Methods for treating tnfα-related diseases

Abstract

The present invention relates to a method for treating a TNFα-related disease by subcutaneously administering an antibody (anti-TNFα antibody) or an antigen-binding fragment thereof that binds to TNFα. The treatment method, composition, kit or use thereof according to the present invention provides an advantage of increased patient satisfaction, through the improvement of convenience and enhancement of the quality of life, by reducing the time taken for administration compared to intravenous injections and decreasing the time that patients stay in a hospital.

Description

Methods for treating TNFα-related diseases

[0001] The present application relates to a method for treating a TNFα-related disease by subcutaneously administering an antibody that binds to TNFα (anti-TNFα antibody).

[0002] Tumor necrosis factor alpha (TNFα) is a cell signaling protein (cytokine) involved in systemic inflammation and is one of the cytokines that contributes to the acute phase response. TNFα has been implicated in various diseases and disorders, including sepsis, infections, autoimmune diseases, and transplant rejection. TNFα promotes immune responses, which contribute to many clinical problems associated with autoimmune disorders, such as rheumatoid arthritis, ankylosing spondylitis, ulcerative colitis, adult Crohn's disease, pediatric Crohn's disease, psoriasis, and psoriatic arthritis. These disorders can be treated with TNFα inhibitors.

[0003] Infliximab is a type of chimeric monoclonal antibody that can perform the role of the above TNFα inhibitor. Currently commercially available products include Remsima, Remicade, and Renflexis. However, all of these products are manufactured as lyophilized powder, which is re-dissolved and diluted and injected intravenously according to the dosage and route of administration for each disease.

[0004] However, the intravenous administration method described above requires patients to visit a hospital for medication, which can take 2-4 hours, including waiting time. This creates a significant burden and inconvenience in daily life. Furthermore, the limitation of administering the medication to only medically trained individuals exists.

[0005] Therefore, subcutaneous (SC) administration is proposed as an alternative route of administration, which can be administered by trained patients themselves and can shorten the administration time from the existing 30 to 90 minutes to 2 to 5 minutes.

[0006] Products developed and marketed as subcutaneous formulations along with intravenous formulations include Rituxan (Rituximab), Simponi (Golimumab), Herceptin (Trastuzumab), Actemra (Tocilizumab), and Xolair (Omalizumab), but there is no subcutaneous formulation of infliximab yet.

[0007] For subcutaneous administration, a stable liquid formulation containing a high concentration of antibodies is required, and efficacy and safety must be proven through clinical trials.

[0008] The present applicant has completed a subcutaneous administration regimen that improves patient convenience of administration and quality of life by demonstrating that subcutaneous administration of infliximab formulations has equivalent efficacy and safety to existing intravenous formulations.

[0009] The problem to be solved by the present invention is to provide a therapeutic method of subcutaneously administering to a subject a pharmaceutical composition containing an anti-TNFα antibody or an antigen-binding fragment thereof for the treatment of a TNFα-related disease.

[0010] Another problem to be solved by the present invention is to provide a pharmaceutical composition for treating a disease treatable with an anti-TNFα antibody, which comprises an anti-TNFα antibody or an antigen-binding fragment thereof and is administered subcutaneously to a subject.

[0011] Another problem to be solved by the present invention is to provide a kit comprising a pharmaceutical composition comprising an anti-TNFα antibody or an antigen-binding fragment thereof and instructions directing subcutaneous administration of the pharmaceutical composition to a subject for treating a disease treatable with the anti-TNFα antibody.

[0012] Another problem to be solved by the present invention is to provide a use of an anti-TNFα antibody or an antigen-binding fragment thereof in the manufacture of a medicament for treating a disease treatable with an anti-TNFα antibody by subcutaneously administering the medicament to a subject.

[0013] The present invention provides a method for treating a disease treatable with an anti-TNFα antibody, comprising the step of subcutaneously administering to a subject a pharmaceutical composition containing an anti-TNFα antibody or an antigen-binding fragment thereof.

[0014] The present invention also provides a pharmaceutical composition for treating a disease treatable with an anti-TNFα antibody, which comprises an anti-TNFα antibody or an antigen-binding fragment thereof and is administered subcutaneously to a subject.

[0015] The present invention also provides a kit comprising (a) a pharmaceutical composition comprising an anti-TNFα antibody or antigen-binding fragment thereof and a pharmaceutically acceptable carrier; and (b) instructions directing subcutaneous administration of the pharmaceutical composition to a subject to treat a disease treatable by the anti-TNFα antibody.

[0016] The present invention also provides the use of an anti-TNFα antibody or an antigen-binding fragment thereof in the manufacture of a pharmaceutical composition for treating a disease treatable with an anti-TNFα antibody by subcutaneous administration to a subject.

[0017] In one embodiment of the present invention, the anti-TNFα antibody may comprise one or more selected from the group consisting of infliximab, adalimumab, certoizumab pegol, golimumab, and biosimilars thereof.

[0018] In one embodiment of the present invention, the anti-TNFα antibody may be infliximab.

[0019] In one embodiment of the present invention, the anti-TNFα antibody may comprise a chimeric human-mouse IgG monoclonal antibody.

[0020] In one embodiment of the present invention, the anti-TNFα antibody may comprise a light chain variable region comprising a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 1, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 2, and a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3; and a heavy chain variable region comprising a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 4, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 5, and a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 6.

[0021] In one embodiment of the present invention, the anti-TNFα antibody may comprise a light chain variable region comprising the amino acid sequence of SEQ ID NO: 7; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 8.

[0022] In one embodiment of the present invention, the anti-TNFα antibody may comprise a light chain comprising the amino acid sequence of SEQ ID NO: 9; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 10.

[0023] In one embodiment of the present invention, the composition may comprise a surfactant; a sugar or a derivative thereof; and a buffer comprising acetate or histidine.

[0024] In one embodiment of the present invention, the composition may comprise polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, or a mixture thereof as a surfactant.

[0025] In one embodiment of the present invention, the surfactant concentration of the composition may be 0.02 to 0.1% (w / v).

[0026] In one embodiment of the present invention, the composition may include sorbitol, mannitol, trehalose, sucrose or a mixture thereof as the sugar or derivative thereof.

[0027] In one embodiment of the present invention, the concentration of sugar or its derivative in the composition may be 1 to 10% (w / v).

[0028] In one embodiment of the present invention, the composition may comprise acetate as a buffering agent.

[0029] In one embodiment of the present invention, the buffer concentration of the composition may be 1 to 50 mM.

[0030] In one embodiment of the present invention, the pH of the composition may be 4.0 to 5.5.

[0031] In one embodiment of the present invention, the composition may comprise (A) 90 to 180 mg / ml of anti-TNFα antibody; (B) 0.02 to 0.1 % (w / v) polysorbate; (C) 1 to 10 % (w / v) sorbitol; and (D) 1 to 50 mM of a buffer comprising acetate or histidine.

[0032] In one embodiment of the present invention, the composition may not comprise aspartic acid, lysine, arginine or mixtures thereof.

[0033] In one embodiment of the present invention, the composition may not include NaCl, KCl, NaF, KBr, NaBr, Na2SO4, NaSCN, K2SO4 or mixtures thereof.

[0034] In one embodiment of the present invention, the composition may not include a chelating agent.

[0035] In one embodiment of the present invention, the composition may have a viscosity of 0.5 cp to 10.0 cp after 1 month at a temperature of 40°C±2°C, or a viscosity of 0.5 cp to 5 cp after 6 months at a temperature of 5°C±3°C.

[0036] In one embodiment of the present invention, the composition may not undergo a reconstitution step, a dilution step, or both, prior to use.

[0037] In one embodiment of the present invention, the composition may be filled into a pre-filled syringe or an auto-injector and administered to a subject.

[0038] In one embodiment of the present invention, the subject may comprise a mammal.

[0039] In one embodiment of the present invention, the subject may include a human.

[0040] In one embodiment of the present invention, the antibody or antigen-binding fragment thereof may be administered in an amount of 60 to 300 mg.

[0041] In one embodiment of the present invention, the antibody or antigen-binding fragment thereof may be administered at 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290 or 300 mg.

[0042] In one embodiment of the present invention, 90 to 180 mg of the antibody or antigen-binding fragment thereof may be administered.

[0043] In one embodiment of the present invention, the antibody or antigen-binding fragment thereof may be administered in an amount of 120 to 240 mg.

[0044] In one embodiment of the present invention, the antibody or antigen-binding fragment thereof may be administered in an amount of 80 to 100 mg, 110 to 130 mg, 170 to 190 mg or 230 to 250 mg.

[0045] In one embodiment of the present invention, the antibody or antigen-binding fragment thereof may be administered at 90 mg, 120 mg, 180 mg or 240 mg.

[0046] In one embodiment of the present invention, when the patient weighs less than 80 kg, the antibody or antigen-binding fragment thereof may be administered in an amount of 90 to 180 mg, and when the patient weighs 80 kg or more, 190 to 270 mg.

[0047] In one embodiment of the present invention, the antibody or antigen-binding fragment thereof may be administered at intervals of 1 to 8 weeks.

[0048] In one embodiment of the present invention, the antibody or antigen-binding fragment thereof may be administered at intervals of 1, 2, 3, 4, 5, 6, 7 or 8 weeks.

[0049] In one embodiment of the present invention, the antibody or antigen-binding fragment thereof may be administered at intervals of 2 or 4 weeks.

[0050] In one embodiment of the present invention, diseases treatable with anti-TNFα antibodies may include rheumatoid arthritis, ulcerative colitis, Crohn's disease, plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis.

[0051] In one embodiment of the present invention, a patient receiving anti-TNFα antibody administration may have one or more characteristics selected from the following:

[0052] a) Patients who have had an inadequate response to disease-modifying anti-rheumatic drugs (DMARDs), including methotrexate.

[0053] b) Patients who have not previously been treated with methotrexate or other DMARDs.

[0054] c) Patients with severe inflammatory symptoms and elevated serum markers associated with inflammation who do not respond adequately to conventional treatment.

[0055] d) Patients who have not responded to, are contraindicated in, or are intolerant to systemic therapy, including methotrexate, cyclosporine, or psoralen ultraviolet A therapy (PUVA).

[0056] e) Patients who do not respond adequately to treatment with corticosteroids, 6-mercaptopurine, azathioprine, or immunosuppressants, are intolerant to them, or for whom these treatments are contraindicated.

[0057] f) Patients who do not respond to conventional treatment including antibiotics, drainage methods, or immunosuppressive therapy.

