or pharmaceutical formulation thereof (e.g., a pharmaceutical formulation comprising about 80 mg of the anti-IL-17 antibody) 14 days after the said step of administering the initial dose; and administering subcutaneous a dose of about 80 mg of the anti-IL-17 antibody or pharmaceutical formulation thereof every 14 days after said step of administering the second dose, wherein the anti-IL-17 antibody or pharmaceutical formulation thereof comprises an antibody with a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein said LCVR is the amino acid sequence of SEQ ID NO: 2 and
  • the antibody comprises a light chain (LC) and a heavy chain (HC), wherein said LC is the amino acid sequence of SEQ ID NO: 4 and said HC is the amino acid sequence of SEQ ID NO: 5.
  • the antibody is ixekizumab.
  • the step of administering subcutaneous an initial dose of about 160 mg comprises administering two subcutaneous doses of about 80 mg of the anti-IL-17 antibody or pharmaceutical formulation thereof, the two subcutaneous doses being administered on the same day.
  • the patient is in need of treatment for one of Psoriasis (Ps), Ankylosing Spondilitis (AS), Psoriatic Arthritis (PA), Rheumatoid Arthritis (RA) or Multiple Myeloma (MM).
  • Ps Psoriasis
  • AS Ankylosing Spondilitis
  • PA Psoriatic Arthritis
  • RA Rheumatoid Arthritis
  • MM Multiple Myeloma
  • the patient is in need of treatment for psoriasis.
  • some embodiments of the dose regimen provided herein include said steps of
  • administering comprise administering a pharmaceutical formulation of the anti-IL-17 antibody, said pharmaceutical formulation comprising the anti-IL-17 antibody at a concentration of about 80 mg/mL, citrate buffer at a concentration of about 20 mM, sodium chloride at a concentration of about 200 mM, polysorbate-80 at a concentration in the range of about 0.02% (w/v) to about 0.03% (w/v), and pH at about 5.7.
  • the concentration of polysorbate-80 is about 0.03% (w/v).
  • Embodiments of the present invention further provide a method of treating a patient in need of treatment for psoriasis comprising: (a) during an initial 12-week period, administering an initial dose subcutaneous of about 160 mg of an anti-IL-17 antibody, or a pharmaceutical formulation thereof (e.g., a pharmaceutical formulation comprising about 160 mg of the anti-IL-17 antibody or two doses of a pharmaceutical formulation each comprising about 80 mg of the anti-IL-17 antibody), on day 0, followed by administering subcutaneous about 80 mg of the anti-IL-17 antibody, or pharmaceutical formulation thereof (e.g., a pharmaceutical formulation comprising about 80 mg of the anti-IL-17 antibody), at each of Days 14, 28, 42, 56, 70 and 84; (b) following the initial 12-week period, assessing the patient for a clinical response of one of static Physician Global Assessment 0, 1 ("sPGA 0,1"), sPGA 0, and Psoriasis Area and Severity Index 75 ("PASI 75"); and for patients assessed as not achieving or maintaining the one of sPGA 0, 1,
  • the step of administering subcutaneous an initial dose of about 160 mg comprises administering two subcutaneous doses of about 80 mg of the anti-IL-17 antibody or pharmaceutical formulation thereof.
  • patients assessed as not achieving or maintaining the one of sPGA 0,1, sPGA 0, or PASI 75 the step of administering subcutaneous about 80 mg of the anti-IL- 17 antibody or pharmaceutical formulation thereof every two weeks is performed for a period of 16 weeks following said step of assessing the patient.
  • the method of treating further includes, following the period of 16 weeks following said step of assessing the patient, administering subcutaneous about 80 mg of the anti-IL-17 antibody or pharmaceutical formulation thereof every four weeks.
  • the antibody comprises a light chain (LC) and a heavy chain (HC), wherein said LC is the amino acid sequence of SEQ ID NO: 4 and said HC is the amino acid sequence of SEQ ID NO: 5.
