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WO2018158741A1 - Modification de la maladie du psoriasis suite à un traitement à long terme avec un antagoniste de l'il-17 - Google Patents

Modification de la maladie du psoriasis suite à un traitement à long terme avec un antagoniste de l'il-17 Download PDF

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Publication number
WO2018158741A1
WO2018158741A1 PCT/IB2018/051343 IB2018051343W WO2018158741A1 WO 2018158741 A1 WO2018158741 A1 WO 2018158741A1 IB 2018051343 W IB2018051343 W IB 2018051343W WO 2018158741 A1 WO2018158741 A1 WO 2018158741A1
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patient
antibody
seq
antigen
binding fragment
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PCT/IB2018/051343
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English (en)
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Marina MILUTINOVIC
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Novartis Ag
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    • 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
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • 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]

Definitions

  • the present disclosure relates to methods of modifying the psoriasis disease course in patients having chronic plaque-type psoriasis and inhibiting the progression to psoriatic arthritis (PsA) and other psoriasis-related comorbidities, e.g., cardiovascular disease and diabetes, in these patients, using IL-17 antagonists, e.g., secukinumab.
  • PsA psoriatic arthritis
  • IL-17 antagonists e.g., secukinumab.
  • Plaque psoriasis is a chronic, systemic, relapsing disease characterized by thick, red and scaly plaques of the skin that can cover the majority of the body. (Agency EM. Guideline on clinical investigation of medicinal products indicated for treatment of psoriasis. London 2004). Psoriasis has a detrimental impact on patients' functional, psychological, and social well-being. More than 90% of plaque psoriasis patients have chronic disease. (Nast Aet al. S3 - Guidelines on the treatment of psoriasis vulgaris (English version). Update. J Dtsch Dermatol Ges. 2012; 10 Suppl 2:Sl-95).
  • Psoriasis is unfortunately not just a skin disease, it is a systemic inflammatory condition that impacts other organs. Consequently, patients can develop psoriatic arthritis, cardiovascular disease, metabolic syndrome (diabetes mellitus, obesity) and other conditions. Patients with more severe psoriasis are at a particularly high risk to develop these conditions. Therefore, psoriasis patients need to be treated as a whole, not just for their skin. Modifying the course of psoriasis beyond the skin, by preventing or delaying the onset of some of the most debilitating comorbidities is the best a treatment can do for the patients, without being able to cure the disease - the ultimate goal.
  • Secukinumab is the first IL-17A inhibitor approved for the treatment of psoriasis in patients requiring systemic treatment.
  • IL-17 antagonists such as secukinumab
  • the observed clinical outcome is a change in the natural course of the disease to a milder state, i.e., inducing minimal, or no, disease activity.
  • PsA psoriatic arthritis
  • IL-17 antagonist e.g., secukinumab
  • IL-17 antagonists for use in, slowing psoriasis disease progression in a patient having chronic plaque-type psoriasis, decreasing the severity of psoriasis flares in a patient having chronic plaque-type psoriasis, decreasing the frequency of psoriasis flares in a patient having chronic plaque-type psoriasis, preventing psoriasis flares in a patient having chronic plaque-type psoriasis, changing the natural course of the psoriasis disease to a milder state in a patient having chronic plaque- type psoriasis, preventing progression from psoriasis to psoriatic arthritis (PsA) in a patient having chronic plaque-type psoriasis, and/or decreasing the risk that a patient having chronic plaque-type psoriasis will develop PsA and other psA
  • the IL-17 antagonist is an IL-17 antibody or antigen-binding fragment thereof.
  • the IL-17 antibody or antigen-binding fragment thereof is selected from the group consisting of: a) an IL-17 antibody or antigen-binding fragment thereof that binds to an epitope of human IL-17 comprising Leu74, Tyr85, His86, Met87, Asn88, Vail 24, Thrl25, Prol26, Ilel27, Vall28, Hisl29; b) an IL-17 antibody or antigen-binding fragment thereof that binds to an epitope of human IL-17 comprising Tyr43, Tyr44, Arg46, Ala79, Asp80; c) an IL-17 antibody or antigen-binding fragment thereof that binds to an epitope of an IL-17 homodimer having two mature human IL-17 protein chains, said epitope comprising Leu74, Tyr85, His86, Met87, As
  • immunoglobulin V H domain comprising the hypervariable regions set forth as SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3; v) an immunoglobulin V L domain comprising the hypervanable regions set forth as SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6; vi) an immunoglobulin V H domain comprising the hypervariable regions set forth as SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13; vii) an immunoglobulin V H domain comprising the hypervariable regions set forth as SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 and an immunoglobulin V L domain comprising the hypervariable regions set forth as SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6; viii) an immunoglobulin V H domain comprising the hypervariable regions set forth as SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13 and an immunoglobulin V L domain comprising the hypervariable regions
  • the IL-17 antibody or antigen-binding fragment thereof is a human or humanized antibody. In some embodiments of the disclosed uses, methods and kits, the IL-17 antibody or antigen-binding fragment thereof is secukinumab.
  • Figure 3 Mean absolute PASI score in patients maintaining at least 50% of the PASI improvement for at least 1 year after the last dose of secukinumab 300 mg (given at 48 weeks) from CAIN457A2302E1 study. Also shown is the mean baseline PASI score at first dose of secukinumab in the core CAIN457A2302/2303 trial and the mean PASI score following the last dose of secukinumab at the end of the core CAIN457A2302/2303 trial and during the CAIN457A2302E1 extension study.
  • Figure 4 Mean absolute PASI score in patients maintaining at least 50% of the PASI improvement for at least 1 year after the last dose of secukinumab 300 mg (given at 48 weeks) from CAIN457A2302E1 study. Also shown is the mean baseline PASI score at first dose of secukinumab in the core CAIN457A2302/2303 trial and the mean PASI score following the last dose of secukinumab at the end of the
  • Figure 6 Representative nonlesional and lesional skin biopsies showing marked improvement (histological disease reversal; Score +3) from baseline following 12 weeks of secukinumab 300 mg treatment in CAIN457A2223 study.
  • FIG. 7 Heat map of changes in psoriasis transcriptome genes following secukinumab treatment. Secukinumab induces rapid and progressive changes in lesional plaque skin gene expression signatures through 1 year of treatment.
  • IL-17 refers to interleukin-17A (IL-17A).
  • composition “comprising” encompasses “including” as well as “consisting,” e.g., a composition “comprising” X may consist exclusively of X or may include something additional, e.g., X + Y.
  • antibody as referred to herein includes naturally-occurring and whole antibodies.
  • a naturally-occurring “antibody” is a glycoprotein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds.
  • Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as V H ) and a heavy chain constant region.
  • the heavy chain constant region is comprised of three domains, CHI, CH2 and CH3.
  • Each light chain is comprised of a light chain variable region (abbreviated herein as V L ) and a light chain constant region.
  • the light chain constant region is comprised of one domain, CL.
  • V H and V L regions can be further subdivided into regions of hypervariability, termed hypervariable regions or complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR).
  • CDR complementarity determining regions
  • FR framework regions
  • Each V H and V L is composed of three CDRs and four FRs arranged from amino-terminus to carboxy-terminus in the following order: FRl, CDRl, FR2, CDR2, FR3, CDR3, FR4.
  • the variable regions of the heavy and light chains contain a binding domain that interacts with an antigen.
  • the constant regions of the antibodies may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system.
  • exemplary antibodies include secukinumab (Table 1), antibody XAB4 (US Patent No. 9,193,788), and ixekizumab (U.S. Patent No. 7,838,638), the disclosures of which are incorporated by reference herein in their entirety.
  • antigen-binding fragment of an antibody, as used herein, refers to fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., IL-17). It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full- length antibody.
  • binding fragments encompassed within the term "antigen-binding portion" of an antibody include a Fab fragment, a monovalent fragment consisting of the V L , V H , CL and CHI domains; a F(ab) 2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; a Fd fragment consisting of the V H and CHI domains; a Fv fragment consisting of the V L and V H domains of a single arm of an antibody; a dAb fragment (Ward et al, 1989 Nature 341 :544-546), which consists of a V H domain; and an isolated CDR.
  • Exemplary antigen-binding fragments include the CDRs of secukinumab as set forth in SEQ ID NOs: 1-6 and 11-13 (Table 2), preferably the heavy chain CDR3.
  • the two domains of the Fv fragment, V L and V H are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the V L and V H regions pair to form monovalent molecules (known as single chain Fv (scFv); see, e.g., Bird et al., 1988 Science 242:423-426; and Huston et al, 1988 Proc. Natl. Acad. Sci. 85:5879-5883).
  • Such single chain antibodies are also intended to be encompassed within the term "antibody”.
  • Single chain antibodies and antigen-binding portions are obtained using conventional techniques known to those of skill in the art.
  • an “isolated antibody”, as used herein, refers to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds IL-17 is substantially free of antibodies that specifically bind antigens other than IL-17).
  • the term "monoclonal antibody” or “monoclonal antibody composition” as used herein refer to a preparation of antibody molecules of single molecular composition.
  • the term "human antibody”, as used herein, is intended to include antibodies having variable regions in which both the framework and CDR regions are derived from sequences of human origin. A "human antibody” need not be produced by a human, human tissue or human cell.
  • the human antibodies of the disclosure may include amino acid residues not encoded by human sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro, by N-nucleotide addition at junctions in vivo during recombination of antibody genes, or by somatic mutation in vivo).
  • the IL-17 antibody is a human antibody, an isolated antibody, and/or a monoclonal antibody.
  • IL-17 refers to IL-17A, formerly known as CTLA8, and includes wild-type IL- 17A from various species (e.g., human, mouse, and monkey), polymorphic variants of IL-17A, and functional equivalents of IL-17 A.
  • Functional equivalents of IL-17A according to the present disclosure preferably have at least about 65%, 75%, 85%, 95%, 96%, 97%, 98%, or even 99% overall sequence identity with a wild- type IL-17A (e.g., human IL-17A), and substantially retain the ability to induce IL-6 production by human dermal fibroblasts.
  • K D is intended to refer to the dissociation rate of a particular antibody-antigen interaction.
  • K D is intended to refer to the dissociation constant, which is obtained from the ratio of K d to K a (i.e., 3 ⁇ 4/ ⁇ 3 ) and is expressed as a molar concentration (M).
  • K D values for antibodies can be determined using methods well established in the art. A preferred method for determining the KD of an antibody is by using surface plasmon resonance, or using a biosensor system such as a Biacore® system.
  • the IL-17 antibody or antigen-binding fragment thereof e.g., secukinumab, binds human IL-17 with a KD of about 100-250 pM.