[0058] In one embodiment of the present invention, the patient may be a patient who has received intravenous administration of an anti-TNFα antibody or an antigen-binding fragment thereof at least once prior to subcutaneous administration.

[0059] In one embodiment of the present invention, the patient may be a patient who has received intravenous administration of 1 to 10 mg / kg per dose of an anti-TNFα antibody or antigen-binding fragment thereof prior to subcutaneous administration.

[0060] In one embodiment of the present invention, the first subcutaneous administration may be performed 2 to 8 weeks after the last intravenous administration.

[0061] In one embodiment of the present invention, the first subcutaneous administration may be performed four weeks after the last intravenous administration.

[0062] In one embodiment of the present invention, a composition containing an anti-TNFα antibody or an antigen-binding fragment thereof can be administered before, during, or after administration of one or more selected from the group consisting of infliximab, adalimumab, certoizumab pegol, golimumab, and biosimilars thereof.

[0063] In one embodiment of the present invention, a composition containing an anti-TNFα antibody or antigen-binding fragment thereof can be administered together with, before, or after administration of methotrexate, leflunomide and sulfasalazine, hydroxychloroquine, or a combination thereof.

[0064] In one embodiment of the present invention, after subcutaneous administration, the patient may have one or more characteristics selected from the following:

[0065] a) DAS28 (Disease Activity Score in 28 joints) decreased by at least 2.0.

[0066] b) CDAI (Crohn's disease activity index) decreases by at least 70.

[0067] The treatment method, composition, kit, or use according to the present invention can treat TNFα-related diseases by subcutaneously administering an anti-TNFα antibody or an antigen-binding fragment thereof. Furthermore, the treatment method, composition, kit, or use according to the present invention provides the advantage of increased patient satisfaction through improved convenience and quality of life by reducing the administration time compared to intravenous injection and reducing the length of time patients spend in the hospital.

[0068] In addition, the treatment method, composition, kit or use according to the present invention is added as a new treatment option for infliximab, and provides the advantage of not causing burden or resistance due to drug change to patients and healthcare workers who were previously administered infliximab by intravenous injection.

[0069] Figure 1 shows an overview of the design of a clinical trial of subcutaneous infliximab in patients with rheumatoid arthritis (RA).

[0070] Figure 2 shows the design outline of a clinical trial of subcutaneous infliximab in patients with Crohn's disease (CD).

[0071] The present invention relates to a method for treating a disease treatable with an anti-TNFα antibody, comprising the step of subcutaneously administering to a subject a pharmaceutical composition containing an anti-TNFα antibody or an antigen-binding fragment thereof.

[0072] To facilitate a better understanding of the present invention, terms used in the present invention are defined below.

[0073] "TNFα" is intended to refer to a human cytokine that exists as a 17 kD secreted form and a 26 kD membrane associated form, the biologically active form of which is composed of a trimer noncovalently bound to a 17 kD molecule. The structure of TNFα is also described, for example, in the literature [see, e.g., Pennica, D., et al. (1984) Nature 312:724-729; Davis, JM, et al. (1987) Biochemistry 26:1322-1326; and Jones, EY, et al. (1989) Nature 338:225-228].

[0074] "Antibody" refers to an immunoglobulin molecule composed of four polypeptide chains, each of which consists of two heavy chains and two light chains linked by disulfide bonds. Naturally occurring antibodies with other altered structures, such as camelid antibodies, are also included in this definition. Each heavy chain consists of a heavy chain variable region and a heavy chain constant region. The heavy chain constant region is composed of three domains (CH1, CH2, and CH3). Each light chain consists of a light chain variable region and a light chain constant region. The light chain constant region is composed of a single domain (CL). The heavy and light chain variable regions can be further subdivided into hypervariable regions, called complementarity determining regions (CDRs), which are arranged alongside more conserved regions, called framework regions (FRs). Each heavy chain variable region and light chain variable region consists of three CDRs and four FRs, which are arranged in the following order from amino terminus to carboxy terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.

[0075] "Antigen-binding fragment" refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen bound by a complete antibody. Exemplary antigen-binding fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv.

[0076] A “biosimilar” is a biological product that is highly similar to an FDA-approved biological product (reference drug) and has no clinically meaningful differences from the reference drug in terms of pharmacokinetics, safety, and efficacy.

[0077] “Administration” refers to the administration of a substance (e.g., an anti-TNFα antibody) to achieve a therapeutic purpose (e.g., a TNFα-related disease).

[0078] "TNFα-associated disease" refers to a local and / or systemic physiological condition in which TNFα is the primary mediator inducing the symptoms of the condition. The terms "TNFα-associated disease," "disease treatable with anti-TNFα," and "disease in which TNFα activity is detrimental" are used interchangeably herein.

[0079] "Subject" includes any human or non-human animal. The term "non-human animal" includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, cats, rabbits, and ferrets, rodents such as mice, rats, and guinea pigs, avian species such as chickens, amphibians, and reptiles. In a preferred embodiment, the subject is a mammal such as a non-human primate, sheep, dogs, cats, rabbits, ferrets, or rodents. In a more preferred embodiment, the subject is a human. The terms "subject," "patient," and "individual" are used interchangeably herein.

[0080] "IC50" is intended to refer to the concentration of inhibitor required to inhibit a desired biological outcome, for example, to neutralize cytotoxic activity.

[0081] A "kit" refers to a packaged product comprising components for administering a TNFα antibody of the present invention for the treatment of a TNFα-related disorder. The kit preferably includes a container or box for holding the components of the kit. The box or container is accompanied by a Food and Drug Administration-approved protocol or label. The box or container contains the components of the present invention contained within a plastic, polyethylene, polypropylene, ethylene, or propylene container. The container may be a capped tube or bottle. The kit also includes instructions for administering the TNFα antibody of the present invention.

[0082]

[0083] Various aspects of the present invention are further described in detail herein.

[0084] - Anti-TNFα antibody of the present invention or antigen-binding fragment thereof

[0085] In one embodiment of the present invention, the antibody may include a polyclonal antibody, a monoclonal antibody, a recombinant antibody, a single-chain antibody, a hybrid antibody, a chimeric antibody, a humanized antibody, or a fragment thereof. A chimeric antibody refers to an antibody comprising heavy and light chain variable region sequences from one species and constant region sequences from another species. In one embodiment of the present invention, the antibody may include a chimeric human-mouse IgG monoclonal antibody. A chimeric human-mouse IgG monoclonal antibody is composed of mouse heavy and light chain variable regions and human heavy and light chain constant regions linked thereto. A chimeric human-mouse IgG monoclonal antibody can be produced by a method known in the art. For example, infliximab can be produced by the method described in U.S. Patent No. 6,284,471.

[0086] In one embodiment of the present invention, the antibody may include TNFα or an antibody that binds to an epitope of TNFα. The antibody may include one or more selected from the group consisting of infliximab, adalimumab, certoizumab pegol, golimumab, and biosimilars thereof. In one embodiment of the present invention, the antibody may include infliximab.

[0087] In one embodiment of the present invention, the antibody or antigen-binding fragment thereof may comprise a light chain variable region comprising a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 1, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 2, and a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3; and a heavy chain variable region comprising a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 4, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 5, and a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 6.

[0088] In one embodiment of the present invention, the antibody or antigen-binding fragment thereof may comprise a light chain variable region comprising the amino acid sequence of SEQ ID NO: 7; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 8.

[0089] In one embodiment of the present invention, the antibody may comprise a light chain comprising the amino acid sequence of SEQ ID NO: 9; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 10.

[0090] - Composition containing the anti-TNFα antibody of the present invention or an antigen-binding fragment thereof

[0091] As used herein, the term “composition containing the anti-TNFα antibody or antigen-binding fragment thereof of the present invention” is used interchangeably with “stable liquid pharmaceutical preparation”.

[0092] A composition according to the present invention comprises (A) an antibody or an antigen-binding fragment thereof; (B) a surfactant; (C) a sugar or a derivative thereof; and (D) a buffer.

[0093] The term “not including” in the specification of the present application means not including the component at all. In addition, the term means not including substantially the component, i.e., including the component in an amount that does not affect the activity of the antibody, the stability and viscosity of the liquid pharmaceutical preparation, for example, including 0 to 1% (w / v), 0 to 1 ppm (w / v), or 0 to 1 ppb (w / v) based on the total weight of the liquid pharmaceutical preparation.

[0094] (A) Antibody or antigen-binding fragment thereof

[0095] In one embodiment, the composition according to the present invention may comprise the anti-TNFα antibody of the present invention or an antigen-binding fragment thereof as described above.

[0096] The concentration of the antibody or antigen-binding fragment thereof can be freely adjusted within a range that does not substantially adversely affect the stability and viscosity of the composition according to the present invention. In one embodiment of the present invention, the concentration of the antibody or antigen-binding fragment thereof may be 10 to 200 mg / mL. In another embodiment of the present invention, the concentration of the antibody or antigen-binding fragment thereof may be 50 to 200 mg / mL. In yet another embodiment of the present invention, the concentration of the antibody or antigen-binding fragment thereof may be 80 to 150 mg / mL. In yet another embodiment of the present invention, the concentration of the antibody or antigen-binding fragment thereof may be 90 to 145 mg / mL. In yet another embodiment of the present invention, the concentration of the antibody or antigen-binding fragment thereof may be 110 to 130 mg / mL. When the concentration of the antibody or its antigen-binding fragment is within this range, the degree of freedom in administration dose and administration cycle can be increased according to the high content of the antibody or its antigen-binding fragment, and long-term stability and low viscosity can be excellently exhibited.

[0097] (B) Surfactant

[0098] Examples of surfactants include, but are not limited to, polyoxyethylene sorbitan fatty acid esters (e.g., polysorbates), polyoxyethylene alkyl ethers (e.g., Brij), alkylphenyl polyoxyethylene ethers (e.g., Triton-X), polyoxyethylene-polyoxypropylene copolymers (e.g., Poloxamer, Pluronic), sodium dodecyl sulfate (SDS), and the like.

[0099] In one embodiment of the present invention, the surfactant may include polyoxyethylene sorbitan fatty acid ester (polysorbate). The polysorbate may include polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, or a mixture of two or more thereof. In one embodiment of the present invention, the polysorbate may include polysorbate 20, polysorbate 80, or a mixture thereof. In another embodiment of the present invention, the polysorbate may include polysorbate 80.