  • said steps of administering comprise administering a pharmaceutical formulation of the anti-IL-17 antibody, said pharmaceutical formulation comprising the anti-IL-17 antibody at a concentration of about 80 mg/mL, citrate buffer at a concentration of about 20 mM, sodium chloride at a concentration of about 200 mM, polysorbate-80 at a concentration in the range of about 0.02% (w/v) to about 0.03% (w/v), and pH at about 5.7.
  • the concentration of polysorbate-80 is about 0.03% (w/v).
  • the anti-IL-17-antibody is ixekizumab.
  • an improved method of treating a patient in need of treatment for psoriasis comprising, during an initial 12-week period, administering an initial dose subcutaneous of about 160 mg of an anti-IL-17 antibody, or a pharmaceutical formulation thereof (e.g., a pharmaceutical formulation comprising about 160 mg of the anti-IL-17 antibody or two doses of a pharmaceutical formulation each comprising about 80 mg of the anti-IL-17 antibody), on day 0, followed by administering subcutaneously about 80 mg of the anti-IL-17 antibody, or pharmaceutical formulation thereof (e.g., a
  • the anti-IL-17 antibody or pharmaceutical formulation thereof comprises an antibody with a light chain (LC) and a heavy chain (HC), wherein said LC is the amino acid sequence of SEQ ID NO: 4 and said HC is the amino acid sequence of SEQ ID NO: 5, wherein the improvement comprises, following the initial 12-week period, assessing the patient for a clinical response of one of sPGA 0, 1, sPGA 0, or PASI 75, and for patients assessed as not achieving or maintaining the one of sPGA 0,1, sPGA 0, or PASI 75, administering subcutaneously about 80 mg of the anti-IL-17 antibody or pharmaceutical formulation thereof every two weeks.
  • LC light chain
  • HC heavy chain
  • the step of administering subcutaneously about 80 mg of the anti-IL-17 antibody or pharmaceutical formulation thereof every two weeks is performed for a period of 16 weeks following said step of assessing the patient.
  • Some embodiments include the further step of, following the period of 16 weeks following said step of assessing the patient, administering subcutaneously about 80 mg of the anti-IL-17 antibody or pharmaceutical formulation thereof every four weeks.
  • the step of administering subcutaneously an initial dose of about 160 mg comprises administering two subcutaneous doses of about 80 mg of the anti-IL-17 antibody or pharmaceutical formulation thereof, the two subcutaneous doses being administered on the same day.
  • the steps of administering comprise administering a pharmaceutical formulation of the anti-IL-17 antibody, said pharmaceutical formulation comprising the anti-IL-17 antibody at a concentration of about 80 mg/mL, citrate buffer at a concentration of about 20 mM, sodium chloride at a concentration of about 200 mM, polysorbate-80 at a concentration in the range of about 0.02% (w/v) to about 0.03% (w/v), and pH at about 5.7.
  • the concentration of polysorbate-80 is about 0.03% (w/v).
  • the anti-IL-17-antibody is ixekizumab.
  • Ps Psoriasis
  • AS Ankylosing Spondilitis
  • PA Psoriatic Arthritis
  • RA Rheumatoid Arthritis
  • Myeloma comprising, administering subcutaneously an initial dose of about 160 mg of an anti-IL-17 antibody, or a pharmaceutical formulation thereof (e.g., a
  • the anti-IL-17 antibody or pharmaceutical formulation thereof comprises an antibody with a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein said LCVR is the amino acid sequence of SEQ ID NO: 2 and said HCVR is the amino acid sequence of SEQ ID NO: 3.
  • LCVR light chain variable region
  • HCVR heavy chain variable region
  • the antibody comprises a light chain (LC) and a heavy chain (HC), wherein said LC is the amino acid sequence of SEQ ID NO: 4 and said HC is the amino acid sequence of SEQ ID NO: 5.
  • the step of administering comprises a light chain (LC) and a heavy chain (HC), wherein said LC is the amino acid sequence of SEQ ID NO: 4 and said HC is the amino acid sequence of SEQ ID NO: 5.