  • affinity refers to the strength of interaction between antibody and antigen at single antigenic sites. Within each antigenic site, the variable region of the antibody “arm” interacts through weak non-covalent forces with antigen at numerous sites; the more interactions, the stronger the affinity.
  • Standard assays to evaluate the binding affinity of the antibodies toward IL-17 of various species are known in the art, including for example, ELISAs, western blots and RIAs.
  • the binding kinetics (e.g., binding affinity) of the antibodies also can be assessed by standard assays known in the art, such as by Biacore analysis.
  • an antibody that "inhibits" one or more of these IL-17 functional properties will be understood to relate to a statistically significant decrease in the particular activity relative to that seen in the absence of the antibody (or when a control antibody of irrelevant specificity is present).
  • An antibody that inhibits IL-17 activity affects a statistically significant decrease, e.g., by at least about 10% of the measured parameter, by at least 50%, 80% or 90%, and in certain embodiments of the disclosed methods and compositions, the IL-17 antibody used may inhibit greater than 95%, 98% or 99% of IL-17 functional activity.
  • “Inhibit IL-6” as used herein refers to the ability of an IL-17 antibody or antigen-binding fragment thereof (e.g., secukinumab) to decrease IL-6 production from primary human dermal fibroblasts.
  • the production of IL-6 in primary human (dermal) fibroblasts is dependent on IL-17 (Hwang et al., (2004) Arthritis Res Ther; 6:R120-128).
  • human dermal fibroblasts are stimulated with recombinant IL-17 in the presence of various concentrations of an IL-17 binding molecule or human IL-17 receptor with Fc part.
  • the chimeric anti-CD25 antibody Simulect may be conveniently used as a negative control.
  • An IL-17 antibody or antigen-binding fragment thereof typically has an IC 50 for inhibition of IL-6 production (in the presence 1 nM human IL-17) of about 50 nM or less (e.g., from about 0.01 to about 50 nM) when tested as above, i.e., said inhibitory activity being measured on IL-6 production induced by hu-IL-17 in human dermal fibroblasts.
  • IL-17 antibodies or antigen-binding fragments thereof e.g., secukinumab, and functional derivatives thereof have an IC 50 for inhibition of IL-6 production as defined above of about 20 nM or less, more preferably of about 10 nM or less, more preferably of about 5 nM or less, more preferably of about 2 nM or less, more preferably of about 1 nM or less.
  • derivative unless otherwise indicated, is used to define amino acid sequence variants, and covalent modifications (e.g., pegylation, deamidation, hydroxylation, phosphorylation, methylation, etc.) of an IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab, according to the present disclosure, e.g., of a specified sequence (e.g., a variable domain).
  • a "functional derivative” includes a molecule having a qualitative biological activity in common with the disclosed IL-17 antibodies.
  • a functional derivative includes fragments and peptide analogs of an IL-17 antibody as disclosed herein.
  • Fragments comprise regions within the sequence of a polypeptide according to the present disclosure, e.g., of a specified sequence.
  • Functional derivatives of the IL-17 antibodies disclosed herein preferably comprise V H and/or V L domains that have at least about 65%, 75%, 85%, 95%, 96%, 97%, 98%, or even 99% overall sequence identity with the V H and/or V L sequences of the IL-17 antibodies and antigen-binding fragments thereof disclosed herein (e.g., the V H and/or V L sequences of Table 1), and substantially retain the ability to bind human IL-17 or, e.g., inhibit IL-6 production of IL-17 induced human dermal fibroblasts.
  • substantially identical means that the relevant amino acid or nucleotide sequence (e.g., V H or V L domain) will be identical to or have insubstantial differences (e.g., through conserved amino acid substitutions) in comparison to a particular reference sequence. Insubstantial differences include minor amino acid changes, such as 1 or 2 substitutions in a 5 amino acid sequence of a specified region (e.g., V H or V L domain).
  • the second antibody has the same specificity and has at least 50% of the affinity of the same. Sequences substantially identical (e.g., at least about 85% sequence identity) to the sequences disclosed herein are also part of this application.
  • sequence identity of a derivative IL-17 antibody can be about 90% or greater, e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher relative to the disclosed sequences.
  • Identity with respect to a native polypeptide and its functional derivative is defined herein as the percentage of amino acid residues in the candidate sequence that are identical with the residues of a corresponding native polypeptide, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent identity, and not considering any conservative substitutions as part of the sequence identity.
  • N- or C-terminal extensions nor insertions shall be construed as reducing identity.
  • Methods and computer programs for the alignment are well known.
  • the percent identity can be determined by standard alignment algorithms, for example, the Basic Local Alignment Search Tool (BLAST) described by Altshul et al. ((1990) J. Mol. Biol., 215: 403 410); the algorithm of Needleman et al. ((1970) J. Mol. Biol, 48: 444 453); or the algorithm of Meyers et al. ((1988) Comput. Appl. Biosci., 4: 11 17).
  • a set of parameters may be the Blosum 62 scoring matrix with a gap penalty of 12, a gap extend penalty of 4, and a frameshift gap penalty of 5.
  • the percent identity between two amino acid or nucleotide sequences can also be determined using the algorithm of E. Meyers and W. Miller ((1989) CABIOS, 4: 11-17) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4.
  • amino acid(s) refer to all naturally occurring L-a-amino acids, e.g., and include D-amino acids.
  • amino acid sequence variant refers to molecules with some differences in their amino acid sequences as compared to the sequences according to the present disclosure. Amino acid sequence variants of an antibody according to the present disclosure, e.g., of a specified sequence, still have the ability to bind the human IL-17 or, e.g., inhibit IL-6 production of IL-17 induced human dermal fibroblasts.
  • Amino acid sequence variants include substitutional variants (those that have at least one amino acid residue removed and a different amino acid inserted in its place at the same position in a polypeptide according to the present disclosure), insertional variants (those with one or more amino acids inserted immediately adjacent to an amino acid at a particular position in a polypeptide according to the present disclosure) and deletional variants (those with one or more amino acids removed in a polypeptide according to the present disclosure).
  • pharmaceutically acceptable means a nontoxic material that does not interfere with the effectiveness of the biological activity of the active ingredient(s).
  • a "therapeutically effective amount” refers to an amount of an IL-17 antagonist, e.g., IL-17 binding molecule (e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab) or IL-17 receptor binding molecule (e.g., IL-17 antibody or antigen- binding fragment thereof) that is effective, upon single or multiple dose administration to a patient (such as a human) for treating, preventing, preventing the onset of, curing (if applicable), delaying, reducing the severity of, ameliorating at least one symptom of a disorder or recurring disorder, or prolonging the survival of the patient beyond that expected in the absence of such treatment.
  • an IL-17 antagonist e.g., IL-17 binding molecule (e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab) or IL-17 receptor binding molecule (e.g., IL-17 antibody or antigen- binding fragment thereof) that is effective,
  • an active ingredient e.g., an IL-17 antagonist, e.g., secukinumab
  • the term refers to that ingredient alone.
  • the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously.
  • treatment or “treat” is herein defined as the application or administration of an IL-17 antibody according to the disclosure, for example, secukinumab or ixekizumab, or a pharmaceutical composition comprising said anti-IL-17 antibody, to a subject or to an isolated tissue or cell line from a subject, where the subject has a particular disease (e.g., psoriasis), a symptom associated with the disease (e.g., psoriasis), or a predisposition towards development of the disease (e.g., psoriasis), where the purpose is to cure (if applicable), delay the onset of, reduce the severity of, alleviate, ameliorate one or more symptoms of the disease, improve the disease, reduce or improve any associated symptoms of the disease or the predisposition toward the development of the disease.
  • treatment or “treat” includes treating a patient suspected to have the disease as well as patients who are ill or who have been diagnosed as suffering from the disease or medical condition, and includes suppression of
  • the patient is administered the IL-17 antagonist (e.g., IL-17 antibody, like secukinumab) monthly (e.g., following an initial weekly induction regimen during week 0, 1, 2, 3 and 4), which extends to at least 48 weeks.
  • the patient is administered the IL-17 antagonist (e.g., IL-17 antibody, like secukinumab) monthly (e.g., following an initial weekly induction regimen during week 0, 1 , 2, 3 and 4), which extends to at at least 100 weeks, at least 152 weeks, at least 204 weeks, at least 5 years, or at least 10 years.
  • treatment is withdrawn.
  • the phrases "withdrawing treatment”, “treatment withdrawal” and “withdrawal of treatment” and the like refer to discontinuing administration of a given drug, e.g., an IL-17 antagonist (e.g., an IL-17 antibody, e.g., secukinumab).
  • the IL-17 antibody is administered during week 0, 1, 2, 3, and 4, and then monthly thereafter, wherein the monthly dosing extends to at least 48 weeks, at least 100 weeks, at least 152 weeks, at least 204 weeks, at least 5 years, or at least 10 years before withdrawal of treatment.
  • the final administration of the IL-17 antibody (e.g., secukinumab) delivered prior to withdrawal of treatment is referred to as the "the last dose.”
  • the phrase "monthly dosing extends to at least X" means that the last dose before withdrawal of treatment is delivered at time point X.
  • the phrase "chronic" is used to mean plaque-type psoriasis in which the first psoriasis plaque appeared (deted) over 12 months (>12 months) prior to the start of treatment with the IL-17 antagonist (e.g., secukinumab).
  • the patient has had chronic plaque-type psoriasis for at least 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, 15 years, 20 years, or more.
  • the phrase "has not been previously treated with phototherapy for psoriasis” refers to a psoriasis patient who has not been previously treated with narrow band- UVB (nb-UVB) for psoriasis. In some embodiments of the disclosed methods, regimens, uses, kits, and pharmaceutical compositions, the patient has not been previously treated with phototherapy for psoriasis. As used herein, the phrase "has been previously treated with phototherapy for psoriasis” refers to a psoriasis patient who has been previously treated with narrow band-UVB (nb-UVB) for psoriasis. In some embodiments of the disclosed methods, regimens, uses, kits, and pharmaceutical compositions, the patient has been previously treated with a systemic treatment for psoriasis.
  • nb-UVB narrow band- UVB
  • the phrases "has not been previously treated with a systemic treatment for psoriasis" and "naive” refer to a psoriasis patient who has not been previously treated with a systemic agent, e.g., methotrexate, cyclosporine, a biological (e.g., ustekinumab, infliximab, TNF alpha inhibitors, etc.), etc., for psoriasis.
  • Systemic agents i.e., agents given orally, by injection, etc.
  • the patient has not been previously treated with a systemic treatment for psoriasis.
  • the phrase "has been previously treated with a systemic treatment for psoriasis” is used to mean a patient that has previously undergone psoriasis treatment using a systemic agent.
  • a biological agent i.e., a drug produced by a living organisim, e.g., antibodies, receptor decoys, etc.