[0100] In one embodiment of the present invention, the concentration of the surfactant can be freely adjusted within a range that does not adversely affect the stability and viscosity of the stable liquid pharmaceutical preparation according to the present invention. For example, the concentration of the surfactant may be 0.001 to 5% (w / v), 0.01 to 1% (w / v), or 0.02 to 0.1% (w / v). When the concentration of the surfactant is within this range, excellent long-term stability and low viscosity can be exhibited.

[0101] (C) sugar or sugar derivative

[0102] The sugar may include a monosaccharide, a disaccharide, an oligosaccharide, a polysaccharide, or a mixture of two or more thereof. Examples of monosaccharides include, but are not limited to, glucose, fructose, and galactose. Examples of disaccharides include, but are not limited to, sucrose, lactose, maltose, and trehalose. Examples of oligosaccharides include, but are not limited to, fructooligosaccharides, galactooligosaccharides, and mannan-oligosaccharides. Examples of polysaccharides include, but are not limited to, starch, glycogen, cellulose, chitin, and pectin.

[0103] The sugar derivatives may include sugar alcohols, sugar acids, or mixtures thereof. Examples of sugar alcohols include, but are not limited to, glycerol, erythritol, threitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt, maltitol, lactitol, maltotriitol, maltotetraitol, and polyglycitol. Examples of sugar acids include, but are not limited to, aldonic acid (e.g., glyceric acid), ulosonic acid (e.g., neuraminic acid), uronic acid (e.g., glucuronic acid), and aldaric acid (e.g., tartaric acid).

[0104] In one embodiment of the present invention, the sugar or its derivative may include sorbitol, mannitol, trehalose, sucrose or a mixture of two or more thereof.

[0105] In one embodiment of the present invention, the concentration of the sugar or its derivative can be freely adjusted within a range that does not substantially adversely affect the stability and viscosity of the liquid pharmaceutical preparation according to the present invention. For example, the concentration of the sugar or its derivative can be 0.1 to 30% (w / v), 1 to 20% (w / v), or 1 to 10% (w / v). When the concentration of the sugar or its derivative is within this range, excellent long-term stability and low viscosity can be exhibited.

[0106] (D) Buffer

[0107] A buffer is a neutralizing substance that minimizes changes in pH caused by acids or alkalis. Examples of buffers include phosphate, acetate, succinate, gluconate, glutamate, citrate, and histidine. In one embodiment of the present invention, the buffer may include acetate or histidine. If both acetate and histidine are included as a buffer, stability may be reduced.

[0108] In one embodiment of the present invention, the buffer may include acetate. Examples of acetate include, but are not limited to, sodium acetate, zinc acetate, aluminum acetate, ammonium acetate, and potassium acetate. An acid, such as acetic acid, may be additionally included to adjust pH. Including acetate as the buffer may be most preferred in terms of pH adjustment and stability.

[0109] In one embodiment of the present invention, the buffer may include histidine. When histidine is used as the buffer, a histidine salt, such as histidine chloride, histidine acetate, histidine phosphate, or histidine sulfate, may be included. For pH adjustment, an acid, such as hydrochloric acid, acetic acid, phosphoric acid, or sulfuric acid, may be included.

[0110] In one embodiment of the present invention, the stable liquid pharmaceutical preparation may not contain citrate, phosphate, or a mixture thereof.

[0111] In one embodiment of the present invention, the content of the buffer (or the anion of the buffer) can be freely adjusted within a range that does not substantially adversely affect the stability and viscosity of the liquid pharmaceutical preparation according to the present invention. For example, the content of the buffer or its anion may be 1 to 50 mM, 5 to 30 mM, or 10 to 25 mM. When the content of the buffer or its anion is within this range, excellent long-term stability and low viscosity can be exhibited.

[0112] (E) pH

[0113] In one embodiment of the present invention, the pH of the stable liquid pharmaceutical composition may be 4.0 to 5.5 or 4.7 to 5.3. When the pH is within this range, excellent long-term stability and low viscosity can be exhibited. The pH can be adjusted using a buffer. In other words, when a buffer is included in a predetermined amount, the pH within the above range can be maintained without a separate pH adjusting agent. When citrate, phosphate, or a mixture thereof is used as a buffer, it may be difficult to maintain the pH within the above range. When an acid (e.g., hydrochloric acid) or a base (e.g., sodium hydroxide) is additionally included as a separate pH adjusting agent, the stability of the antibody may be reduced.

[0114] (F) Other ingredients

[0115] In one embodiment of the present invention, the stable liquid pharmaceutical preparation may not contain aspartic acid, lysine, arginine, or a mixture thereof. If it contains these amino acids, the preparation may be in a solid state. In one embodiment of the present invention, the stable liquid pharmaceutical preparation may contain one or more of the remaining amino acids excluding the three amino acids. In this case, the amino acid may be contained in an amount of 5% (w / v), for example, in a range of 0.001 to 5% (w / v), in a range of 0.001 to 1% (w / v), in a range of 0.01 to 5% (w / v), in a range of 0.01 to 1% (w / v), in a range of 0.1 to 5% (w / v), or in a range of 0.1 to 1% (w / v).

[0116] In another embodiment of the present invention, the stable liquid pharmaceutical preparation may contain taurine. In this case, the taurine may be contained in an amount of less than 5% (w / v), for example, in an amount of 0.001 to 5% (w / v), in an amount of 0.001 to 1% (w / v), in an amount of 0.01 to 5% (w / v), in an amount of 0.01 to 1% (w / v), in an amount of 0.1 to 5% (w / v), or in an amount of 0.1 to 1% (w / v).

[0117] In one embodiment of the present invention, the stable liquid pharmaceutical preparation may not contain metal salts such as NaCl, KCl, NaF, KBr, NaBr, Na2SO4, NaSCN, K2SO4, etc. If these metal salts are contained, precipitation may occur, the preparation may have a gelatinous shape, and stability may be poor.

[0118] In one embodiment of the present invention, the stable liquid pharmaceutical formulation may not include a chelating agent (e.g., EDTA). If a chelating agent is included, the oxidation rate may increase.

[0119] In one embodiment of the present invention, the stable liquid pharmaceutical preparation may not include a preservative. Examples of preservatives include octadecyldimethylbenzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl alcohol, benzyl alcohol, alkyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, m-cresol, and the like. Including a preservative may not help improve stability.

[0120] In one embodiment of the present invention, the stable liquid pharmaceutical preparation of the present invention may further comprise additives known in the art, as long as they do not substantially adversely affect the activity of the antibody, the stability of the preparation, and the low viscosity of the preparation. For example, the preparation may further comprise an aqueous carrier, an antioxidant, or a mixture of two or more thereof. Aqueous carriers are pharmaceutically acceptable (safe and non-toxic when administered to humans) and useful in the manufacture of liquid pharmaceutical preparations. Examples of aqueous carriers include, but are not limited to, sterile water for injection (SWFI), bacteriostatic water for injection (BWFI), sterile saline solution, Ringer's solution, dextrose, and the like. Antioxidants include, but are not limited to, ascorbic acid, and the like.

[0121] (G) “Stable” liquid pharmaceutical preparations

[0122] The term "stable" in the "stable" liquid pharmaceutical formulation of the present invention means that the antibody according to the present invention substantially retains its physical stability, chemical stability, and / or biological activity during the manufacturing process and / or during storage. Various analytical techniques for measuring antibody stability are readily available in the art.

[0123] Physical stability can be assessed by methods known in the art, including measuring the apparent attenuation of light (absorbance or optical density) in a sample. This attenuation measurement correlates with the turbidity of the formulation. Additionally, physical stability can be assessed by measuring the content of high-molecular-weight components, the content of low-molecular-weight components, the amount of intact protein, and the number of insoluble foreign particles.

[0124] Chemical stability can be assessed, for example, by detecting and quantifying chemically altered forms of the antibody. Chemical stability includes charge changes (e.g., resulting from deamidation or oxidation), which can be assessed, for example, by ion exchange chromatography. Charge variants (acidic or basic peaks) can be measured for chemical stability.

[0125] Biological activity can be assessed by methods known in the art, for example, antigen binding affinity can be measured by ELISA.

[0126] In one embodiment of the present invention, the liquid pharmaceutical preparation can be stable for a long period of time.

[0127] In one embodiment of the present invention, the term “stable” liquid pharmaceutical formulation means a liquid pharmaceutical formulation that satisfies one or more of the following:

[0128] Turbidity

[0129] - Absorbance A measured with a spectrophotometer after storage for 4 weeks at a temperature of 40℃±2℃ 600 Liquid pharmaceutical preparations having a viscosity of 0 to 0.0300 or 0 to 0.0700;

[0130] - Absorbance A measured with a spectrophotometer after storage for 4 weeks at a temperature of 40°C±2°C, a relative humidity of 75±5%, and in an airtight condition. 600 Liquid pharmaceutical preparations having a viscosity of 0 to 0.0300 or 0 to 0.0700;

[0131] Main ingredient content (main peak)

[0132] - A liquid pharmaceutical preparation containing 98% to 100% of the active ingredient as measured by SE-HPLC after storage at a temperature of 40°C±2°C for 4 weeks;

[0133] - A liquid pharmaceutical preparation containing 98 to 100% of the active ingredient as measured by SE-HPLC after storage for 4 weeks under sealed conditions at a temperature of 40°C±2°C and a relative humidity of 75±5%;

[0134] High molecular weight component (peak with a retention time earlier than the main peak (intact IgG))

[0135] - A liquid pharmaceutical preparation containing 0 to 1.00% of high molecular weight components as measured by SE-HPLC after storage for 12 months at a temperature of 5℃±3℃;

[0136] - A liquid pharmaceutical preparation having 0 to 1.00% of high molecular weight components as measured by SE-HPLC after storage for 12 months at a temperature of 5°C±3°C and in a sealed condition;

[0137] Low molecular weight component (peak with a later retention time than the main peak (intact IgG))

[0138] - Liquid pharmaceutical preparations containing 0 to 0.40% of low molecular weight components as measured by SE-HPLC after storage for 12 months at a temperature of 5℃±3℃;

[0139] - Liquid pharmaceutical preparations containing 0 to 0.40% of low molecular weight components as measured by SE-HPLC after storage for 12 months at a temperature of 5°C±3°C and in sealed conditions;

[0140] Content of intact immunoglobulin G

[0141] - A liquid pharmaceutical preparation having an intact immunoglobulin G content (Intact IgG%) of 94.0% to 100% as measured by non-reducing CE-SDS after storage for 12 months at a temperature of 5°C±3°C;

[0142] - A liquid pharmaceutical preparation having an intact immunoglobulin G content (Intact IgG%) of 94.0% to 100% as measured by non-reducing CE-SDS after storage for 12 months at a temperature of 5°C±3°C and in a sealed condition;