  • subcutaneously an initial dose of about 160 mg comprises administering two
  • the steps of administering comprise administering a pharmaceutical formulation of the anti-IL-17 antibody, said pharmaceutical formulation comprising the anti-IL-17 antibody at a concentration of about 80 mg/mL, citrate buffer at a concentration of about 20 mM, sodium chloride at a concentration of about 200 mM, polysorbate-80 at a concentration in the range of about 0.02% (w/v) to about 0.03% (w/v), and pH at about 5.7.
  • the concentration of polysorbate-80 is about 0.03% (w/v).
  • the anti-IL-17-antibody is ixekizumab.
  • the present invention also provides a method of treating Psoriasis comprising, administering subcutaneously an initial dose of about 160 mg of an anti-IL-17 antibody, or a pharmaceutical formulation thereof (e.g., a pharmaceutical formulation comprising about 160 mg of the anti-IL-17 antibody or two doses of a pharmaceutical formulation each comprising about 80 mg of the anti-IL-17 antibody), on Day 0, and administering subcutaneously subsequent doses of about 80 mg of the anti-IL-17 antibody or pharmaceutical formulation thereof (e.g., a pharmaceutical formulation comprising about 80 mg of the anti-IL-17 antibody) at every 14th day interval after the initial dose, wherein the anti-IL-17 antibody or pharmaceutical formulation thereof comprises an antibody with a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein said LCVR is the amino acid sequence of SEQ ID NO: 2 and said HCVR is the amino acid sequence of SEQ ID NO: 3.
  • the antibody comprises a light chain (LC) and a heavy chain (HC), wherein said LC is the amino acid
  • the step of administering subcutaneously an initial dose of about 160 mg comprises administering two subcutaneous doses of about 80 mg of the anti-IL-17 antibody or pharmaceutical formulation thereof.
  • the steps of administering comprises administering a pharmaceutical formulation of the anti-IL-17 antibody, said pharmaceutical formulation comprising the anti-IL-17 antibody at a concentration of about 80 mg/mL, citrate buffer at a concentration of about 20 mM, sodium chloride at a concentration of about 200 mM, polysorbate-80 at a concentration in the range of about 0.02% (w/v) to about 0.03% (w/v), and pH at about 5.7.
  • the concentration of polysorbate-80 is about 0.03% (w/v).
  • the anti-IL-17-antibody is ixekizumab.
  • the invention provides an improved method of treating Psoriasis comprising, during an initial 12-week period, administering an initial dose subcutaneously of about 160 mg of an anti-IL-17 antibody, or a pharmaceutical formulation thereof (e.g., a pharmaceutical formulation comprising about 160 mg of the anti-IL-17 antibody or two doses of a pharmaceutical formulation each comprising about 80 mg of the anti-IL-17 antibody), on Day 0, followed by administering
  • subcutaneouslyabout 80 mg of the anti-IL-17 antibody, or pharmaceutical formulation thereof e.g., a pharmaceutical formulation comprising about 80 mg of the anti-IL-17 antibody
  • the anti-IL-17 antibody or pharmaceutical formulation thereof comprises an antibody with a light chain (LC) and a heavy chain (HC), wherein said LC is the amino acid sequence of SEQ ID NO: 4 and said HC is the amino acid sequence of SEQ ID NO: 5, wherein the improvement comprises: following the initial 12-week period, assessing the patient for a clinical response, the clinical response being of one of sPGA 0, 1, sPGA 0, and PASI 75; and for patients assessed as not achieving or maintaining the one of sPGA 0,1, sPGA 0, or PASI 75, administering subcutaneously about 80 mg of the anti-IL-17 antibody or pharmaceutical formulation thereof every two weeks.
  • the step of administering subcutaneously an initial dose of about 160 mg comprises administering two
  • subcutaneous doses of about 80 mg of the anti-IL-17 antibody or pharmaceutical formulation thereof.
  • Some embodiments further comprises the step of, following the period of 16 weeks following said step of assessing the patient, administering
  • the steps of administering comprise administering a pharmaceutical formulation of the anti-IL-17 antibody, said pharmaceutical formulation comprising the anti-IL-17 antibody at a concentration of about 80 mg/mL, citrate buffer at a concentration of about 20 mM, sodium chloride at a concentration of about 200 mM, polysorbate-80 at a concentration in the range of about 0.02% (w/v) to about 0.03% (w/v), and pH at about 5.7.