  • ustekinumab a drug produced by a living organisim, e.g., antibodies, receptor decoys, etc.
  • a biological agent i.e., a drug produced by a living organisim, e.g., antibodies, receptor decoys, etc.
  • ustekinumab i.e., a TNF alpha inhibitor (e.g., etanercept, adalimumab, remicade), an IL-17 antagonist (e.g., broadalumab, ixekizumab), etc.
  • non- biologics such as methotrexate
  • the patient has been previously treated with a systemic agent for psoriasis (e.g., methotrexate, cyclosporine), but the patient has not been previously treated with a systemic biological agent for psoriasis (e.g., ustekinumab, ixekizumab, broadalumab, TNF alpha inhibitors (etanercept, adalimumab, remicade, etc.), secukinumab, etc.).
  • a systemic agent for psoriasis e.g., methotrexate, cyclosporine
  • a systemic biological agent for psoriasis e.g., ustekinumab, ixekizumab, broadalumab, TNF alpha inhibitors (etanercept, adalimumab, remicade, etc.), secukinumab, etc.
  • the patient is referred to as
  • TNF failure refers to a patient who had an inadequate response to a TNF alpha antagonist (e.g., etanercept, adalimumab, remicade, etc.) or a patient who was intolerant to prior treatment with a TNF alpha antagonist.
  • a TNF alpha antagonist e.g., etanercept, adalimumab, remicade, etc.
  • a patient who has been treated with a TNF antagonist, but who did not achieve a treatment goal e.g., PASI 50 or PASI 75, in the case of a patient having psoriasis
  • PASI 50 or PASI 75 in the case of a patient having psoriasis
  • TNF alpha antagonist A patient who responded adequately to prior treatment with a TNF alpha antagonist (i.e., the patient did achieve a treatment goal), but who discontinued due to a side effect, is referred to as being intolerant to prior treatment with a TNF alpha antagonist. TNF failures are also sometimes referred to as "TNF-IR" patients. In some embodiments, prior to administering the IL-17 antagonist, the patient is a TNF failure.
  • selecting and “selected” in reference to a patient is used to mean that a particular patient is specifically chosen from a larger group of patients on the basis of (due to) the particular patient having a predetermined criteria.
  • selecting refers to providing treatment to a patient having a particular disease, where that patient is specifically chosen from a larger group of patients on the basis of the particular patient having a predetermined criterion.
  • selective administering refers to administering a drug to a patient that is specifically chosen from a larger group of patients on the basis of (due to) the particular patient having a predetermined criterion.
  • a patient is delivered a personalized therapy based on the patient's personal history (e.g., prior therapeutic interventions, e.g., prior treatment with biologies), biology (e.g., particular genetic markers), and/or manifestation (e.g., not fulfilling particular diagnostic criteria), rather than being delivered a standard treatment regimen based solely on the patient's membership in a larger group.
  • Selecting, in reference to a method of treatment as used herein, does not refer to fortuitous treatment of a patient having a particular criterion, but rather refers to the deliberate choice to administer treatment to a patient based on the patient having a particular criterion.
  • selective treatment/administration differs from standard treatment/administration, which delivers a particular drug to all patients having a particular disease, regardless of their personal history, manifestations of disease, and/or biology.
  • the patient having chronic plaque-type psoriasis e.g., moderate to severe chronic plaque-type psoriasis
  • the patient having achieved PASI 75 following treatment e.g., with administration extending to at least 48 weeks
  • the IL-17 antibody or antigen-binding fragment thereof e.g.,
  • the patient being biological-nai ' ve, the patient being TNF-nai ' ve, the patient having a low baseline PASI score (e.g., a baseline PASI score of ⁇ 39, ⁇ 26, ⁇ 25, ⁇ 23, ⁇ 22, ⁇ 21.4, ⁇ 21, ⁇ 20, ⁇ _ ⁇ 9, ⁇ 15, ⁇ 10), and any combination thereof.
  • a baseline PASI score e.g., a baseline PASI score of ⁇ 39, ⁇ 26, ⁇ 25, ⁇ 23, ⁇ 22, ⁇ 21.4, ⁇ 21, ⁇ 20, ⁇ _ ⁇ 9, ⁇ 15, ⁇ 10
  • CHMP Committee for medicinal products for human use
  • EWP European Medicines Agency for the Evaluation of Medicines for Human Use. (2004) Guideline on clinical investigation of medicinal products indicated for the treatment of psoriasis.
  • Treatment response Patients achieving > 75% improvement (reduction) in Psoriasis Area and Severity Index (PASI) score compared to baseline (also referred to as PASI 75) are defined as treatment responders.
  • Psoriasis Area and Severity Index PASI 75
  • Partial response Patients achieving a > 50% improvement from baseline PASI score (also referred to as PASI 50) but less than 75% (also referred to as PASI 75) are defined as partial responders.
  • Non response Patients achieving a PASI reduction of ⁇ 50% from baseline PASI score are defined as non-responders.
  • erythrodermic or more inflammatory psoriasis occurring within 8 weeks of stopping therapy e.g., a PASI of > 125% of the value at baseline PASI.
  • the head, trunk, upper limbs and lower limbs are assessed separately for erythema, thickening (plaque elevation, induration), and scaling (desquamation) as defined in Table 1.
  • the average degree of severity of each sign in each of the four body regions is assigned a score of 0 to 4.
  • the area covered by lesions on each body region is estimated as a percentage of the total area of that particular body region. Because the head and neck, upper limbs, trunk and lower limbs correspond to approximately 10%, 20%, 30% and 40% of the body surface area, respectively, the PASI score is calculated using the formula:
  • PASI 0.1 (EH+IH+DH)AH + 0.2(EU+IU+DU)AU + 0.3(ET+IT+DT)AT +
  • PASI scores can range from a lower value of 0, corresponding to no signs of psoriasis, up to a theoretic maximum of 72.0.
  • PASI scores are specific to a tenth of a point, e.g., 9.0, 10.1, 14.2, 17.3, etc. Further information on PASI scoring is available in Henseler T, Schmitt-Rau K (2008) Int. J. Dermatol.; 47: 1019 - 1023.
  • patients are assessed using the PASI scoring system (physician assessed or patient assessed, preferably physician assessed).
  • the patient achieves at least a 50% reduction of the Psoriasis Area and Severity Index Score (PASI 50) at week 12 of treatment. In some embodiments of the disclosed methods, kits, and uses, the patient achieves at least a 75% reduction of the Psoriasis Area and Severity Index Score (PASI 75) at week 12 of treatment. In some embodiments of the disclosed methods, kits, and uses, the patient achieves at least a 90% reduction of the Psoriasis Area and Severity Index Score (PASI 90) at week 12 of treatment. In some embodiments of the disclosed methods, kits, and uses, the patient achieves 100% reduction of the Psoriasis Area and Severity Index Score (PASI 100) at week 12 of treatment.
  • PSI 50 Psoriasis Area and Severity Index Score
  • PASI 75 the Psoriasis Area and Severity Index Score
  • PASI 90 90% reduction of the Psoriasis Area and Severity Index Score
  • the patient achieve
  • the patient has a baseline PASI score of ⁇ 39 or ⁇ 26.
  • the patient has a baseline PASI score of ⁇ 39 and the patient maintains at least 50% of the PASI improvement achieved between baseline and week 52 for at least 1 year after the last dose of the IL-17 antibody or antigen-binding fragment thereof.
  • the patient has a baseline PASI score of ⁇ 26 and the patient maintains at least 50% of the PASI improvement achieved between baseline and week 52 for at least 2 years after the last dose of the IL-17 antibody or antigen-binding fragment thereof.
  • the patient has a baseline PASI score of ⁇ 25, ⁇ 24, ⁇ 23, ⁇ 22, ⁇ 21.4, ⁇ 21, ⁇ 20, ⁇ 19, ⁇ 15, or ⁇ 12.
  • baseline refers to an initial score, e.g., PASI score.
  • PASI improvement refers to the difference between a baseline score, e.g., PASI score, and a score, e.g., PASI score, at a later time point. For example, if a patient has a baseline PASI score of 12 and a PASI score of 2 at week 52, the PASI improvement is 10. If that patient maintains a PASI score of ⁇ 7 ((50% of 10) + 2), he/she has maintained at least 50% of this PASI improvement. If that patient maintains a PASI score of ⁇ 3 ((90% of 10) + 2) he/she has maintained at least 90% of this PASI improvement. A loss of over 50% PASI improvement is considered a relapse.
  • Psoriasis patient's response to treatment may be measured by other available scoring system, e.g., physician's assessed efficacy measures, such as visual assessment of index lesions, body surface measurement (BSA), clinical signs score: Total Severity Sign score (TSS), Physician's global assessment of improvement (PGA) or other global score (e.g., Investigators global assessment of improvement (IGA)); or patient's assessed efficacy measures, such as symptom improvement (pruritis, soreness), Patient's assessment of global improvement, Patient's assessment of PASI (self-administered PASI -SAPASI), or HRQL scales for dermatology (general scales, such as DLQI, DQOLS and specific psoriasis scales, such as PDI, PLSI)).
  • physician's assessed efficacy measures such as visual assessment of index lesions, body surface measurement (BSA), clinical signs score: Total Severity Sign score (TSS), Physician's global assessment of improvement (PGA) or
  • the plaque (also called “plaque-type”) psoriasis disease course begins with small skin plaques ⁇ 1/8 of an inch wide, typically in the same areas on opposite sides of the body. They grow slowly and develop into thick, dry plaques. If the plaque is scratched or scraped, bleeding spots the sizes of pinheads appear underneath. This is known as the Auspitz sign. Some patches become annular, with a clear center and scaly raised borders. Eventually, separate patches join together to form larger areas. In some cases, the patches cover wide areas of the back or chest, termed geographic plaques. As used herein, the phrase “slowing psoriasis disease progression" means decelerating the advancement rate of the disease course of plaque-type psoriasis. In some embodiments of the disclosure, treatment with the IL-17 antagonist (e.g., secukinumab) slows psoriasis disease progression.
  • the IL-17 antagonist e.g., secukinumab
  • IL-17 antagonist e.g., IL-17 antibody, like secukinumab
  • IL-17 antibody like secukinumab
  • reducing tissue resident memory T-cells in the skin reducing subset effector T- cells producing interleukin -17 (IL-17) and/or interleukin -22 (IL-22) in the skin
  • IL-17 interleukin -17
  • IL-22 interleukin -22
  • reducing regulatory T cells in the skin reducing dermal dendritic cell-T cell aggregates in the skin (e.g., reducing cell-mediated immunity in the skin, reducing T-cell-mediated immune response in the skin), etc.
  • modifying the psoriasis disease course refers to changing the underlying cellular pathology of psoriasis which leads to change in the course of the disease (clinical presentation).