[0143] - A liquid pharmaceutical preparation having an intact immunoglobulin G content (Intact IgG%) of 94.0% to 100% as measured by non-reducing CE-SDS after storage at a temperature of 40°C±2°C for 4 weeks;

[0144] - A liquid pharmaceutical preparation having an intact immunoglobulin G content (Intact IgG%) of 94.0% to 100% as measured by non-reducing CE-SDS after storage for 4 weeks under sealed conditions at a temperature of 40°C±2°C and a relative humidity of 75±5%;

[0145] Content of intact heavy and light chains

[0146] - A liquid pharmaceutical preparation having an intact heavy and light chain content (Intact HC+LC%) of 99.0% to 100% as measured by reducing CE-SDS after storage for 12 months at a temperature of 5℃±3℃;

[0147] - A liquid pharmaceutical preparation having an intact heavy and light chain content (Intact HC+LC%) of 99.0% to 100% as measured by reducing CE-SDS after storage for 12 months at a temperature of 5°C±3°C and in a sealed condition;

[0148] - A liquid pharmaceutical preparation having an intact heavy and light chain content (Intact HC+LC%) of 98.0% to 100% as measured by reducing CE-SDS after storage at a temperature of 40°C±2°C for 4 weeks;

[0149] - A liquid pharmaceutical preparation having an intact heavy and light chain content (Intact HC+LC%) of 98.0% to 100% as measured by reducing CE-SDS after storage for 4 weeks at a temperature of 40°C±2°C, a relative humidity of 75±5%, and in a sealed condition;

[0150] Number of insoluble foreign particles

[0151] - A liquid pharmaceutical preparation having 0 to 1,000 insoluble foreign particles (10.00㎛≤, <400.00㎛) measured by HIAC after storage for 12 months at a temperature of 5℃±3℃;

[0152] - A liquid pharmaceutical preparation having 0 to 1,000 insoluble foreign particles (10.00㎛≤, <400.00㎛) measured by HIAC after storage for 12 months at a temperature of 5℃±3℃ and in a sealed condition;

[0153] - A liquid pharmaceutical preparation in which the number of insoluble foreign particles (1.00㎛≤, <100.00㎛) measured by MFI after storage for 4 weeks at a temperature of 40℃±2℃ is 0 to 30,000;

[0154] - A liquid pharmaceutical preparation having a number of insoluble foreign particles (1.00㎛≤, <100.00㎛) of 0 to 30,000 as measured by MFI after storage for 4 weeks under a temperature of 40℃±2℃, a relative humidity of 75±5%, and a sealed condition;

[0155] - A liquid pharmaceutical preparation in which the number of insoluble foreign particles (10.00㎛≤, <100.00㎛) measured by MFI after storage for 4 weeks at a temperature of 40℃±2℃ is 0 to 200;

[0156] - A liquid pharmaceutical preparation having 0 to 200 insoluble foreign particles (10.00㎛≤, <100.00㎛) measured by MFI after storage for 4 weeks under sealed conditions at a temperature of 40℃±2℃, a relative humidity of 75±5%;

[0157] - A liquid pharmaceutical preparation in which the number of insoluble foreign particles (10.00㎛≤, <100.00㎛) measured by MFI after storage for 6 weeks at a temperature of 40℃±2℃ is 0 to 500;

[0158] - A liquid pharmaceutical preparation having 0 to 500 insoluble foreign particles (10.00㎛≤, <100.00㎛) measured by MFI after storage for 6 weeks under sealed conditions at a temperature of 40℃±2℃, a relative humidity of 75±5%;

[0159] Oxidation rate

[0160] - A liquid pharmaceutical preparation having an oxidation rate of heavy chain Met 255 of 0% to 2.5% as measured by LC-MS after storage at a temperature of 40°C±2°C for 4 weeks;

[0161] - A liquid pharmaceutical preparation having an oxidation rate of heavy chain Met 255 of 0% to 2.5% as measured by LC-MS after storage for 4 weeks at a temperature of 40°C±2°C, a relative humidity of 75±5%, and in a sealed condition;

[0162] charge transformant

[0163] - A liquid pharmaceutical preparation having an acid peak of 20% to 35% as measured by IEC-HPLC after storage at a temperature of 40°C±2°C for 4 weeks;

[0164] - A liquid pharmaceutical preparation having an acid peak of 20% to 35% as measured by IEC-HPLC after storage for 4 weeks at a temperature of 40°C±2°C, a relative humidity of 75±5%, and in a sealed condition;

[0165] - A liquid pharmaceutical preparation having a basicity peak of 33% to 40% as measured by IEC-HPLC after storage at a temperature of 40℃±2℃ for 4 weeks;

[0166] - A liquid pharmaceutical preparation having a basicity peak of 33% to 40% as measured by IEC-HPLC after storage for 4 weeks at a temperature of 40°C±2°C, a relative humidity of 75±5%, and in a sealed condition;

[0167] TNFα binding affinity

[0168] - A liquid pharmaceutical preparation having a TNFα binding affinity of 80% to 120% as measured by ELISA after storage at a temperature of 5°C±3°C for 12 months; and

[0169] - A liquid pharmaceutical preparation having a TNFα binding affinity of 80% to 120% as measured by ELISA after storage for 12 months at a temperature of 5°C±3°C and in a sealed condition.

[0170] In one embodiment of the present invention, the viscosity measured after one month at a temperature of 40°C±2°C may be from 0.5 cP to 10.0 cP. In another embodiment of the present invention, the viscosity measured after six months at a temperature of 5°C±3°C may be from 0.5 cP to 5.0 cP.

[0171] (H) Method for manufacturing a stable liquid pharmaceutical preparation

[0172] The stable liquid pharmaceutical preparation of the present invention can be prepared using known methods, and is not limited to a specific method. For example, a liquid pharmaceutical preparation can be prepared by adjusting the pH by adding a buffer to a solution containing a surfactant and a sugar or its derivative, and then adding an antibody to the mixed solution. Furthermore, a liquid pharmaceutical preparation can be prepared by preparing a solution containing some excipients in the final stage of the purification process and then adding the remaining ingredients. For example, a liquid pharmaceutical preparation can be prepared by preparing a solution containing an antibody, a buffer, and a sugar or its derivative in the final stage of the purification process and then adding a surfactant to the solution.

[0173] Additionally, the formulation may not include a freeze-drying process during manufacture or may include a freeze-drying process.

[0174] If a freeze-drying process is not included, for example, the liquid pharmaceutical preparation of the present invention can be prepared and placed in a sealed container immediately after sterilization or other treatment.

[0175] In the case where a freeze-drying process is included, for example, after preparing and freeze-drying the liquid pharmaceutical preparation of the present invention, or after preparing and freeze-drying and storing / storing the liquid pharmaceutical preparation of the present invention, the components removed or modified by freeze-drying and / or storage / storage can be supplemented or replaced to prepare the liquid pharmaceutical preparation according to the present invention. In addition, the liquid pharmaceutical preparation according to the present invention can be prepared by freeze-drying only the components from which components that can be removed or modified by freeze-drying and / or storage / storage are excluded, or after freeze-drying and storing / storing only those components, and then adding the excluded components.

[0176] Korean Patent Application No. 10-2017-0081814, previously filed by the applicant, is incorporated by reference into the specification of the present invention.

[0177] - Method for treating a disease treatable with the anti-TNFα antibody of the present invention

[0178] The present invention provides a method for treating a disease treatable with an anti-TNFα antibody, comprising subcutaneously administering to a subject a pharmaceutical composition containing an anti-TNFα antibody or an antigen-binding fragment thereof.

[0179] In one embodiment of the present invention, the antibody may comprise at least one selected from the group consisting of infliximab, adalimumab, certoizumab pegol, golimumab, and biosimilars thereof.

[0180] In one embodiment of the present invention, the antibody may comprise infliximab.

[0181] In one embodiment of the present invention, the antibody may comprise a chimeric human-mouse IgG monoclonal antibody.

[0182] In one embodiment of the present invention, the antibody or antigen-binding fragment thereof may comprise a light chain variable region comprising a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 1, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 2, and a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3; and a heavy chain variable region comprising a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 4, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 5, and a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 6.

[0183] In one embodiment of the present invention, the antibody or antigen-binding fragment thereof may comprise a light chain variable region comprising the amino acid sequence of SEQ ID NO: 7; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 8.

[0184] In one embodiment of the present invention, the antibody may comprise a light chain comprising the amino acid sequence of SEQ ID NO: 9; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 10.

[0185] In one embodiment of the present invention, the concentration of the antibody or antigen-binding fragment thereof may be 10 to 200 mg / mL.

[0186] The present invention also provides a method for treating a disease treatable with an anti-TNFα antibody, comprising subcutaneously administering to a subject a composition comprising: (A) an anti-TNFα antibody or an antigen-binding fragment thereof; (B) a surfactant; (C) a sugar or derivative thereof; and (D) a buffer.

[0187] In one embodiment of the present invention, (B) the surfactant may include polysorbate, poloxamer or a mixture thereof.

[0188] In one embodiment of the present invention, the (B) surfactant may include polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, or a mixture of two or more thereof.

[0189] In one embodiment of the present invention, (B) the surfactant may include polysorbate 80.

[0190] In one embodiment of the present invention, the concentration of (B) surfactant may be 0.02 to 0.1% (w / v).

[0191] In one embodiment of the present invention, (C) the sugar may include a monosaccharide, a disaccharide, an oligosaccharide, a polysaccharide, or a mixture of two or more thereof, and the sugar derivative may include a sugar alcohol, a sugar acid, or a mixture thereof.

[0192] In one embodiment of the present invention, (C) the sugar or derivative thereof may include sorbitol, mannitol, trehalose, sucrose or a mixture of two or more thereof.

[0193] In one embodiment of the present invention, the concentration of (C) sugar or its derivative may be 1 to 10% (w / v).

[0194] In one embodiment of the present invention, the (D) buffer may include acetate or histidine.

[0195] In one embodiment of the present invention, the content of the (D) buffer may be 1 to 50 mM.

[0196] In one embodiment of the present invention, the pH of the composition may be 4.0 to 5.5.

[0197] In one embodiment of the present invention, the composition may not contain aspartic acid, lysine, arginine or mixtures thereof.

[0198] In one embodiment of the present invention, the composition may not contain NaCl, KCl, NaF, KBr, NaBr, Na2SO4, NaSCN, K2SO4 or mixtures thereof.