  • the concentration of polysorbate-80 is about 0.03% (w/v).
  • the anti-IL-17-antibody is ixekizumab.
  • the present invention provides use of an anti-IL-17 antibody in any of the dose regimens or methods provided herein.
  • the present invention provides use of anti-IL-17 antibody in the treatment of Psoriasis (Ps) in a patient not achieving or maintaining sufficient clinical response at the completion of a 12 week induction treatment period, the induction treatment period comprising an initial dose of about 160 mg of an anti-IL-17 antibody administered subcutaneously on Day 0 and treatment doses of about 80 mg of the anti-IL-17 antibody administered
  • the anti-IL-17 antibody or pharmaceutical formulation thereof comprises an antibody with a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein said LCVR is the amino acid sequence of SEQ ID NO: 2 and said HCVR is the amino acid sequence of SEQ ID NO: 3.
  • the antibody comprises a light chain (LC) and a heavy chain (HC), wherein said LC is the amino acid sequence of SEQ ID NO: 4 and said HC is the amino acid sequence of SEQ ID NO: 5.
  • the antibody is ixekizumab.
  • administering subcutaneously about 80 mg of the anti-IL-17 antibody every two weeks after the induction treatment period is performed for a period of 16 weeks.
  • the invention provides use of an anti-IL-17 antibody in an improved dose regimen for treating Psoriasis (Ps) in a patient not achieving or maintaining sufficient clinical response at the completion of a 12 week induction treatment period, the induction treatment period comprising administering subcutaneously an initial dose of about 160 mg of the anti-IL-17 antibody on Day 0 and treatment doses of about 80 mg of the anti-IL-17 antibody administered subcutaneously at each of days 14, 28, 42, 56, 70 and 84, said improvement comprising administering subcutaneously about 80 mg of the anti-IL-17 antibody every two weeks after the induction treatment period, wherein the anti-IL-17 antibody or pharmaceutical formulation thereof comprises an antibody with a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein said LCVR is the amino acid sequence of SEQ ID NO: 2 and said HCVR is the amino acid sequence of SEQ ID NO: 3.
  • LCVR light chain variable region
  • HCVR heavy chain variable region
  • the antibody comprises a light chain (LC) and a heavy chain (HC), wherein said LC is the amino acid sequence of SEQ ID NO: 4 and said HC is the amino acid sequence of SEQ ID NO: 5.
  • the antibody is ixekizumab.
  • administering subcutaneous about 80 mg of the anti-IL-17 antibody every two weeks after the induction treatment period is performed for a period of 16 weeks.
  • dose regimens for anti-IL-17 antibodies As referred to herein, and as generally known in the art, the term “dose” refers to an amount (e.g., a concentration) of anti-IL-17 antibody which is administered to a subject.
  • dose regimen or “dosage regimen” as generally known in the field and as may be referred to interchangably herein includes a treatment schedule for administering a set (i.e., series or sequence) of doses to be administered to a patient over a period of time.
  • the invention describes a dose regimen for the administration of anti-IL-17 antibody, or pharmaceutical formulation thereof, wherein the antibody or formulation thereof, at a given dose (e.g., two separate 80 mg subcutaneous injections) is first administered as an initial dose on a first day (e.g., Day 0) and then administered in treatment doses (e.g., a single 80 mg subcutaneous injection) given at every two week interval (e.g., Day 14, 28, 42, 56, 70, 84 and so on respectively).
  • a given dose e.g., two separate 80 mg subcutaneous injections
  • treatment doses e.g., a single 80 mg subcutaneous injection
  • an initial dose of about 160 mg of an anti-IL-17 antibody or pharmaceutical formulation thereof (comprising two separate doses of about 80 mg) is administered subcutaneously on the first day of treatment (e.g., Day 0), followed by subcutaneous administration of treatment doses of about 80 mg of the anti-IL-17 antibody or formulation thereof at 14- day (or two week intervals) (e.g., a treatment dose given at each of Days 14, 28, 42, 56, 70 and 84 during the initial 12-week period), whereby following the initial 12-week period, the patient is assessed for a desired or sufficient clinical response.