  • patients whose psoriasis disease course has been modified are capable of maintaining low PASI levels (e.g., ⁇ 11.2 [e.g., ranging from 0.3 to 11.2], ⁇ 7.2 [ranging from 0.3 to 7.2], ⁇ 5.0, ⁇ 4.0, ⁇ 3.3, ⁇ 3.0, ⁇ 1, etc.) after the last dose of the IL-17 antagonist (e.g., IL-17 antibody, like secukinumab).
  • the IL-17 antagonist e.g., IL-17 antibody, like secukinumab
  • the patient is capable of maintaining a PASI score of ⁇ 11.2 for at least six months or at least one year after the last dose of the IL-17 antibody or antigen-binding fragment thereof. In some embodiments, the patient is capable of maintaining a PASI score of ⁇ 7.2 for at least 6 months, at least one year, or at least two years after the last dose of the IL-17 antibody or antigen-binding fragment thereof.
  • the patient is capable of maintaining at least 50% of the PASI improvement (preferably at least 90% of the PASI improvement) achieved between baseline and treatment withdrawal (e.g., the last dose being given at week 48, week 100, week 204, 3 years, 5 years, 7 years, 10 years, 12 years, 15 year) after the last dose of the IL-17 antibody or antigen-binding fragment thereof.
  • baseline and treatment withdrawal e.g., the last dose being given at week 48, week 100, week 204, 3 years, 5 years, 7 years, 10 years, 12 years, 15 year
  • the patient is capable of maintaining at least 50% of the PASI improvement (preferably at least 75% of the PASI improvement) achieved between baseline and treatment withdrawal (e.g., the last dose being given at week 48, week 100, week 204, 3 years, 5 years, 7 years, 10 years, 12 years, 15 year) after the last dose of the IL-17 antibody or antigen-binding fragment thereof.
  • baseline and treatment withdrawal e.g., the last dose being given at week 48, week 100, week 204, 3 years, 5 years, 7 years, 10 years, 12 years, 15 year
  • the patient is capable of maintaining at least 50% of the PASI improvement (preferably at least 90% of the PASI improvement) achieved between baseline and treatment withdrawal (e.g., the last dose being given at week 48, week 100, week 204, 3 years, 5 years, 7 years, 10 years, 12 years, 15 year) for at least 6 months, at least 1 year, or at least 2 years (preferably at least 2 years) after the last dose of the IL-17 antibody or antigen-binding fragment thereof.
  • the PASI improvement preferably at least 90% of the PASI improvement
  • psoriasis flare comprises the manifestation of plaque-type psoriasis, including plaques, irritated patches of skin, redness (e.g., particularly on elbows, knees, trunk and scalp), changes and/or disfiguration in nails, dandruff, and any combination thereof.
  • a psoriasis flare includes the formation of psoriasis plaques.
  • treatment with the IL-17 antagonist e.g., secukinumab
  • the phrase "decreasing the severity of psoriasis flares" and the like means reducing the intensity of a psoriasis flare, e.g., reducing the percentage of skin affected by psoriasis, reducing the intensity of a particular flare component (e.g., reducing the number, size, thickness, etc. of plaques, reducing the extent of skin irritation, reducing scaling, reducing erythema, reducing changes and/or disfigurations in nails, reducing dandruff, etc.), and/or reducing the amount of time a flare (or component thereof) persists.
  • a flare component e.g., reducing the percentage of skin affected by psoriasis
  • a particular flare component e.g., reducing the number, size, thickness, etc. of plaques, reducing the extent of skin irritation, reducing scaling, reducing erythema, reducing changes and/or disfigurations in nails, reducing dandruff, etc.
  • the severity of a flare may be measured using various tools, e.g., the body surface area (BSA) test, the investigator's global assessment (IGA, IGA mod 2011), physicians global assessment (PGA), the psoriasis area and severity index (PASI), and patient reported outcomes, e.g., the Dermatology life quality index (DLQI) and the Work productivity and activity impairment questionnaire: psoriasis
  • BSA body surface area
  • IGA investigator's global assessment
  • PGA physicians global assessment
  • PASI psoriasis area and severity index
  • patient reported outcomes e.g., the Dermatology life quality index (DLQI) and the Work productivity and activity impairment questionnaire: psoriasis
  • the phrase "decreasing the frequency of psoriasis flares" and the like means reducing the incidence of psoriasis flares, e.g., reducing the incidence of plaques and/or other psoriasis flare components (e.g., plaques, skin irritation, scaling, erythema, changes in nails, dandruff, etc.).
  • psoriasis flares By decreasing the frequency of psoriasis flares, a patient will experience fewer psoriasis relapses.
  • the incidence of flares may be assessed by monitoring a patient over time to determine if the prevalence of flares decreases.
  • preventing psoriasis flares means eliminating future psoriasis flares and/or flare components.
  • IL-17 antagonist e.g., an IL-17 antibody, like secukinumab
  • IL-17 antagonist e.g., an IL-17 antibody, like secukinumab
  • the phrase "decreasing the likelihood that a psoriasis patient will develop psoriatic arthritis” refers to a reduction in the probability that a psoriasis patient will develop psoriatic arthritis.
  • the phrase "delaying the onset of psoriatic arthritis in a psoriasis patient” refers to postponing development of the signs and symptoms, and/or structural damage associated with PsA in a psoriasis patient.
  • the phrase “delaying the onset of psoriatic arthritis in a psoriasis patient” refers to postponing development of the signs and symptoms, and/or structural damage associated with PsA in a psoriasis patient.
  • the phrase “delaying the onset of psoriatic arthritis in a psoriasis patient” refers to postponing development of the signs and symptoms, and/or structural damage associated with PsA in a psoriasis patient.
  • preventing progression from psoriasis to psoriatic arthritis in a psoriasis patient refers to inhibiting the development of PsA in a psoriasis patient.
  • mild psoriasis is defined as psoriasis disease in which body surface area (BSA) ⁇ 10 and psoriasis area and severity index (PASI) ⁇ 10 and dermatology life quality index (DLQI) ⁇ 10.
  • BSA body surface area
  • PASI psoriasis area and severity index
  • DLQI dermatology life quality index
  • “moderate to severe psoriasis” is defined as psoriasis disease in which (BSA > 10 or PASI > 10) and DLQI > 10. See Mrowietz et al. (2011) Arch Dermatol Res. 303(1): 1-10. In some embodiments of the disclosed methods, uses and kits, the patient has mild psoriasis.
  • the patient has moderate to severe psoriasis.
  • long-term treatment with the IL-17 antagonist e.g., IL-17 antibody, such as secukinumab
  • the IL-17 antagonist converts from having moderate to severe psoriasis to having mild psoriasis due to a modification of the psoriasis disease course.
  • the methods and uses disclosed herein provide treatment of moderate to severe chronic plaque-type psoriasis in adult patients who are candidates for systemic therapy (or phototherapy).
  • that adult patient has a BSA > 5%, preferably a BSA > 3%.
  • IL-17 antagonist e.g., IL-17 binding molecule (e.g., soluble IL-17 receptor, IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab) or IL-17 receptor binding molecule (e.g., IL-17 receptor antibody or antigen-binding fragment thereof).
  • the IL-17 antagonist is an IL-17 binding molecule, preferably an IL-17 antibody or antigen-binding fragment thereof.
  • the IL-17 antibody or antigen-binding fragment thereof comprises at least one immunoglobulin heavy chain variable domain (V H ) comprising hypervariable regions CDR1, CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO: l, said CDR2 having the amino acid sequence SEQ ID NO: 2, and said CDR3 having the amino acid sequence SEQ ID NO: 3.
  • V H immunoglobulin heavy chain variable domain
  • the IL-17 antibody or antigen-binding fragment thereof comprises at least one immunoglobulin light chain variable domain (V L ) comprising hypervariable regions CDR1 ', CDR2' and CDR3', said CDR1 ' having the amino acid sequence SEQ ID NO:4, said CDR2' having the amino acid sequence SEQ ID NO:5 and said CDR3' having the amino acid sequence SEQ ID NO: 6.
  • V L immunoglobulin light chain variable domain
  • the IL-17 antibody or antigen-binding fragment thereof comprises at least one immunoglobulin heavy chain variable domain (V H ) comprising hypervariable regions CDRl-x, CDR2-X and CDR3-X, said CDRl-x having the amino acid sequence SEQ ID NO: 11, said CDR2-x having the amino acid sequence SEQ ID NO: 12, and said CDR3-x having the amino acid sequence SEQ ID NO: 13.
  • V H immunoglobulin heavy chain variable domain
  • the IL-17 antibody or antigen-binding fragment thereof comprises at least one immunoglobulin V H domain and at least one immunoglobulin V L domain
  • the immunoglobulin V H domain comprises (e.g., in sequence): i) hypervariable regions CDR1, CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO: l, said CDR2 having the amino acid sequence SEQ ID NO: 2, and said CDR3 having the amino acid sequence SEQ ID NO: 3; or ii) hypervariable regions CDRl-x, CDR2-X and CDR3-X, said CDRl-x having the amino acid sequence SEQ ID NO: 11, said CDR2-x having the amino acid sequence SEQ ID NO: 12, and said CDR3-x having the amino acid sequence SEQ ID NO: 13; and b) the immunoglobulin V L domain comprises (e.g., in sequence) hypervariable regions CDR1 ', CDR2' and CDR3', said CDR1
  • the IL-17 antibody or antigen-binding fragment thereof comprises: a) an immunoglobulin heavy chain variable domain (V H ) comprising the amino acid sequence set forth as SEQ ID NO: 8; b) an immunoglobulin light chain variable domain (V L ) comprising the amino acid sequence set forth as SEQ ID NO: 10; c) an immunoglobulin V H domain comprising the amino acid sequence set forth as SEQ ID NO: 8 and an immunoglobulin V L domain comprising the amino acid sequence set forth as SEQ ID NO: 10; d) an immunoglobulin V H domain comprising the hypervariable regions set forth as SEQ ID NO: l, SEQ ID NO: 2, and SEQ ID NO: 3; e) an immunoglobulin V L domain comprising the hypervariable regions set forth as SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6; f) an immunoglobulin V H domain comprising the hypervariable regions set forth as SEQ ID NO: 11, SEQ ID NO: 12 and S
  • amino acid sequences of the hypervariable regions of the secukinumab monoclonal antibody based on the Kabat definition and as determined by the X- ray analysis and using the approach of Chothia and coworkers, is provided in Table 2, below.
  • Table 2 Amino acid sequences of the hypervariable regions of secukinumab.
  • the constant region domains also comprise suitable human constant region domains, for instance as described in "Sequences of Proteins of Immunological Interest", Kabat E.A. et al, US Department of Health and Human Services, Public Health Service, National Institute of Health.