[0199] In one embodiment of the present invention, the composition may not include a chelating agent.

[0200] In one embodiment of the present invention, the composition may not contain a preservative.

[0201] In one embodiment of the present invention, the composition may further comprise an aqueous carrier, an antioxidant, or a mixture of two or more thereof.

[0202] In one embodiment of the present invention, the composition may have a viscosity of 0.5 cp to 10.0 cp measured after 1 month at a temperature of 40°C±2°C, or a viscosity of 0.5 cp to 5.0 cp measured after 6 months at 5°C±3°C.

[0203] In one embodiment of the present invention, the composition may comprise: (A) an antibody or antigen-binding fragment thereof, comprising a light chain variable region comprising a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 1, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 2, and a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3; and a heavy chain variable region comprising a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 4, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 5, and a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 6; (B) a surfactant; (C) a sugar or derivative thereof; and (D) a buffer comprising acetate or histidine.

[0204] In one embodiment of the present invention, the composition may comprise (A) 90 to 180 mg / ml of an antibody or antigen-binding fragment thereof, comprising a light chain variable region comprising a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 1, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 2, and a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3; and a heavy chain variable region comprising a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 4, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 5, and a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 6; (B) 0.02 to 0.1% (w / v) of a surfactant; (C) 1 to 10% (w / v) of a sugar or derivative thereof; and (D) 1 to 50 mM of a buffer comprising acetate or histidine.

[0205] In one embodiment of the present invention, the composition can be administered subcutaneously.

[0206] In one embodiment of the present invention, the composition may not undergo a reconstitution step, a dilution step, or both, prior to use.

[0207] In one embodiment of the present invention, the stable composition may be filled into a pre-filled syringe prior to use.

[0208] In one embodiment of the present invention, the composition may be included in an auto-injector prior to use.

[0209] Diseases treatable with anti-TNFα antibodies

[0210] In one embodiment of the present invention, the disease treatable with the anti-TNFα antibody is selected from the group consisting of rheumatoid arthritis, ulcerative colitis, Crohn's disease, plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, hemolytic disease of the newborn, inflammatory bowel disease, multiple sclerosis, prevention of organ transplant rejection, non-Hodgkin's lymphoma, metastatic cancer, retinopathy of prematurity, ovarian cancer, gastric cancer, head and neck cancer, osteoporosis, paroxysmal nocturnal hemoglobinuria, invasive Candida infection, breast cancer, melanoma, chronic lymphocytic leukemia, acute myeloid leukemia, renal cell carcinoma, colorectal cancer, asthma, nasopharyngeal cancer, hemorrhagic shock, Staphylococcus aureus infection, and follicular lymphoma.

[0211] In one embodiment of the present invention, the disease treatable with an anti-TNFα antibody may be a disease treatable with intravenous administration of infliximab.

[0212] In one embodiment of the present invention, the disease treatable with an anti-TNFα antibody may be rheumatoid arthritis, ulcerative colitis, Crohn's disease, plaque psoriasis, psoriatic arthritis, or ankylosing spondylitis, which are treatable with intravenous administration of infliximab.

[0213] In one embodiment of the present invention, the subject of anti-TNFα antibody administration is a patient who has an inadequate response to disease-modifying anti rheumatic drugs (DMARDs), including methotrexate.

[0214] In one embodiment of the present invention, the subject of anti-TNFα antibody administration is a patient who has not previously been treated with methotrexate or other DMARDs.

[0215] In one embodiment of the present invention, the subject of anti-TNFα antibody administration is a patient who does not show an adequate response to conventional treatment and exhibits severe inflammatory symptoms and elevated serum indicators related to inflammation.

[0216] In one embodiment of the present invention, the subject of anti-TNFα antibody administration is a patient who does not respond to, is contraindicated in, or is intolerant to systemic therapy including methotrexate, cyclosporine, or psoralen ultraviolet A therapy (PUVA).

[0217] In one embodiment of the present invention, the subject of anti-TNFα antibody administration is a patient who does not show an adequate response to treatment with a corticosteroid, 6-mercaptopurine, azathioprine, or immunosuppressant, is intolerant to such treatment, or is contraindicated in such treatment.

[0218] In one embodiment of the present invention, the subject of anti-TNFα antibody administration is a patient who does not respond to conventional treatment including antibiotics, excretion methods, or immunosuppressive treatment.

[0219] Dosage and dosing interval

[0220] In one embodiment of the present invention, the anti-TNFα antibody or binding fragment thereof may be administered in an amount of 60 to 300 mg. Specifically, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, or 300 mg may be administered.

[0221] In another embodiment of the present invention, the anti-TNFα antibody or binding fragment thereof may be administered in a dose of 90 to 180 mg. In another embodiment, the anti-TNFα antibody or binding fragment thereof may be administered in a dose of 120 to 240 mg. In another embodiment, the anti-TNFα antibody or binding fragment thereof may be administered in a dose of 120 to 240 mg.

[0222] In one embodiment of the present invention, the anti-TNFα antibody or binding fragment thereof may be administered in an amount of 90 to 180 mg when the patient weighs less than 80 kg, and in an amount of 190 to 270 mg when the patient weighs 80 kg or more.

[0223] In one embodiment of the present invention, the anti-TNFα antibody or binding fragment thereof may be administered at intervals of 1 to 8 weeks. Specifically, the anti-TNFα antibody or binding fragment thereof may be administered at intervals of 1 week, 1.5 weeks, 2 weeks, 2.5 weeks, 3 weeks, 3.5 weeks, 4 weeks, 4.5 weeks, 5 weeks, 5.5 weeks, 6 weeks, 6.5 weeks, 7 weeks, 7.5 weeks, or 8 weeks.

[0224] In another embodiment of the present invention, the anti-TNFα antibody or binding fragment thereof may be administered at intervals of 2 to 4 weeks.

[0225] Pre-medication

[0226] Prior to the step of subcutaneous administration of the anti-TNFα antibody or binding fragment thereof, a step of intravenous administration of the anti-TNFα antibody or antigen-binding fragment thereof may be included.

[0227] In one embodiment of the present invention, prior to the subcutaneous administration step, a step may be included in which an anti-TNFα antibody or antigen-binding fragment thereof is intravenously administered at a dose of 1 to 10 mg / kg. Specifically, a step in which 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg / kg is intravenously administered may be included.

[0228] In another embodiment of the present invention, prior to the subcutaneous administration step, a step of intravenously administering 2 to 8 mg / kg of an anti-TNFα antibody or antigen-binding fragment thereof may be included. In another embodiment of the present invention, prior to the subcutaneous administration step, a step of intravenously administering 3 to 5 mg / kg of an anti-TNFα antibody or antigen-binding fragment thereof may be included.

[0229] In one embodiment of the present invention, prior to the subcutaneous administration step, a step of intravenously administering an anti-TNFα antibody or antigen-binding fragment thereof at intervals of 1 to 8 weeks may be included. Specifically, a step of intravenously administering at intervals of 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, or 8 weeks may be included.

[0230] In another embodiment of the present invention, prior to the subcutaneous administration step, a step may be included in which an anti-TNFα antibody or antigen-binding fragment thereof is administered intravenously at intervals of 2 to 4 weeks.

[0231] In one embodiment of the present invention, prior to the subcutaneous administration step, a step may be included in which an anti-TNFα antibody or an antigen-binding fragment thereof is administered intravenously, wherein the interval between the final intravenous administration and the first subcutaneous administration is 1 to 8 weeks. Specifically, a step may be included in which administration is administered at intervals of 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, or 8 weeks.

[0232] In another embodiment of the present invention, prior to the subcutaneous administration step, a step may be included in which an anti-TNFα antibody or an antigen-binding fragment thereof is administered intravenously, provided that the interval between the last intravenous administration and the first subcutaneous administration is 2 to 4 weeks.

[0233] Combination administration

[0234] Other biologic agents or chemotherapeutic agents may be administered together with the anti-TNFα antibody or antigen-binding fragment thereof of the present invention.

[0235] Administration is administered simultaneously with, before, or after administration of the anti-TNFα antibody or antigen-binding fragment thereof.

[0236] In one embodiment of the present invention, the co-administered biologic agent may include etanercept, infliximab, adalimumab, sertolizumab pegol, golimumab, or a combination thereof.

[0237] In one embodiment of the present invention, the co-administered chemotherapeutic agent may include a disease-modifying antirheumatic drug (DMARD).

[0238] In one embodiment of the present invention, the co-administered chemotherapeutic agent may include Methotrexate, Leflunomide, Sulfasalazine, Hydroxychloroquine, or a combination thereof.

[0239] -product

[0240] The present invention also provides a product comprising a composition containing an anti-TNFα antibody or a binding fragment thereof; and a container containing the composition in a sealed state.

[0241] The composition containing the anti-TNFα antibody or binding fragment thereof is as described above.

[0242] In one embodiment of the present invention, the container may be formed from a material such as glass, polymer (plastic), metal, or the like, but is not limited thereto. In one embodiment of the present invention, the container is, but is not limited to, a bottle, a vial, a cartridge, a syringe (pre-filled syringe, automatic syringe), or a tube. In one embodiment of the present invention, the container may be a glass or polymer vial, or a glass or polymer pre-filled syringe.

[0243] Specific product forms such as the vials, cartridges, pre-filled syringes, and auto-injectors, and methods for filling the stable liquid pharmaceutical preparation into the vials, cartridges, pre-filled syringes, and auto-injectors, etc., can be easily obtained or practiced by those skilled in the art to which the present invention pertains. For example, U.S. Patent Nos. 4,861,335 and 6,331,174 disclose specific product forms and filling methods for pre-filled syringes. For example, U.S. Patent Nos. 5,085,642 and 5,681,291 disclose specific product forms and assembly methods for auto-injectors. Commercially available products such as the vials, cartridges, pre-filled syringes, and auto-injectors can be used as they are, or products that are separately custom-made can be used in consideration of the physical properties, administration site, dosage, etc. of the composition containing the anti-TNFα antibody or binding fragment thereof.

[0244] In one embodiment of the present invention, the interior of the container may not be coated with silicone oil. If coated with silicone oil, stability may be reduced. The container may be a single-dose or multi-dose container.

[0245] In one embodiment of the present invention, the product may further include instructions for using, storing, or both a composition containing the anti-TNFα antibody or binding fragment thereof. The instructions for use may include treatment of a disease in which TNFα activity is detrimental, and may include the route of administration, dosage, and timing of administration.