  • a desired or sufficient clinical response for example, with Ps, may be based on sPGA 0, 1, sPGA 0, PASI 75, PASI 90, or the like, or a combination of any of these assessment metrics.
  • Patients not achieving or maintaining the desired or sufficient clinical response are administered subcutaneous about 80 mg of the anti-IL-17 antibody or pharmaceutical formulation thereof every two weeks, for example for an additional 16 weeks after the initial 12-week period.
  • the instant invention also provides improved dose regimens for administering anti- IL-17 antibodies (or pharmaceutical formulation thereof) or treating a specific condition (e.g., treating a patient for Ps).
  • the anti-IL-17 antibody is ixekizumab.
  • Day 0 refers to the day on which the initial dose is administered (which, in at least some dose regimens provided herein marks the start of an "initial 12-week period" as also referred to herein).
  • Day 14 or “Day 14, 28,” and so on, refers to the calendar day which comes 14 days (or 28 days in the case of Day 28; or 42 days in the case of Day 42, and so on) after Day 0, inclusive of Day 14, 28 and so on.
  • Day 0 falls on the calendar date January 1 st
  • Day 14 would fall on the calendar date January 15 th and Day 28 would fall on the calendar date January 29 th and so on.
  • “2 week intervaP'or "2 week intervals” refer to the calendar days which come on the 14 day intervals following Day 0 (e.g., administration of the initial dose).
  • sPGA 0,1 refers to a physican's global assessment of a patient's Ps lesions at a given point.
  • the sPGA includes assement of the Ps lesions for induration, erythema, and scaling, and an overall rating of Ps severity is given using the anchors of clear (0), minimal (1), mild (2), moderate (3), severe (4), or very severe (5).
  • An assessment of sPGA 0, 1, is understood to represent clinically meaningful response of minimal plaque severity and / or complete resolution of Ps plaque (where sPGA 0 is indicative of complete resolution of psoriatic plaques).
  • Information, as understood in the art, regarding sPGA is further provided at "European Medicines Agency, Committee for Medicinal Products for Human Use, Guidelines on clinical investigation of medicinal products indicated for the treatment of psoriasis, November 2004, available at:
  • Psoriasis Area and Severity Index refers to a combined assessment of the extent of body-surface involvement in four anatomical regions (head, and neck, trunk, arms, and legs) and the severity of scaling, redness, and plaque induration / infiltration (thickness) in each region.
  • PASI 75 represents at least a 75% decrease (improvement) from the baseline PASI score and with increased levels of clearance referred to with higher numbers, e.g. "PASI 90").
  • PASI90 response the new standard in therapeutic efficacy for psoriasis, J Eur Acad
  • human interleukin 17 or human IL-17 refers to human IL-17A.
  • human IL-17A is a 20-30 kD dimeric (i.e., IL17AA homodimeric or IL17AF heterodimeric) glycoprotein which functions as a proinflammatory cytokine.
  • antibody as used herein, is an anti-IL-17 antibody that comprises two light chain variable regions (LCVR) each having the amino acid sequence SEQ ID NO: 2 and two heavy chain variable regions (HCVR) each having the amino acid sequence SEQ ID NO: 3.
  • LCVR light chain variable regions
  • HCVR heavy chain variable regions
  • the antibody comprises two light chains (LC) each having the amino acid sequence SEQ ID NO: 4 and two heavy chains (HC) each having the amino acid sequence SEQ ID NO: 5, and wherein the HCs are cross-linked by disulfide bonds.
  • LC light chains
  • HC heavy chains
  • the anti-IL-17 antibody is ixekizumab.
  • Anti-IL-17 antibodies for use in the present invention are engineered to have frameworks, hinge regions, and constant regions of human origin that are identical with or substantially identical (substantially human) with frameworks and constant regions derived from human genomic sequences.
  • Fully human frameworks, hinge regions, and constant regions are those human germline sequences as well as sequences with naturally- occurring somatic mutations and/or those with engineered mutations.
  • An antibody for use in the present invention may comprise framework, hinge, or constant regions derived from a fully human framework, hinge, or constant region containing one or more amino acid substitutions, deletions, or additions therein.