  • the DNA encoding the VL of secukinumab is set forth in SEQ ID NO: 9.
  • the DNA encoding the V H of secukinumab is set forth in SEQ ID NO: 7.
  • the IL-17 antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 10. In other embodiments, the IL-17 antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 8. In other embodiments, the IL-17 antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 10 and the three CDRs of SEQ ID NO: 8. CDRs of SEQ ID NO: 8 and SEQ ID NO: 10 may be found in Table 2. The free cysteine in the light chain (CysL97) may be seen in SEQ ID NO: 6.
  • IL-17 antibody or antigen-binding fragment thereof comprises the light chain of SEQ ID NO: 14. In other embodiments, the IL-17 antibody or antigen-binding fragment thereof comprises the heavy chain of SEQ ID NO: 15. In other embodiments, the IL-17 antibody or antigen-binding fragment thereof comprises the light chain of SEQ ID NO: 14 and the heavy domain of SEQ ID NO: 15. In some embodiments, the IL-17 antibody or antigen- binding fragment thereof comprises the three CDRs of SEQ ID NO: 14. In other embodiments, IL-17 antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 15.
  • the IL-17 antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 14 and the three CDRs of SEQ ID NO: 15.
  • CDRs of SEQ ID NO: 14 and SEQ ID NO: 15 may be found in Table 2.
  • Hypervariable regions may be associated with any kind of framework regions, though preferably are of human origin. Suitable framework regions are described in Kabat E.A. et al, ibid.
  • the preferred heavy chain framework is a human heavy chain framework, for instance that of the secukinumab antibody. It consists in sequence, e.g. of FR1 (amino acid 1 to 30 of SEQ ID NO: 8), FR2 (amino acid 36 to 49 of SEQ ID NO: 8), FR3 (amino acid 67 to 98 of SEQ ID NO: 8) and FR4 (amino acid 117 to 127 of SEQ ID NO: 8) regions.
  • another preferred heavy chain framework consists in sequence of FRl-x (amino acid 1 to 25 of SEQ ID NO: 8), FR2-x (amino acid 36 to 49 of SEQ ID NO:8), FR3-x (amino acid 61 to 95 of SEQ ID NO:8) and FR4 (amino acid 119 to 127 of SEQ ID NO:8) regions.
  • the light chain framework consists, in sequence, of FR1 ' (amino acid 1 to 23 of SEQ ID NO: 10), FR2' (amino acid 36 to 50 of SEQ ID NO: 10), FR3' (amino acid 58 to 89 of SEQ ID NO: 10) and FR4' (amino acid 99 to 109 of SEQ ID NO: 10) regions.
  • the IL-17 antibody or antigen-binding fragment thereof is selected from a human IL-17 antibody that comprises at least: a) an immunoglobulin heavy chain or fragment thereof which comprises a variable domain comprising, in sequence, the hypervariable regions CDRl, CDR2 and CDR3 and the constant part or fragment thereof of a human heavy chain; said CDRl having the amino acid sequence SEQ ID NO: l, said CDR2 having the amino acid sequence SEQ ID NO: 2, and said CDR3 having the amino acid sequence SEQ ID NO: 3; and b) an immunoglobulin light chain or fragment thereof which comprises a variable domain comprising, in sequence, the hypervariable regions CDRl ', CDR2', and CDR3' and the constant part or fragment thereof of a human light chain, said CDRl ' having the amino acid sequence SEQ ID NO:4, said CDR2' having the amino acid sequence SEQ ID NO: 5, and said CDR3' having the amino acid sequence SEQ ID NO:
  • the IL-17 antibody or antigen-binding fragment thereof is selected from a single chain antibody or antigen-binding fragment thereof that comprises an antigen- binding site comprising: a) a first domain comprising, in sequence, the hypervariable regions CDRl, CDR2 and CDR3, said CDRl having the amino acid sequence SEQ ID NO: l, said CDR2 having the amino acid sequence SEQ ID NO: 2, and said CDR3 having the amino acid sequence SEQ ID NO: 3; and b) a second domain comprising, in sequence, the hypervariable regions CDR1', CDR2' and CDR3', said CDR1 ' having the amino acid sequence SEQ ID NO:4, said CDR2' having the amino acid sequence SEQ ID NO: 5, and said CDR3' having the amino acid sequence SEQ ID NO: 6; and c) a peptide linker which is bound either to the N-terminal extremity of the first domain and to the C-terminal extremity of the second domain or to the C-terminal extrem
  • an IL-17 antibody or antigen-binding fragment thereof as used in the disclosed methods may comprise a derivative of the IL-17 antibodies set forth herein by sequence (e.g., a pegylated version of secukinumab).
  • the V H or V L domain of an IL-17 antibody or antigen-binding fragment thereof used in the disclosed methods may have V H or V L domains that are substantially identical to the V H or V L domains set forth herein (e.g., those set forth in SEQ ID NO: 8 and 10).
  • a human IL-17 antibody disclosed herein may comprise a heavy chain that is substantially identical to that set forth as SEQ ID NO: 15 and/or a light chain that is substantially identical to that set forth as SEQ ID NO: 14.
  • a human IL-17 antibody disclosed herein may comprise a heavy chain that comprises SEQ ID NO: 15 and a light chain that comprises SEQ ID NO: 14.
  • a human IL-17 antibody disclosed herein may comprise: a) a heavy chain which comprises a variable domain having an amino acid sequence substantially identical to that shown in SEQ ID NO: 8 and the constant part of a human heavy chain; and b) a light chain which comprises a variable domain having an amino acid sequence substantially identical to that shown in SEQ ID NO: 10 and the constant part of a human light chain.
  • an IL-17 antibody or antigen-binding fragment thereof used in the disclosed methods may be an amino acid sequence variant of the reference IL-17 antibodies set forth herein, as long as it contains CysL97.
  • the disclosure also includes IL-17 antibodies or antigen-binding fragments thereof (e.g., secukinumab) in which one or more of the amino acid residues of the V H or V L domain of secukinumab (but not CysL97), typically only a few (e.g., 1- 10), are changed; for instance by mutation, e.g., site directed mutagenesis of the corresponding DNA sequences.
  • the IL-17 antibodies or antigen-binding fragments thereof bind to an epitope of mature human IL-17 comprising Leu74, Tyr85, His86, Met87, Asn88, Vail 24, Thrl25, Prol26, Ilel27, Vail 28, Hisl29.
  • the IL- 17 antibody e.g., secukinumab, binds to an epitope of mature human IL-17 comprising Tyr43, Tyr44, Arg46, Ala79, Asp80.
  • the IL-17 antibody e.g., secukinumab
  • the residue numbering scheme used to define these epitopes is based on residue one being the first amino acid of the mature protein (i.e., IL-17A lacking the 23 amino acid N-terminal signal peptide and beginning with Glycine).
  • the sequence for immature IL-17A is set forth in the Swiss-Prot entry Q 16552.
  • the IL-17 antibody has a K D of about 100-200 pM (e.g., as determined by a Biacore® assay).
  • the IL-17 antibody has an IC 50 of about 0.4 nM for in vitro neutralization of the biological activity of about 0.67 nM human IL- 17A.
  • the absolute bioavailability of subcutaneously (SC) administered IL-17 antibody has a range of about 60 - about 80%, e.g., about 76%.
  • the IL-17 antibody such as secukinumab
  • the IL-17 antibody (such as secukinumab) has a T max of about 7-8 days.
  • IL-17 antibodies or antigen-binding fragments thereof used in the disclosed methods are human antibodies, especially secukinumab as described in Examples 1 and 2 of WO 2006/013107.
  • Secukinumab is a recombinant high-affinity, fully human monoclonal anti-human interleukin-17A (IL-17A, IL-17) antibody of the IgGl /kappa isotype that is currently in clinical trials for the treatment of immune-mediated inflammatory conditions.
  • Secukinumab (see, e.g., WO2006/013107 and WO2007/117749) has a very high affinity for IL- 17, i.e., a K D of about 100-200 pM and an IC 50 for in vitro neutralization of the biological activity of about 0.67 nM human IL-17A of about 0.4 nM.
  • secukinumab inhibits antigen at a molar ratio of about 1 : 1.
  • This high binding affinity makes the secukinumab antibody particularly suitable for therapeutic applications.
  • secukinumab has a very long half-life, i.e., about 4 weeks, which allows for prolonged periods between administration, an exceptional property when treating chronic life-long disorders, such as psoriasis.
  • IL-17 antibodies for use in the disclosed methods, kits and regimens are those set forth in US Patent Nos: 8,057,794; 8,003,099; 8,110,191; and 7,838,638 and US Published Patent Application Nos: 20120034656 and 20110027290, which are incorporated by reference herein in their entirety.
  • IL-17 antagonists e.g., IL-17 binding molecules (e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab) or IL-17 receptor binding molecules (e.g., IL-17 receptor antibody or antigen-binding fragment thereof), may be used in vitro, ex vivo, or incorporated into pharmaceutical compositions and administered in vivo to treat chronic plaque- type psoriasis patients (e.g., human patients).
  • IL-17 binding molecules e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab
  • IL-17 receptor binding molecules e.g., IL-17 receptor antibody or antigen-binding fragment thereof
  • chronic plaque- type psoriasis patients e.g., human patients.
  • the IL-17 antagonists may be used as a pharmaceutical composition when combined with a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier may contain, in addition to an IL-17 antagonist, carriers, various diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. The characteristics of the carrier will depend on the route of administration.
  • the pharmaceutical compositions for use in the disclosed methods may also contain additional therapeutic agents for treatment of the particular targeted disorder.
  • a pharmaceutical composition may also include anti-inflammatory agents.
  • additional factors and/or agents may be included in the pharmaceutical composition to produce a synergistic effect with the IL-17 binding molecules, or to minimize side effects caused by the IL-17 antagonists, e.g., IL-17 binding molecules (e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab) or IL-17 receptor binding molecules (e.g., IL-17 antibody or antigen-binding fragment thereof).
  • IL-17 binding molecules e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab
  • IL-17 receptor binding molecules e.g., IL-17 antibody or antigen-binding fragment thereof
  • compositions for use in the disclosed methods may be manufactured in conventional manner.
  • the pharmaceutical composition is provided in lyophilized form.
  • a suitable aqueous carrier for example sterile water for injection or sterile buffered physiological saline.
  • a suitable aqueous carrier for example sterile water for injection or sterile buffered physiological saline.
  • a suitable aqueous carrier for example sterile water for injection or sterile buffered physiological saline.
  • a suitable aqueous carrier for example sterile water for injection or sterile buffered physiological saline.
  • albumin a suitable concentration is from 0.5 to 4.5% by weight of the saline solution.