[0246] In one embodiment of the present invention, the product may include other tools necessary from a commercial and user standpoint, such as needles, syringes, and the like.

[0247]

[0248] Hereinafter, the present invention will be described in detail by way of examples. The following examples are intended only to illustrate the present invention, and the scope of the present invention is not limited by the following examples.

[0249]

[0250] Example 1. Evaluation of safety and therapeutic efficacy of subcutaneous infliximab in patients with rheumatoid arthritis (RA).

[0251]

[0252] This randomized, multicenter, parallel-group, phase 1 / 3 trial was designed to evaluate the efficacy, pharmacokinetics, and safety of subcutaneous infliximab (infliximab SC) and intravenous infliximab (infliximab IV) in combination with methotrexate (MTX) and folic acid in patients with active rheumatoid arthritis who had not responded adequately to methotrexate (MTX) monotherapy for at least 3 months. The trial consisted of two parts.

[0253] Part 1 was designed to determine the optimal dose of infliximab SC and to evaluate the steady-state area under the concentration-time curve (AUC) between weeks 22 and 30. τ ) was used to identify the optimal dose of infliximab SC equivalent to 3 mg / kg infliximab IV over the first 30 weeks. For Part 1, the trial duration was up to 65 weeks, including screening (up to 3 weeks) through the end-of-trial visit.

[0254] Part 2 is designed to demonstrate non-inferiority between infliximab SC and infliximab IV in terms of efficacy. Clinical response, measured by change from baseline in the Disease Activity Score in 28 joints (DAS28; C-reactive protein [CRP]) at week 22, will demonstrate that infliximab SC is non-inferior to infliximab IV in terms of efficacy. The dose and dosing interval for infliximab SC in Part 2 was 120 mg every 2 weeks.

[0255]

[0256] Part 1

[0257] Patients were eligible for enrollment in this clinical trial if they met all of the following criteria:

[0258] * Active disease defined as at least 6 swollen and tender joints out of 28 joints and a serum C-reactive protein (CRP) concentration >0.6 mg / dL

[0259] * If you have been treated with methotrexate 12.5-25 mg / week (or 10-25 mg / week for patients in Korea) for at least 3 months prior to administration of the test drug (Day 0), and have been treated with the same dose for the last 4 weeks

[0260] Patients were not eligible for enrollment in the clinical trial if they met any of the following criteria:

[0261] * Patients who have previously received biological agents for the treatment of RA and / or TNFα inhibitors for the treatment of other diseases.

[0262] * Patients with allergy to infliximab or any other murine and / or human protein excipients, or hypersensitivity to immunoglobulin products.

[0263] This clinical trial consisted of three clinical trial periods: screening, administration period, and end of trial period. Screening was conducted between days -21 and -1 before the first dose of the study drug to assess the patients' eligibility for the study. All tests were performed, including tests for hepatitis B, hepatitis C, and human immunodeficiency virus (HIV-1, HIV-2) infection, urine and serum pregnancy tests for women of childbearing potential, rheumatoid factor, anti-cyclic citrullinated peptide, 12-lead ECG, and clinical laboratory tests. In addition, interferon-gamma release assay (IGRA) and chest X-ray were performed to exclude patients with tuberculosis.

[0264] All patients enrolled in the trial received IV infliximab at weeks 0 and 2, administered once daily. Folic acid was administered concomitantly with MTX and the study drug to minimize or prevent adverse events associated with MTX side effects, and patients were reminded to maintain their MTX dose throughout the study. In addition, patients had the option, at the investigator's discretion, to receive premedication 30 to 60 minutes prior to the start of study drug administration to prevent hypersensitivity reactions to the study drug, including but not limited to: an antihistamine [e.g., 2 to 4 mg chlorpheniramine equivalents], hydrocortisone, paracetamol, and / or a non-sedating antihistamine [10 mg cetirizine equivalents].

[0265] Patients who received two full doses and had no safety concerns at the investigator's discretion were randomly assigned to receive SC infliximab or IV infliximab prior to the 6-week, 42-day dosing. Randomization was stratified by country, week 2 serum CRP concentration (≤0.6 mg / dL or >0.6 mg / dL), and week 6 body weight (≤70 kg or >70 kg). A total of 50 patients with active rheumatoid arthritis were enrolled, of whom 48 patients were randomly assigned 1:1:1:1 to four trial cohorts and received study drug for up to week 54 (Table 1).

[0266]

[0267] Cohort number Dosage Clinical trial drug Administration method Number of patients Cohort 13 mg / kg Infliximab IV 100 mg / vial 2-hour IV infusion 13 Cohort 290 mg Infliximab SC 90 mg / PFS Single SC injection 11 Cohort 3120 mg Infliximab SC 120 mg / PFS Single SC injection 12 Cohort 4180 mg Infliximab SC 90 mg / PFS 2 SC injections 12

[0268] PFS, prefilled syringe

[0269]

[0270] For patients assigned to cohort 1, an additional seven doses of IV infliximab were administered at week 6 and then every 8 weeks (weeks 14, 22, 30, 38, 46, and 54). For patients assigned to cohorts 2, 3, and 4, the first SC infliximab dose was administered at week 6, and additional SC infliximab doses were administered every 2 weeks until week 54. For all patients in cohorts 2, 3, and 4, the initial dose was adjusted to the optimal dose after dose verification. Additional SC injections using the optimal dose were administered until week 54. Infliximab SC was administered by a healthcare provider at each study site visit (weeks 6, 8, 10, 14, 22, 24, 26, 28, 30, 38, 46, and 54), and at all other weeks (weeks 12, 16, 18, 20, 32, 34, 36, 40, 42, 44, 48, 50, and 52), patients were allowed to self-inject infliximab SC if determined appropriate by the investigator after training in appropriate injection technique.

[0271] Patients returned to the study site at predefined intervals for clinical evaluation and blood sampling. At each visit, patients were questioned about adverse events (AEs) and concomitant medications and monitored for clinical signs and symptoms of TB. The primary pharmacokinetic endpoint was assessed during the maintenance phase between weeks 22 and 30, and secondary pharmacokinetic endpoints were assessed throughout the treatment period up to week 54. Blood samples for analysis, efficacy, PD, and safety assessments were collected and performed at time points specified in the assessment schedule.

[0272] The end-of-trial visit was conducted 8 weeks after the last dose, either at the end of the maintenance phase or if the patient dropped out. Every effort was made to complete all end-of-trial assessments at 8 weeks after the patient received the last dose.

[0273]

[0274] Part 2

[0275] Part 2 was initiated based on the Independent Data and Safety Monitoring Board's review of the PK modeling report data, which included the first 30 weeks of PK, efficacy, PD, and safety data identified in Part 1.

[0276] Part 2 consisted of three clinical trial periods: screening, a double-blind period of up to 30 weeks, followed by a 24-week open-label period, and the end of the trial. Screening was conducted between days -42 and 0 before the first dose of study drug, and patients' eligibility for the study was assessed. All tests were performed, including tests for hepatitis B, C, and human immunodeficiency virus (HIV-1, HIV-2) infection, urine and serum pregnancy tests for women of childbearing potential, rheumatoid factor, anti-cyclic citrullinated peptide, 12-lead ECG, and clinical laboratory tests. In addition, interferon-gamma release assays (IGRAs) and chest X-rays were performed to rule out patients with tuberculosis.

[0277] All patients enrolled in the trial received IV infliximab at weeks 0 and 2, administered once daily. Folic acid was administered concomitantly with MTX and the study drug to minimize or prevent adverse events associated with MTX side effects, and patients were reminded to maintain their MTX dose throughout the study. Patients may receive premedication, at the investigator's discretion, 30 to 60 minutes prior to the start of study drug administration to prevent hypersensitivity reactions to the study drug, including but not limited to: an antihistamine [e.g., 2 to 4 mg chlorpheniramine equivalents], hydrocortisone, paracetamol, and / or a non-sedating antihistamine [10 mg cetirizine equivalents].

[0278] Patients who received two full doses and had no safety concerns at the investigator's discretion were randomly assigned to receive infliximab SC plus placebo IV, or infliximab IV plus placebo SC (PFS), administered by prefilled syringe (PFS) for 42 days over 6 weeks. Randomization was stratified by country, week 2 serum CRP concentration (≤0.6 mg / dL or >0.6 mg / dL), and week 6 body weight (≤100 kg or >100 kg). A minimum of 218 patients with active rheumatoid arthritis were randomly assigned 1:1 to the two trial arms, who received study drug for up to week 54. A double-blind, placebo-controlled design was used to maintain blinding for up to week 30 (Table 2).

[0279]

[0280] Group number Dosage Clinical trial drug Administration method Number of patients Group 1 3 mg / kg Infliximab IV 100 mg / vial 2-hour IV infusion Minimum 109 people Group 2 120 mg Infliximab SC 120 mg / PFS Single SC injection Minimum 109 people

[0281] PFS, prefilled syringe

[0282]

[0283] For patients assigned to Group 1, an additional 3 doses of infliximab IV were administered at Week 6 and then every 8 weeks (Weeks 14 and 22) through Week 22, and placebo SC was administered at Week 6 and then every 2 weeks through Week 28. Infliximab IV was then switched to infliximab SC (PFS) at Week 30. Infliximab SC (PFS) was then administered through Week 54. For patients assigned to Group 2, the first dose of infliximab SC (PFS) was administered at Week 6 and then every 2 weeks through Week 54, and placebo IV was administered at Weeks 6, 14, and 22.

[0284] Infliximab SC (placebo SC during the double-blind period) will be injected by a healthcare provider at each study site visit (weeks 6, 14, 22, 24–28 [patients undergoing PK assessment visits], 30, 38, 46, and 54). At all other weeks (weeks 8, 10, 12, 16, 18, 20, 24–28 [patients not undergoing PK assessment visits], 32, 34, 36, 40, 42, 44, 48, 50, and 52), patients may self-inject infliximab SC (placebo SC during the double-blind period) if determined appropriate by the investigator after training in appropriate injection technique.

[0285] In some countries, infliximab SC is administered by autoinjector (AI) every two weeks, beginning at week 46. To assess the usability of infliximab SC (AI), pre- and post-self-administration diagnostic questionnaires, a self-administration diagnostic checklist, and a potential risk checklist are assessed.

[0286] Part 2 clinical assessments, blood sampling and clinical trial type visits are conducted in the same manner as Part 1 and are collected and performed at the times specified in the assessment schedule.