  • an antibody for use in the present invention is substantially non-immunogenic in humans. Further characterization of antibodies for use in the present invention are provided in U.S. Patent Number
  • Embodiments of the present invention also include the use of anti-IL-17 antibodies incorporated in pharmaceutical formulations.
  • a pharmaceutical formulation as used herein, is a stable formulation comprising the anti-IL-17 antibody of the present invention, preferably ixekizumab, wherein the degree of degradation, modification, aggregation, loss of biological activity and the like, of proteins/antibodies therein is acceptably controlled, and does not increase unacceptably with time. Stability of an antibody in solution depends on the chemical and physical stability of the antibody in the formulation in which the antibody is solubilized.
  • Stability may be assessed by methods well-known in the art, including measurement of a sample's light scattering, apparent attenuation of light (absorbance, or optical density), size (e.g. by size exclusion chromatography (SEC)), in vitro or in vivo biological activity and/or properties measured by differential scanning calorimetry (DSC).
  • SEC size exclusion chromatography
  • compositions for use in the improved dose regimens of the present invention can be in the liquid dosage form of a solution, emulsion, or suspension and may be administered via parenteral administration including intravenous, intramuscular, subcutaneous, and intraperitoneal.
  • parenteral administration including intravenous, intramuscular, subcutaneous, and intraperitoneal.
  • Specific embodiments of anti-IL-17 antibody pharmaceutical formulations include the pharmaceutical formulation of Table 1.
  • anti-IL-17 antibody pharmaceutical formulations for use in the present invention are provided in U.S. Patent Number 9,376,491.
  • the pharmaceutical formulations for use in the dose regimens and methods, and improvements thereof, provided herein preferably include the anti-IL-17 antibody being ixekizumab and even more preferably include the commercially available pharmaceutical formulation Taltz ® .
  • the terms “individual,” “subject,” and “patient,” used interchangeably herein, refer to a human.
  • the subject is further characterized with a disease or disorder or condition that would benefit from a decreased bioactivity of IL-17.
  • treatment and/or “treating” and/or “treat” are intended to refer to all processes wherein there may be a slowing, interrupting, arresting, controlling, stopping, or reversing of the progression of the disorders described herein, but does not necessarily indicate a total elimination of all disorder symptoms.
  • Treatment includes administration of an antibody of the present invention for treatment of a disease or condition in a human that would benefit from a reduction in IL-17 activity, and includes: (a) inhibiting further progression of the disease, i.e., arresting its development; and (b) relieving the disease, i.e., causing regression of the disease or disorder or alleviating symptoms or complications thereof.
  • the dose regimen consisted of an induction period comprising: an initial dose of 160 mg of ixekizumab (administered as two subcutaneous doses of 80 mg) administered on Day 0, followed by an 80 mg dose administered subcutaneously at every 2 week interval following the initial dose (e.g., at Weeks 2, 4, 6, 8, 10 and 12).
  • the maintenance period (that followed the induction period) comprised an 80 mg dose administered subcutaneous at every 4 week interval following the Week 12 dose (e.g., the first injection of the maintenance period given at week 16 followed by weeks 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, and 60).
  • a double-blind, parallel group, Phase 3 trial is conducted over 52 weeks for patients with moderate-to-severe psoriasis for three dose regimens of ixekizumab (an anti-IL-17 antibody having heavy chains of amino acid sequence of SEQ ID NO: 5 and light chains of amino acid sequence of SEQ ID NO: 4, described herein and in U.S.
  • Dose regimens include: (a) Dose Regimen 1, an initial dose of 160 mg of the anti-IL-17 antibody at Day 0 (administered as two subcutaneous 80 mg injections), and then a treatment dose of 80 mg of the anti-IL-17 antibody administered subcutaneous at every four week interval starting from Day 0 (e.g., week 4, 8, 12, and so on) through week 50; and (b) Dose Regimen 2: an initial dose of 160 mg of the anti-IL-17 antibody at Day 0 (administered as two subcutaneous 80 mg injections) and then a treatment dose of 80 mg of the anti-IL-17 antibody administered subcutaneous at every four week interval starting from Day 0 (e.g., week 4, 8, 12 and so on), with a possible dose frequency adjustment to every 2 weeks during weeks 16-40 for patients having a sPGA score of > 2 over two consecutive months; and (c) Dose Regimen 3: an initial dose of
  • sPGA scores are entered into the rWRS every 4 weeks, beginning at Week 0 through Week 48 wherein two consecutive sPGA scores of > 2 between Week 12 through Week 40 results in dose titration / dose-adjustment to 80 mg every two weeks beginning at Week 16.