  • Other formulations comprise liquid or lyophilized formulation.
  • Antibodies e.g., antibodies to IL-17
  • the IL-17 antagonist e.g., IL-17 antibody, e.g., secukinumab
  • IL-17 antibody e.g., secukinumab
  • Suitable lyophilisate formulations can be reconstituted in a small liquid volume (e.g., 2ml or less, e.g., 1 ml) to allow subcutaneous administration and can provide solutions with low levels of antibody aggregation.
  • a small liquid volume e.g., 2ml or less, e.g., 1 ml
  • IL-17 antagonist e.g., IL-17 binding molecules (e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab) or IL-17 receptor binding molecules (e.g., IL-17 antibody or antigen-binding fragment thereof)
  • the IL-17 antagonist will be in the form of a pyrogen-free, parenterally acceptable solution.
  • compositions for intravenous, cutaneous, or subcutaneous injection may contain, in addition to the IL-17 antagonist, an isotonic vehicle such as sodium chloride, Ringer's solution, dextrose, dextrose and sodium chloride, lactated Ringer's solution, or other vehicle as known in the art.
  • an isotonic vehicle such as sodium chloride, Ringer's solution, dextrose, dextrose and sodium chloride, lactated Ringer's solution, or other vehicle as known in the art.
  • the appropriate dosage will vary depending upon, for example, the particular IL-17 antagonists, e.g., IL-17 binding molecules (e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab) or IL-17 receptor binding molecules (e.g., IL-17 antibody or antigen- binding fragment thereof) to be employed, the host, the mode of administration and the nature and severity of the condition being treated, and on the nature of prior treatments that the patient has undergone.
  • the attending health care provider will decide the amount of the IL- 17 antagonist with which to treat each individual patient.
  • the attending health care provider may administer low doses of the IL-17 antagonist and observe the patient's response.
  • the initial dose(s) of IL-17 antagonist administered to a patient are high, and then are titrated downward until signs of relapse occur. Larger doses of the IL-17 antagonist may be administered until the optimal therapeutic effect is obtained for the patient, and the dosage is not generally increased further.
  • a therapeutically effective amount of an IL-17 antagonist e.g., IL-17 binding molecule (e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab) or IL-17 receptor binding molecule (e.g., IL-17 antibody or antigen-binding fragment thereof) is administered to a patient, e.g., a mammal (e.g., a human).
  • a mammal e.g., a human
  • the IL-17 antagonist e.g., secukinumab
  • the IL-17 antagonist may be administered in accordance with the methods of the disclosure either alone or in combination with other agents and therapies for treating chronic plaque-type psoriasis patients, e.g., in combination with at least one additional psoriasis agent.
  • an IL-17 antagonist may be administered either simultaneously with the other agent, or sequentially. If administered sequentially, the attending physician will decide on the appropriate sequence of administering the IL-17 antagonist in combination with other agents and the appropriate dosages for co-delivery.
  • IL-17 antibodies such as secukinumab
  • therapies include topicals (over the counter, non-steroidal compounds, and steroidal compound), phototherapy and systemic treatment (e.g., with biologicals or chemical entities).
  • Non-limiting examples of topical psoriasis agents for use with the disclosed IL-17 antibodies include salicylic acid, coal tar, Dovonex® (calcipotriene), Taclonex® (calcipotriene and betamethasone dipropionate), Tazorec® (tazarotene), pimecrolimus, tacrolimus, Vectical® (calcitriol), Zithranol-RR® (anthralin) and topical steroids (e.g., corticosteroids).
  • Examples of phototherapy for use with the disclosed IL-17 antibodies, such as secukinumab, include treatment with psoralen + UVA (PUVA) or treatment with UVB (with or without tar).
  • PUVA psoralen + UVA
  • UVB with or without tar
  • psoriasis agents used in systemic treatment for use with the disclosed IL-17 antibodies include retionoids such as Acitretin (e.g., Soriatane ®), cyclosporine, methotrexate, hydroxyurea (e.g., Hydrea®), isotretinoin, mycophenolate mofetil, mycophenolic acid, sulfasalazine, 6-thioguanine, fumarates (e.g, dimethylfumarate and fumaric acid esters), azathioprine, corticosteroids, leflunomide, tacrolimus, T-cell blockers (such as Amevive® (alefacept) and Raptiva® (efalizumab), tumor necrosis factor-alpha (TNF-alpha) blockers (such as Enbrel® (etanercept), Humira® (adalimumab), Remicade® (inf
  • retionoids such as Acitreti
  • Additional psoriasis agents for use in combination with the disclosed IL-17 antibodies, such as secukinumab, during treatment of psoriasis include apremilast, mometasome, voclosporin, ketokonazol, Neuroskin Forte, recombinant human interleukin- 10, voclosporin, MK-3222, tofacitinib, VX-765, MED-I545, fluphenazine decanoate, acetomuinophn, bimosiamose cream, doxycycline, vancomycin, AbGnl68, Vitamin D3, R05310074, fludarabine Calcipotriol and hydrocortisone (LEO 80190), LE80185 (Taclonex® Scalp topical
  • Focetria Monovalent MF59-Adjuvanted vaccine, tgAAC94 gene therapy vector, Apremilast, Capsaicin, Psirelax, ABT-874 (anti IL-12), IDEC-114, MEDI-522, INCB018424 phosphate cream, LE29102, BMS 587101, CD 2027, CRx-191, 8-methoxypsoralen or 5- methoxypsoralen, Bicillin L-A, LY2525623, INCB018424, LY2439821, CEP-701, CC- 10004, certolizumab (CZP), GW786034 (pazopanib), doxycycline Curcuminoids C3 Complex, NYC 0462, RG3421, hOKT3gammal(Ala-Ala), BT061, teplizumab, Chondroitin sulphate, CNTO 1275, monoclonal antibody to IL-12p40
  • Focetria Monovalent
  • Additional agents for use in combination with secukinumab during treatment of psoriasis include IL-6 antagonists, CD20 antagonists, CTLA4 antagonists, IL-17 antagonists, IL-8 antagonists, IL-21 antagonists, IL-22 antagonist, VGEF antagonists, CXCL antagonists, MMP antagonists, defensin antagonists, IL-lbeta antagonists, and IL-23 antagonists (e.g., receptor decoys, antagonistic antibodies, etc.).
  • IL-6 antagonists include CD20 antagonists, CTLA4 antagonists, IL-17 antagonists, IL-8 antagonists, IL-21 antagonists, IL-22 antagonist, VGEF antagonists, CXCL antagonists, MMP antagonists, defensin antagonists, IL-lbeta antagonists, and IL-23 antagonists (e.g., receptor decoys, antagonistic antibodies, etc.).
  • IL-17 antibodies such as secukinumab.
  • An IL-17 antagonist e.g., IL-17 binding molecule (e.g., IL-17 antibody or antigen- binding fragment thereof, e.g., secukinumab) or IL-17 receptor binding molecule (e.g., IL-17 receptor antibody or antigen-binding fragment thereof) is conveniently administered parenterally, e.g., intravenously (e.g., into the antecubital or other peripheral vein), intramuscularly, or subcutaneously.
  • IV intravenous
  • SC subcutaneous
  • the health care provider will decide on the appropriate duration of IV or SC therapy and the timing of administration of the therapy, using the pharmaceutical composition of the present disclosure.
  • Preferred dosing and treatment regimens for treating chronic plaque-type psoriasis are provided in PCT Application No.
  • the IL-17 antagonist e.g., IL-17 binding molecule (e.g., IL-17 antibody or antigen- binding fragment thereof, e.g., secukinumab) or IL-17 receptor binding molecule (e.g., IL-17 receptor antibody or antigen-binding fragment thereof) may be administered to the patient intravenously (IV), e.g., at about 10 mg/kg every other week during week 0, 2, and 4 and thereafter administered to the patient subcutaneously (SC), e.g., at about 75 mg - about 300 mg (e.g., about 150 mg, about 300 mg) monthly, beginning during week 8.
  • IV intravenously
  • SC subcutaneously
  • the patient may be dosed IV with about 10 mg/kg during week 0, 2, 4, and then the patient is dosed SC with about 150 mg - about 300 mg (e.g., about 150 mg, about 300 mg) of the IL-17 antagonist (e.g., secukinumab) during week 8, 12, 16, 20, etc.
  • the IL-17 antagonist e.g., secukinumab
  • the IL-17 antagonist e.g., IL-17 binding molecule (e.g., IL-17 antibody or antigen- binding fragment thereof, e.g., secukinumab) or IL-17 receptor binding molecule (e.g., IL-17 receptor antibody or antigen-binding fragment thereof) may be administered to the patient SC, e.g., at about 150 mg - about 300 mg (e.g., about 150 mg, about 300 mg) weekly during weeks 0, 1, 2, and 3, and thereafter administered to the patient SC, e.g., at about 150 mg - about 300 mg (e.g., about 150 mg, about 300 mg) monthly, beginning during week 4.
  • IL-17 binding molecule e.g., IL-17 antibody or antigen- binding fragment thereof, e.g., secukinumab
  • IL-17 receptor binding molecule e.g., IL-17 receptor antibody or antigen-binding fragment thereof
  • the patient is dosed SC with about 150 mg - about 300 mg (e.g., about 150 mg, about 300 mg) of the IL-17 antagonist (e.g., secukinumab) during weeks 0, 1, 2, 3, 4, 8, 12, 16, 20, etc.
  • the IL-17 antagonist e.g., secukinumab
  • the IL-17 antagonist e.g., IL-17 binding molecule (e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab) or IL-17 receptor binding molecule (e.g., IL-17 receptor antibody or antigen-binding fragment thereof) may be administered to the patient without a loading regimen, e.g., the antagonist may be administered to the patient SC at about 150 mg - about 300 mg (e.g., about 150 mg, about 300 mg) every 4 weeks (monthly).
  • IL-17 binding molecule e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab
  • IL-17 receptor binding molecule e.g., IL-17 receptor antibody or antigen-binding fragment thereof
  • the antagonist may be administered to the patient SC at about 150 mg - about 300 mg (e.g., about 150 mg, about 300 mg) every 4 weeks (monthly).
  • the patient is dosed SC with about 150 mg - about 300 mg (e.g., about 75 mg, about 150 mg, about 300 mg) of the IL-17 antagonist (e.g., secukinumab) during weeks 0, 4, 8, 12, 16, 20, etc.
  • the IL-17 antagonist e.g., secukinumab
  • dose escalation may be required for certain patients, e.g., patients that display inadequate response to treatment with the IL-17 antagonists, e.g., IL-17 binding molecules (e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab) or IL-17 receptor binding molecules (e.g., IL-17 receptor antibody or antigen-binding fragment thereof).