[0287]

[0288] result

[0289] 1-1. Safety Assessment

[0290] Summary of adverse events

[0291] Safety was assessed as a secondary endpoint in Part 1 and included immunogenicity, hypersensitivity monitoring (including delayed hypersensitivity monitoring), vital signs (including blood pressure, heart rate, and respiratory rate, and body temperature), body weight, interferon-gamma release assay, chest X-ray, HIV-1, HIV-2, and hepatitis B virus infection status, physical examination findings, 12-lead ECG, adverse events (including serious adverse events), adverse events of special interest (infusion-related / hypersensitivity / anaphylactic reactions [drug-related], delayed hypersensitivity, injection site reactions, infections, and malignancies), signs and symptoms of tuberculosis, clinical laboratory analyses, pregnancy testing, previous and concomitant medications, and localized pain using a 10-cm visual analogue scale (VAS).

[0292] Cumulative safety data from this study included adverse reactions (and serious adverse reactions) that occurred regardless of whether they were related to the study drug through the end-of-study visit, and an overall summary of treatment-emergent adverse events (AEs) during the maintenance phase (Weeks 6 to 54) is presented in Table 3 . Overall, 109 treatment-emergent AEs occurred in 33 (68.8%) patients, with 9 (69.2%) in the IV cohort (Cohort 1) and 24 (68.6%) in the overall SC cohort (Cohorts 2, 3, and 4), showing a similar rate in the overall SC cohort to the IV cohort. In addition, the severity of most treatment-emergent AEs was Grade 1 or 2, and 23 (47.9%) of all treatment-emergent AEs were considered to be related to the drug.

[0293] Treatment-related serious adverse events (SAEs) occurred in a total of 6 patients (12.5%), 1 patient (7.7%) in the IV cohort (Cohort 1) and 5 patients (14.3%) in the overall SC cohorts (Cohorts 2 and 4). No SAEs occurred in Cohort 3 of the SC cohort. SAEs were grade 2 or 3, and 2 patients (16.7%) in Cohort 4 were considered drug-related. In addition, among all SAEs, 1 patient (9.1%) in Cohort 2 and 2 patients (16.7%) in Cohort 3 discontinued SAE after 30 weeks of treatment based on the investigator's judgment that the SAEs were important medical events.

[0294] Among the treatment-related adverse events due to drug-related reactions, infusion-related reactions, hypersensitivity, or anaphylaxis occurred in a total of 4 patients (8.3%), 1 patient (7.7%) in the IV cohort (Cohort 1) and 3 patients (8.6%) in the entire SC cohort (Cohorts 2 and 3). In the SC cohort, no treatment-related adverse events due to drug-related reactions, such as infusion-related reactions, hypersensitivity, or anaphylaxis, occurred in Cohort 4. Because infliximab treatment-related reactions are related to antibodies to the drug (ADA) (Remsima SmPC 2017), patients who showed drug-related reactions were investigated for the presence of antibodies to the drug (ADA). A total of 2 patients (one each in Cohorts 1 and 2) tested positive for antibodies to the drug (ADA) and neutralizing antibodies (NAb). One patient in cohort 2 received two IV infliximab doses at weeks 0 and 2 during the loading period, followed by two SC infliximab doses at weeks 6 and 8. A dose-related reaction occurred at weeks 6 and 8, and the patient tested positive for anti- and anti-CD40 antibodies at week 6 and at the end-of-study visit (10 weeks after the week 8 visit). One patient in cohort 1 experienced a dose-related reaction at week 38, and the patient tested positive for anti- and anti-CD40 antibodies at weeks 30, 38, and at the end-of-study visit (10 weeks after the week 38 visit).

[0295] Treatment-related adverse events due to injection site reactions occurred in a total of 5 patients (14.3%) across the entire SC cohort (cohorts 2, 3, and 4), and were all grade 1 or 2 in severity. No treatment-related adverse events due to injection site reactions were reported in the IV cohort (cohort 1). Patients who developed injection site reactions were also evaluated for the presence of anti-drug antibodies (ADAs), and one of the five (cohort 2) tested positive for both ADAs and neutralizing antibodies (NAbs) at the 6-week visit, the day before the onset of the treatment-related adverse event due to injection site reactions.

[0296] Adverse events following treatment due to infection occurred in 5 (38.5%) patients in the IV cohort (cohort 1) and in 13 (37.1%) patients in the overall SC cohort (cohorts 2, 3, and 4).

[0297] There were 6 cases (17.1%) in the SC cohort (cohorts 2, 3, and 4) that required discontinuation of the drug due to adverse reactions after treatment. The reported adverse reactions included antiphospholipid antibody syndrome, injection site reactions, medication-related reactions, pulmonary tuberculosis, and latent tuberculosis. No treatment-related adverse reactions due to infection occurred in the IV cohort.

[0298] There were no reported deaths during the clinical trial period.

[0299]

[0300] Cohort 1IV 3 mg / kg (N=13) Cohort 2SC 90 mg (N=11) Cohort 3SC 120 mg (N=12) Cohort 4SC 180 mg (N=12) SC Total (N=35) Number of patients experiencing at least 1 treatment-related adverse event (%)9 (69.2)7 (63.6)8 (66.7)9 (75.0)24 (68.6)Related4 (30.8)5 (45.5)7 (58.3)7 (58.3)19 (54.3)Unrelated9 (69.2)5 (45.5)2 (16.7)4 (33.3)11 (31.4) Number of patients experiencing at least 1 treatment-related serious adverse event (%)1 (7.7)2 (18.2)03 (25.0)5 (14.3)Related0002 (16.7)2 (5.7)Unrelated1 (7.7)2 (18.2)01 (8.3)3 (8.6)Number of patients who experienced at least one treatment-related adverse event (%)1 (7.7)1 (9.1)2 (16.7)03 (8.6)Number of patients who experienced at least one treatment-related adverse event (%)02 (18.2)1 (8.3)2 (16.7)5 (14.3)Number of patients who experienced at least one treatment-related adverse event (%)5 (38.5)4 (36.4)3 (25.0)6 (50.0)13 (37.1)Related2 (15.4)1 (9.1)3 (25.0)3 (25.0)7 (20.0)Number of patients who discontinued clinical trial study drug among patients who experienced at least one adverse event after treatment (%)02 (18.2)2 (16.7)2 (16.7)6 (17.1)

[0301] * In each summary section, if more than one patient was reported, only the most severe case was counted. Cases were considered relevant only if the relationship was defined as "Possible," "Probable," or "Definite."

[0302]

[0303] Immunogenicity

[0304] In general, the proportion of patients positive for ADA was low in the SC cohort, and most patients were ADA-negative at week 54. Furthermore, the proportion of patients positive for ADA tended to decrease as the SC dose increased. At week 54, the number of patients positive for ADA was 9 (69.2%), 4 (36.4%), 2 (16.7%), and 2 (16.7%) in cohorts 1 to 4, respectively (Table 4).

[0305]

[0306] Visit Cohort 1IV 3 mg / kg (N=13) Cohort 2SC 90 mg (N=11) Cohort 3SC 120 mg (N=12) Cohort 4SC 180 mg (N=12) Total SC (N=35) 0 Week ADA Positive 00000 NAb Positive 00000 6 Week ADA Positive 02 (18.2) 002 (5.7) NAb Positive 02 (18.2) 002 (5.7) 14 Week ADA Positive 5 (38.5) 2 (18.2) 1 (8.3) 1 (8.3) 4 (11.4) NAb Positive 3 (23.1) 1 (9.1) 1 (8.3) 02 (5.7) 22 Week ADA Positive 7 (53.8) 3 (27.3) 2 (16.7) 1 (8.3) 6 (17.1) NAb Positive 5 (38.5)2 (18.2)1 (8.3)03 (8.6)30 Weeks ADA Positive9 (69.2)4 (36.4)3 (25.0)07 (20.0) NAb Positive6 (46.2)2 (18.2)1 (8.3)03 (8.6)38 Weeks ADA Positive9 (69.2)4 (36.4)1 (8.3)1 (8.3)6 (17.1) NAb Positive6 (46.2)3 (27.3)1 (8.3)04 (11.4)46 Weeks ADA Positive7 (53.8)5 (45.5)2 (16.7)07 (20.0) NAb Positive5 (38.5)2 (18.2)1 (8.3)03 (8.6)54 Weeks ADA Positive9 (69.2)4 (36.4)2 (16.7)2 (16.7)8 (22.9) NAb positive 5 (38.5)2 (18.2)1 (8.3)1 (8.3)4 (11.4) ADA positive at least once **11 / 13 (84.6) 5 / 9 (55.6) 4 / 12 (33.3) 3 / 12 (25.0) 12 / 33 (36.4) NAb positive at least once ** 7 / 13 (53.8)2 / 9 (22.2)1 / 12 (8.3)1 / 12 (8.3)4 / 33 (12.1)

[0307] * Abbreviations: ADA, drug-resistant antibody; NAb, neutralizing antibody

[0308] ** Patients who were never confirmed positive for antibodies to the drug or neutralizing antibodies before the 6-week treatment were counted as patients who were confirmed positive for antibodies to the drug or neutralizing antibodies at least once after the 6-week treatment.

[0309]

[0310] Local pain assessment using a visual analog scale (VAS)

[0311] The visual analog scale (VAS) ranges from 0 to 100 mm, with higher scores indicating more severe pain. At the first SC administration (week 6), slightly higher levels of local pain were observed in the SC cohorts (cohorts 2, 3, and 4) than in the IV cohort (cohort 1). However, as SC administration was repeated, local pain gradually decreased, and slightly lower levels of pain were reported in the SC cohorts (cohorts 2, 3, and 4) than in the IV cohort (cohort 1). Among the SC cohorts, Cohort 4, which required two administrations of the SC 90 mg preparation, showed higher pain levels than the other two SC cohorts, but tended to report lower levels of pain than the IV cohort (cohort 1) (Table 5).