  • the patient Upon a patient being dose-adjusted from every four week to every two week dosing, the patient remains on every two week dosing through the final dose at administered at Week 50.
  • PASI 75 (e.g., at least a 75% improvement from baseline in PASI score) and / or sPGA 0, 1 responses of patients from all three studied dose regimens are assessed and compared to results of patients on the FDA approved ixekizumab dose regiment (i.e., 160mg (administered as two 80 mg subcutaneous injections) at Day 0, followed by an 80 mg subcutaneous dose at each of Weeks 2, 4, 6, 8, 10, and 12, then an 80 mg subcutaneous dose every 4 weeks, referred to for purposes of this Example as the "Comparator Dose Regimen"). Patients in each dose
  • non-responders Patients not achieveing sPGA 0, 1 at Week 12 are identified, and may be referred to herein as "non-responders.”
  • Tables 2 through 5 demonstrates Dose Regimens 2 and 3, provided herein, represent unexpectedly improved dose regimen for patients not achieveing sPGA 0, 1 by Week 12. More specifically, Table 2 shows for patients not achieveing sPGA 0, 1 by Week 12, Dose Regimen 3 provides unexpectedly improved sPGA 0, 1 and PASI 75 results by Week 28 over Comparator Dose Regimen (showing a 20.6% improvement in patients achieveing sPGA 0, 1 (95%CI), and greater than approx. 17%) improvement in patients achieveing PASI 75 over Comparator Dose Regimen). Similiarly, benefits in sPGA 0, 1, PASI 75 at week 52, as well as sPGA 0 at both Weeks 28 and 52 are shown in Tables 3 through 5.
  • Dose Regimen 3 provides unexpectedly improved sPGA 0 results at both Week 28 and Week 52, with Week 52 showing a 13.2% improvement in patients achieveing sPGA 0 (95%>CI) over Comparator Dose Regimen.
  • Tables 2 through 5 demonstrate Dose Regimen 2 provides an unexpectedly improved Dose Regimen for the anti-IL-17 antibody in sPGA 0, 1, PASI 75 and sPGA 0, at both Weeks 28 and 52 over Comparator Dose Regimen for patients not achieveing sPGA 0, 1 by Week 12.
  • Safety data is also collected for all patients assigned to a Dose Regimen which is administered at least one dose of the anti-IL-17 antibody.
  • DIVMTQTPLS LSVTPGQPAS ISCRSSRSLV HSRGNTYLHW YLQKPGQSPQ LLIYKVSNRF IGVPDRFSGS GSGTDFTLKI SRVEAEDVGV YYCSQSTHLP FTFGQGTKLE IKRTVAAPSV FIFPPSDEQL KSGTASVVCL LNNFYPREAK VQWKVDNALQ SGNSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE VTHQGLSSPV TKSFNRGEC

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Abstract

La présente invention concerne des schémas posologiques d'anticorps anti-IL-17. Les schémas posologiques d'anticorps anti-IL-17 selon la présente invention peuvent être utilisés pour traiter le psoriasis, la spondylarthrite ankylosante, la polyarthrite rhumatoïde, l'arthrite psoriasique ou le myélome multiple.
PCT/US2018/044064 2017-08-04 2018-07-27 Schéma posologique d'anticorps anti-il-17 WO2019027828A1 (fr)

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EP4136110A4 (fr) * 2020-04-17 2024-04-17 Eli Lilly and Company Traitement d'une maladie respiratoire

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4136110A4 (fr) * 2020-04-17 2024-04-17 Eli Lilly and Company Traitement d'une maladie respiratoire

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