  • IL-17 antagonists e.g., IL-17 binding molecules (e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab) or IL-17 receptor binding molecules (e.g., IL-17 receptor antibody or antigen-binding fragment thereof).
  • SC dosages of secukinumab may be greater than about 150 mg to about 300 mg SC, e.g., about 175 mg, about 200 mg, about 250 mg, about 350 mg, about 400 mg, about 450 mg, etc.; similarly, IV dosages may be greater than about 10 mg/kg, e.g., about 11 mg/kg, 12 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, etc. It will also be understood that dose reduction may also be required for certain patients, e.g., patients that display adverse events or an adverse response to treatment with the IL-17 antagonist (e.g., IL-17 antibody or antigen- binding fragment thereof, e.g., secukinumab).
  • the IL-17 antagonist e.g., IL-17 antibody or antigen- binding fragment thereof, e.g., secukinumab.
  • dosages of the IL-17 antagonist may be less than about 150 mg to about 300 mg SC, e.g., about 80 mg, about 100 mg, about 125 mg, about 175 mg, about 200 mg, 250 mg, etc.; similarly, IV dosages may be less than about 10 mg/kg, e.g., about 9 mg/kg, 8 mg/kg, 5 mg/kg, 4 mg/kg, 3 mg/kg, 2 mg/kg, 1 mg/kg, etc.
  • the IL-17 antagonist e.g., IL-17 binding molecule (e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab) or IL-17 receptor binding molecule (e.g., IL-17 receptor antibody or antigen-binding fragment thereof) may be administered to the patient at an initial dose of 150 mg or 300 mg delivered SC, and the dose is then escalated to about 450 mg if needed, as determined by a physician.
  • IL-17 binding molecule e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab
  • IL-17 receptor binding molecule e.g., IL-17 receptor antibody or antigen-binding fragment thereof
  • induction phase typically the first 16 weeks of treatment, but extendable until week 24 depending on the type of drug and dose regimen used
  • treatment can be continued unchanged if reduction in PASI is >75%.
  • the treatment regimen can be modified (e.g., increased dose [e.g., from 150 mg to 300 mg, or from 300 mg to 400 mg or 450 mg] or frequency [e.g., from every 4 weeks to every 3 weeks or every 2 weeks]) if improvement of PASI is ⁇ 50%.
  • therapy can be modified if the DLQI is >5 but can be continued if the DLQI is ⁇ 5. See Mrowietz et al. (2011) Arch Dermatol Res. 303(1): 1-10.
  • the timing of dosing is generally measured from the day of the first dose of of the IL-17 antibody (e.g., secukinumab) (which is also known as “baseline”).
  • IL-17 antibody e.g., secukinumab
  • baseline which is also known as “baseline”
  • health care providers often use different naming conventions to identify dosing schedules, as shown in
  • Table 3 Common naming conventions for dosing regimens. Bolded items refer to the naming convention used herein.
  • week zero may be referred to as “week one” by some health care providers
  • day zero may be referred to as “day one” by some health care providers.
  • different physicians will designate, e.g., a dose as being given during week 3 / on day 21, during week 3 / on day 22, during week 4 / on day 21, during week 4 / on day 22, while referring to the same dosing schedule.
  • the first week of dosing will be referred to herein as week 0, while the first day of dosing will be referred to as day 1.
  • weekly dosing is the provision of a weekly dose of the IL-17 antibody regardless of whether the physician refers to a particular week as "week 1" or "week 2".
  • the antibody is administered during week 0, 1, 2, 3, 4 8, 12, 16, 20, etc.
  • Some providers may refer to this regimen as weekly for five weeks and then monthly (or every 4 weeks) thereafter, beginning during week 8, while others may refer to this regimen as weekly for four weeks and then monthly (or every 4 weeks) thereafter, beginning during week 4.
  • administering a patient an injection at weeks 0, 1, 2 and 3, followed by once monthly dosing starting at week 4 is the same as: 1) administering the patient an injection at weeks 0, 1, 2, 3, and 4, followed by once monthly dosing starting at week 8; 2) administering the patient an injection at weeks 0, 1, 2, 3 and 4 followed by dosing every 4 weeks; and 3) administering the patient an injection at weeks 0, 1 , 2, 3 and 4 followed by monthly administration.
  • IL-17 antagonists for use in, modifying the psoriasis disease course in a patient having chronic plaque-type psoriasis, comprising: a) administering the patient a dose of about 150 mg - about 300 mg of an IL-17 antibody or antigen-binding fragment thereof by subcutaneous injection at weeks 0, 1, 2, 3, and 4, followed by once monthly dosing extending to at least 48 weeks, and b) thereafter, withdrawing treatment of the IL-17 antibody or antigen-binding fragment thereof, wherein the patient maintains at least 50% (preferably at least 75%, more preferably at least 90%) of the PASI improvement achieved between baseline and week 52 for at least 6 months (preferably at least 1 year, more preferably at least 2 years) after the last dose of the IL-17 antibody or antigen-binding fragment thereof, wherein the IL-17 antibody or antigen-binding fragment thereof binds to an epitope of an IL-17 homodimer having two mature human IL-17 protein chains, said epitope comprising the epitope of an
  • IL-17 antagonists for use in, modifying the psoriasis disease course in a patient having chronic plaque-type psoriasis, comprising administering the patient a dose of about 150 mg - about 300 mg of an IL-17 antibody or antigen-binding fragment thereof by subcutaneous injection at weeks 0, 1, 2, 3, and 4, followed by once monthly dosing extending to at least 48 weeks, wherein the patient is capable of maintaining at least 50% (preferably at least 75%, more preferably at least 90%) of the PASI improvement achieved between baseline and week 52 for at least 6 months (preferably at least 1 year, more preferably at least 2 years) after the last dose of the IL-17 antibody or antigen-binding fragment thereof, wherein the IL-17 antibody or antigen-binding fragment thereof binds to an epitope of an IL-17 homodimer having two mature human IL-17 protein chains, said epitope comprising Leu74, Tyr85, His86, Met87, Asn88, Vall24, Thrl25,
  • IL-17 antagonists for use in, decreasing the likelihood that a psoriasis patient will develop psoriatic arthritis, delaying the onset of psoriatic arthritis in a psoriasis patient, and preventing progression from psoriasis to psoriatic arthritis in a psoriasis patient, comprising administering the patient a dose of about 150 mg - about 300 mg of an IL-17 antibody or antigen-binding fragment thereof by subcutaneous injection at weeks 0, 1, 2, 3, and 4, followed by once monthly dosing extending to at least 48 weeks, wherein the patient is capable of maintaining at least 50% (preferably at least 75%, more preferably at least 90%) of the PASI improvement achieved between baseline and week 52 for at least 6 months (preferably at least 1 year, more preferably at least 2 years) after the last dose of the IL-17 antibody or antigen-binding fragment thereof.
  • the patient has moderate to severe plaque-type psoriasis. In some embodiments of the disclosed uses, methods, and kits, the patient has mild plaque-type psoriasis.
  • the patient has not been previously treated with a systemic treatment for psoriasis. In some embodiments of the disclosed uses, methods, and kits, the patient is biological-naive.
  • the patient has been previously treated with a systemic treatment for psoriasis.
  • the systemic treatment comprises a biological agent.
  • the systemic treatment comprises a biological agent that is a TNF alpha antagonist.
  • the patient is a TNF failure.
  • the patient has been previously treated with phototherapy for psoriasis. In some embodiments of the disclosed uses, methods, and kits, the patient has not been previously treated with phototherapy for psoriasis. In some embodiments of the disclosed uses, methods, and kits, the patient is administered a dose of about 150 mg - about 300 mg of the IL-17 antibody or antigen-binding fragment thereof (e.g., secukinumab) by subcutaneous (SC) injection at weeks 0, 1, 2, 3, and 4, followed by once monthly dosing.
  • SC subcutaneous
  • the once monthly dosing extends to at least 48 weeks, at least 100 weeks, at least 152 weeks, at least 204 weeks, at least 3 years, at least 5 years, or at least 10 years.
  • the dose of the IL-17 antibody or antigen- binding fragment thereof e.g., secukinumab
  • the dose of the IL-17 antibody or antigen-binding fragment thereof is about 300 mg.
  • the dose of the IL-17 antibody or antigen-binding fragment thereof is about 150 mg.
  • the patient has had chronic plaque-type psoriasis for at least 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, 15 years, 20 years, or more.
  • the patient prior to withdrawal of treatment with the IL-17 antibody or antigen-binding fragment thereof (e.g., secukinumab), the patient has achieved at least PASI 75.
  • the IL-17 antibody or antigen-binding fragment thereof e.g., secukinumab
  • the patient has a baseline PASI score of ⁇ 39 or ⁇ 26. In some embodiments of the disclosed uses, methods, and kits, the patient has a baseline PASI score of ⁇ 25, ⁇ 23, ⁇ 22, ⁇ 21.4, ⁇ 21, ⁇ 20, ⁇ 19, ⁇ 15. In some embodiments of the disclosed uses, methods, and kits, the patient has a baseline PASI score of ⁇ 39 and the patient maintains at least 50% of the PASI improvement achieved between baseline and week 52 for at least 1 year after the last dose of the IL-17 antibody or antigen-binding fragment thereof.
  • the patient has a baseline PASI score of ⁇ 26 and the patient maintains at least 50% of the PASI improvement achieved between baseline and week 52 for at least 2 years after the last dose of the IL-17 antibody or antigen-binding fragment thereof.
  • the patient is capable of maintaining a PASI score of ⁇ 7.2 for at least 6 months, at least one year, or at least two years after the last dose of the IL-17 antibody or antigen-binding fragment thereof (e.g., secukinumab). In some embodiments of the disclosed uses, methods, and kits, the patient is capable of maintaining a PASI score of ⁇ 11.2 for at least 6 months or at least one year after the last dose of the IL-17 antibody or antigen-binding fragment thereof (e.g., secukinumab).
  • the patient is capable of maintaining at least 90% of the PASI improvement achieved between baseline and week 52 for at least 6 months, at least one year, or at least two years after the last dose of the IL-17 antibody or antigen-binding fragment thereof.
  • the patient is capable of maintaining at least 75% of the PASI improvement achieved between baseline and week 52 for at least 6 months, at least one year, or at least two years after the last dose of the IL-17 antibody or antigen-binding fragment thereof. In some embodiments of the disclosed uses, methods, and kits, the patient is capable of maintaining at least 50% of the PASI improvement achieved between baseline and week 52 for at least 6 months, at least one year, or at least two years after the last dose of the IL-17 antibody or antigen-binding fragment thereof.
  • the IL-17 antibody or antigen-binding fragment thereof comprises: i) an immunoglobulin heavy chain variable domain (V H ) comprising the amino acid sequence set forth as SEQ ID NO: 8; ii) an immunoglobulin light chain variable domain (V L ) comprising the amino acid sequence set forth as SEQ ID NO: 10; iii) an immunoglobulin V H domain comprising the amino acid sequence set forth as SEQ ID NO: 8 and an immunoglobulin V L domain comprising the amino acid sequence set forth as SEQ ID NO: 10; iv) an immunoglobulin V H domain comprising the hypervariable regions set forth as SEQ ID NO: l, SEQ ID NO: 2, and SEQ ID NO: 3; v) an immunoglobulin V L domain comprising the hypervariable regions set forth as SEQ ID NO:4, SEQ ID NO: 5 and SEQ ID NO:6; vi) an immunoglobulin V H domain comprising the hypervariable regions set forth as SEQ ID NO:
  • the IL-17 antibody or antigen-binding fragment thereof is a monoclonal antibody. In some embodiments, the IL-17 antibody or antigen-binding fragment thereof is a human or humanized antibody. In some embodiments, the IL-17 antibody or antigen-binding fragment thereof is a human antibody. In some embodiments, the IL-17 antibody or antigen-binding fragment thereof is a human antibody of the IgGi subtype. In some embodiments, the IL-17 antibody or antigen-binding fragment thereof is secukinumab.
  • At least 60%, at least 67%, at least 70%, at least 71%, at least 77%, or at least 81% of patients (e.g., adult patients) treated according to the disclosed methods achieve PASI 75 at week 12.
  • at least 50%, at least 51%, at least 62%, or at least 65% of patients (e.g., adult patients) patients treated according to the disclosed methods a response of 0 or 1 on the modified investigator's global assessment (IGA) at week 12.
  • IGA modified investigator's global assessment
  • At least 35%, at least 39%, at least 41%, at least 54%, or at least 59% of patients (e.g., adult patients) treated according to the disclosed methods achieve PASI 90 at week 12.
  • at least 10%, at least 12%, at least 14%, at least 24%, or at least 28% of patients (e.g., adult patients) treated according to the disclosed methods achieve PASI 90 at week 12.
  • the disclosed methods are used to treat a population of patients having moderate to severe chronic plaque psoriasis, and at least 60%, at least 67%, at least 70%, at least 71%, at least 77%, or at least 81%, of said patients achieve at least PASI 75 response at week 12 of the treatment. In some embodiments, the disclosed methods are used to treat a population of patients having moderate to severe chronic plaque psoriasis, and at least 50%, at least 51%, at least 62%, or at least 65% of said patients achieve a response of 0 or 1 on the modified investigator's global assessment (IGA) at week 12 of the treatment.
  • IGA modified investigator's global assessment
  • the disclosed methods are used to treat a population of patients having moderate to severe chronic plaque psoriasis, and at least 35%, at least 39%, at least 41%, at least 54%, or at least 59% of said patients achieve at least PASI 90 response at week 12 of the treatment. In some embodiments, the disclosed methods are used to treat a population of patients having moderate to severe chronic plaque psoriasis, and at least 10%, at least 12%, at least 14%, at least 24%, or at least 28% of said patients achieve PASI 100 response at week 12 of the treatment.
  • kits for treating particular chronic plaque-type psoriasis patients comprise an IL-17 antagonist, e.g., IL-17 binding molecule (e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab) or IL-17 receptor binding molecule (e.g., IL-17 antibody or antigen-binding fragment thereof) (e.g., in liquid or lyophilized form) or a pharmaceutical composition comprising the IL-17 antagonist (described supra).
  • an IL-17 antagonist e.g., IL-17 binding molecule (e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab) or IL-17 receptor binding molecule (e.g., IL-17 antibody or antigen-binding fragment thereof) (e.g., in liquid or lyophilized form) or a pharmaceutical composition comprising the IL-17 antagonist (described supra).
  • kits may comprise means for administering the IL-17 antagonist (e.g., an auto-injector, a syringe and vial, a prefilled syringe, a prefilled pen) and instructions for use.
  • kits may contain additional therapeutic psoriasis agents (described supra) for treating chronic plaque-type psoriasis, e.g., for delivery in combination with the enclosed IL-17 antagonist, e.g., IL-17 binding molecule, e.g., IL-17 antibody, e.g., secukinumab.
  • kits may also comprise instructions for administration of the IL-17 antagonist (e.g., IL-17 antibody, e.g., secukinumab) to treat the chronic plaque-type psoriasis patient.
  • IL-17 antagonist e.g., IL-17 antibody, e.g., secukinumab
  • Such instructions may provide the dose (e.g., 10 mg/kg, 75 mg, 150 mg, 300 mg), route of administration (e.g., IV, SC), and dosing regimen (e.g., every other week during weeks 0, 2, and 4, and thereafter monthly, beginning during week 8; weekly during week 0, 1, 2, and 3 and thereafter monthly (every 4 weeks), beginning during week 4; etc.) for use with the enclosed IL-17 antagonist, e.g., IL-17 binding molecule, e.g., IL-17 antibody, e.g., secukinumab.
  • the enclosed IL-17 antagonist e.g., IL-17 binding molecule, e.g., IL-17
  • phrases "means for administering” is used to indicate any available implement for systemically administering a drug to a patient, including, but not limited to, a pre-filled syringe, a vial and syringe, an injection pen, an auto-injector, an IV drip and bag, a pump, etc.
  • a patient may self-administer the drug (i.e., administer the drug without the assistance of a physician) or a medical practitioner may administer the drug.
  • kits for use in modifying the psoriasis disease course in a patient having chronic plaque-type psoriasis comprising an IL-17 antagonist (e.g., IL-17 binding molecule, e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab).
  • an IL-17 antagonist e.g., IL-17 binding molecule, e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab.
  • the kit further comprises means for administering the IL-17 antagonist to the patient.
  • the kit further comprises instructions for administration of the IL- 17 antagonist, wherein the instructions indicate that the IL-17 antagonist (e.g., IL-17 binding molecule, e.g., IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab) is to be administered to the patient SC at about 150 mg - about 300 mg (e.g., about 150 mg, or about 300 mg) weekly during weeks 0, 1, 2, and 3, and thereafter SC at about 150 mg - about 300 mg (e.g., about 150 mg, about 300 mg) monthly (every 4 weeks), beginning during week 4.
  • the instructions will provide for dose escalation (e.g., from a dose of about 150 mg or about 300 mg to a higher dose of about 450 mg as needed, to be determined by a physician).
  • the IL-17 antagonist is an IL-17 binding molecule.
  • the IL-17 binding molecule is an IL-17 antibody or antigen-binding fragment thereof.
  • the IL-17 antibody or antigen-binding fragment thereof is selected from the group consisting of: a) an IL-17 antibody or antigen- binding fragment thereof that binds to an epitope of human IL-17 comprising Leu74, Tyr85, His86, Met87, Asn88, Vall24, Thrl25, Prol26, Ilel27, Vall28, Hisl29; b) an IL-17 antibody or antigen-binding fragment thereof that binds to an epitope of human IL-17 comprising Tyr43, Tyr44, Arg46, Ala79, Asp80; c) an IL-17 antibody or antigen-binding fragment thereof that binds to an epitope of an IL-17 homodimer having two mature human IL-17 protein chains, said epitope comprising Leu74, Tyr85, His86, Met87, Asn88, Vall24, Thrl25, Prol26, Ilel27, Vall28, Hisl29 on one chain and Tyr43, Tyr44, Arg46, Al
  • the IL-17 antibody or antigen-binding fragment thereof is a monoclonal antibody. In more preferred embodiments, the IL-17 antibody or antigen-binding fragment thereof is a human or humanized antibody, preferably a human antibody. In more preferred embodiments, the IL-17 antibody or antigen-binding fragment thereof is a human antibody of the IgGi isotype. In most preferred embodiments, the antibody or antigen-binding fragment thereof is secukinumab.
  • PASI 75 responders were randomly assigned to either continue with secukinumab treatment or treatment was withdrawn and the patient was switched to placebo, in a double-blinded fashion.
  • secukinumab treatment for at least 52 weeks appears to have modified the course of moderate-to-severe psoriasis, potentially converting it to mild psoriasis, despite intervening late in the course of these patients' disease.
  • Cox regression model assessing time to relapse showed that baseline PASI and time since psoriasis diagnosis in the CAIN457A2302E1 trial appears to influence time to relapse, and hence could be used to identify and select patients amenable to disease course modification, i.e., patients capable of maintaining at least 50% of the PASI improvement achieved between baseline and week 52 for at least 6 months after the last dose of secukinumab.
  • patients that did not relapse for at least one 1 year following treatment withdrawal had baseline PASI 12-38.7; those that did not relapse for at least one 2 years following treatment withdrawal had baseline PASI 12-25.4.
  • Mechanistic study CAIN457A2223 (design in Figure 5), has shown, based on skin biopsies taken at baseline and during the treatment, that, after secukinumab treatment, there is histological disease reversal (Figure 6) and reversal of the majority of gene expression abnormalities in lesional psoriatic skin (Figure 7). Following treatment, lesional psoriatic skin (taken in the areas of psoriatic plaques) looked remarkably like non-lesional skin (skin not affected by plaques) ( Figure 6).
  • CDR1 hypervariable region 1 of heavy chain of AIN457
  • CDR2 hypervariable region 2 of heavy chain of AIN457
  • tgg atg aac tgg gtc cgc cag get cca ggg aaa ggg ctg gag tgg gtg 144 Trp Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val
  • CDRl-x hypervariable domain x of heavy chain of AIN457

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Abstract

La présente invention concerne des procédés permettant de modifier le déroulement d'une maladie du psoriasis chez des patients particuliers ayant un psoriasis de type plaque chronique et d'inhiber la progression de l'arthrite psoriasique (PsA) chez ces patients, à l'aide d'antagonistes d'IL-17, par exemple, le secukinumab. L'invention concerne en outre des utilisations d'antagonistes d'IL-17, par exemple, des anticorps IL-17, tels que le sécukinumab, pour modifier le déroulement d'une maladie du psoriasis chez des patients particuliers ayant un psoriasis de type plaque chronique et d'inhiber la progression de PsA chez ces patients, ainsi que des médicaments, des schémas de traitement, des formulations pharmaceutiques, des formes posologiques et des trousses à utiliser dans les méthodes et utilisations présentées.
PCT/IB2018/051343 2017-03-03 2018-03-02 Modification de la maladie du psoriasis suite à un traitement à long terme avec un antagoniste de l'il-17 WO2018158741A1 (fr)

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CN113316587A (zh) * 2019-05-20 2021-08-27 南通壹宸生物医药科技有限公司 一种双特异性分子及其制备与用途
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