[0312]

[0313] Visit Statistics Cohort 1 IV 3 mg / kg (N=13) Cohort 2 SC 90 mg (N=11) Cohort 3 SC 120 mg (N=12) Cohort 4 SC 180 mg (N=12) Weeks 6 8 1 1 1 2 1 2 Mean (Standard Deviation) 9.63 (12.817) 7.09 (9.648) 17.71 (21.922) 11.21 (12.496) Median 5.00 2.00 8.00 7.50 Minimum, Maximum 1, 390, 300, 650, 35 1 4 Weeks 10 10 1 1 1 2 Mean (Standard Deviation) 11.70 (14.080) 4.20 (6.210) 7.82 (8.072) 10.21 (13.934)Median 7.00 1.25 6.00 5.00Minimum, Maximum 1, 450, 180, 230, 4122 Weeks 13101112Mean (Standard Deviation) 19.15 (32.080) 5.30 (5.912) 6.86 (10.460) 10.17 (10.100)Median 3.00 2.25 2.00 7.00Minimum, Maximum 0, 840, 180, 361, 3130 Weeks 13101112Mean (Standard Deviation) 13.85 (22.649) 7.55 (10.828) 4.36 (5.446) 6.08 (5.351)Median 3.00 2.25 3.00 3.50Minimum, Maximum 0, 770, 350, 171, 1654 Weeks 12998Mean (Standard Deviation) 5.58 (7.868) 5.22 (5.974) 5.22 (5.094) 9.63 (6.718)Median 2.00 2.00 3.00 9.50Minimum, Maximum 1, 260, 150, 171, 19

[0314]

[0315] 1-2. Evaluation of therapeutic efficacy

[0316] Disease activity measured by DAS28

[0317] Analysis of DAS28 (C-reactive protein; CRP) and DAS28 (erythrocyte sedimentation rate; ESR) at weeks 2, 6, 14, 22, 30, and 54 compared to baseline as secondary efficacy endpoints showed no significant clinical differences between the three different doses of infliximab SC and infliximab IV cohorts, and a trend toward decreasing true values ​​over time.

[0318] The actual values ​​and changes from baseline of disease activity as measured by DAS28 are summarized in Tables 6 (CRP) and 7 (ESR). In each cohort, the mean score of disease activity as measured by DAS28 decreased from baseline at weeks 2, 6, 14, 22, 30, and 54. All SC cohorts showed lower DAS28 scores than the IV cohort from week 22 for DAS28 (CRP) and from week 30 for DAS28 (ESR), which may be due to the higher C score in the SC cohort. trough And it was consistent.

[0319]

[0320] IV 3mg / kg (N=13) SC 90mg (N=11) SC 120mg (N=12) SC 180mg (N=12) Visit Statistics Actual Value Change from Baseline Actual Value Change from Baseline Actual Value Change from Baseline Actual Value Change from Baseline Actual Value Change from Baseline Change Baseline Number of people 13111212 Mean 5.4136.2735.7195.527 Standard deviation 0.77760.82340.91200.8185 Minimum 4.115.134.534.62 Median 5.3556.2655.4925.299 Maximum 6.687.467.317.102 Weeks Number of people 1313111112121212 Mean 4.328-1.0865.030-1.2434.421-1.2974.230-1.297 Standard deviation 1.51610.90001.39221.25 090.88150.58991.26470.8990Minimum1.71-2.412.27-4.093.39-2.102.60-2.94Median4.661-1.1435.367-1.1914.067-1.2064.317-1.206Maximum6.590.346.350.246.48-0.236.59-0.046Number of weeks1313111112121111Average3.902-1.5124.600-1.6733.921-1.7983.419-2.007Standard deviation1 .47650.92781.07350.71041.19110.84421.17750.9631Minimum1.82-2.752.90-2.372.55-3.251.56-3.97Median4.414-1.4514.663-1.9193.323-1.8903.370-2.004Maximum6.37-0.286.24-0.036.28-0.435.09-0.2714Number of shares1313101011111212Average3.558-1.8563.968-2.2963.4 46-2.2552.933-2.594Standard deviation1.26120.86211.24850.81311.34061.13761.17790.8486Minimum1.92-2.891.84-3.431.39-4.411.50-4.00Median3.549-2.1023.740-2.3923.223-1.8812.702-2.665Maximum6.15-0.525.58-1.185.83-0.895.63-1.0022Number of weeks1313101011111212Average3.885-1.5293.730-2.5343.257-2.4442.789-2.738Standard deviation1.61671.32281.04300.84911.40771.23801.32660.8753Minimum1.86-3.331.69-4.071.50-4.351.11-3.95Median4.066-1.4043.626-2.3242.977-1.9892.606- 2.922Maximum6.741.385.27-1.455.79-1.075.53-1.1030Number of shares1313101010101212Average3.315-2.0993.029-3.2363.105-2.5862.741-2.786Standard deviation1.25150.84991.14461.24301.00760.97490.96610.5621Minimum1.80-3.021. 35-6.111.77-4.561.15-3.79Median3.150-2.3122.917-2.9313.038-2.3452.831-2.668Maximum6.410.264.78-1.814.74-1.184.51-2.0454Number of weeks12128810101010Average3.548-1.9613.025-3.0903.167-2.5452.911-2.505 Standard Deviation 1.19 28 1.076 6 1.024 20.73 90 0.970 61.39 96 0.99 29 0.9279 Minimum 1.26-3.60 1.57-4.44 1.35-4.46 1.11-3.51 Median 3.685-1.74 22.770-3.02 53.463-2.58 52.877-2.866 Maximum 5.28 0.08 4.58-1.93 4.60 0.00 4.31-0.55.

[0321]

[0322] IV 3mg / kg (N=13) SC 90mg (N=11) SC 120mg (N=12) SC 180mg (N=12) Visit Statistics Actual Value Change from Baseline Actual Value Change from Baseline Actual Value Change from Baseline Actual Value Change from Baseline Actual Value Change from Baseline Change Baseline Number of people 13111212 Mean 6.03 17.09 16.410 6.362 Standard deviation 0.89 40 0.848 11.164 20.8497 Minimum 3.85 5.33 4.54 5.04 Median 6.00 97.18 26.360 6.318 Maximum 7.418 188.117.982 Weeks Number of people 1313111112121212 Mean 4.970 - 1.06 15.773 - 1.31 75.203 - 1.20 75.019 - 1.343 Standard deviation 1.76 49 0.97 20 1.83 421.43131.30030.88371.30650.9234Minimum1.31-2.551.93-4.863.22-3.353.43-3.19Median5.481-0.8166.433-1.1165.073-1.0144.793-1.285Maximum7.510.447.510.108.04-0.077.61-0.016Number of weeks1313111112121212Average4.496-1.5355.387-1.7044.685-1.7254.418 -1.944Standard deviation1.50150.82851.19400.64971.37661.00681.41611.0233Minimum2.13-2.782.88-2.453.27-3.372.25-4.38Median4.714-1.1515.331-1.7754.184-1.5514.361-1.919Maximum7.35-0.067.09-0.357.66-0.037.20-0.4614Number of weeks1313101011111212Average4.236-1. 7954.830-2.2914.306-2.0813.740-2.621StdDev1.27720.78251.47620.90051.39401.31781.17320.7395Minimum2.32-3.141.77-3.562.68-4.162.14-3.94Median4.065-1.5884.821-2.2884.220-1.3953.417-2.732Maximum6.88-0.536.48-0.977.00-0.326.48-1.1922Majority1313101011111212Mean4.354-1.6774.515-2.6063.875-2.5123.380-2.981Standard deviation1.80651.45581.26110.80661.80281.75931.16410.6857Minimum1.60-4.021.57-3.760.60-6.281.85-3.96Median4.267-1.4794.483-2.4703.890-1.7062.989- 2.908Maximum 7.751.765.90-1.596.67-0.575.97-1.7030Number of shares 1313101010101212Average 3.866-2.1653.669-3.4523.776-2.5623.318-3.044Standard deviation 1.34250.96431.35551.12421.11861.24961.01640.5380Minimum 1.83-3.791. 15-5.652.02-4.631.54-3.79Median4.156-2.2263.517-3.2393.642-2.4013.088-2.992Maximum6.72-0.035.32-1.815.55-0.695.38-1.9854Number of weeks12129911111010Average4.134-2.0783.984-3.1294.067-2.3203.434-2.847 Standard Deviation 1.35 2 2 1.24 9 11.18 8 9 0.76 6 5 0.94 26 1.75 8 21.11 2 8 0.86 23 Minimum 1.92-3.67 1.55-4.68 2.24-4.34 1.13-3.91 Median 4.11 2-2.00 14.30 5-3.11 7 4.33 7-2.60 23.28 4-2.970 Maximum 6.50 0.38 5.47-2.00 5.45 0.91 4.87-1.16.

[0323]

[0324] EULAR response assessment

[0325] The proportion of patients with a good or moderate response on the EULAR (European League Against Rheumatism) response assessment, categorized based on DAS28 (C-reactive protein 28), was similar across treatment groups (Table 8). The EULAR response assessment, categorized based on DAS28 (ESR), was also similar across treatment groups (Table 9).

[0326]

[0327] Visit statistics IV 3 mg / kg (N=13) SC 90 mg (N=11) SC 120 mg (N=12) SC 180 mg (N=12) 2 Patients with a major response, number (%) 7 (53.8) 6 (54.5) 10 (83.3) 8 (66.7) - Moderate response 3 (23.1) 4 (36.4) 10 (83.3) 4 (33.3) - Good response 4 (30.8) 2 (18.2) 0 4 (33.3) 6 Patients with a major response, number (%) 9 (69.2) 9 (81.8) 10 (83.3) 10 (88.3) - Moderate response 4 (30.8) 8 (72.7) 5 (41.7) 6 (50.0) - Good response 5 (38.5) 1 (9.1) 5 (41.7) 4 (33.3)14 Patients with a major response, number (%)12 (92.3)9 (81.8)10 (83.3)11 (91.7)- Moderate response6 (46.2)7 (63.6)5 (41.7)2 (16.7)- Good response6 (46.2)2 (18.2)5 (41.7)9 (75.0)22 Patients with a major response, number (%)10 (76.9)10 (90.9)10 (83.3)11 (91.7)- Moderate response5 (38.5)8 (72.7)3 (25.0)4 (33.3)- Good response5 (38.5)2 (18.2)7 (58.3)7 (58.3)30 Patients with a major response, number (%)12 (92.3)10 (90.9)10 (83.3)12 (100.0)- Moderate response 5 (38.5)5 (45.5)5 (41.7)5 (41.7)- Good response 7 (53.8)5 (45.5)5 (41.7)7 (58.3)54 weeks Patients who responded, (%) 11 (84.6)8 (72.7)9 (75.0)9 (75.0)- Moderate response 7 (53.8)3 (27.3)6 (50.0)3 (25.0)- Good response 4 (30.8)5 (45.5)3 (25.0)6 (50.0)

[0328]

[0329] Visit statistics IV 3 mg / kg (N=13) SC 90 mg (N=11) SC 120 mg (N=12) SC 180 mg (N=12) 2 Patients with a major response, number (%) 6 (46.2) 5 (45.5) 7 (58.3) 9 (75.0) - Moderate response 4 (30.8) 3 (27.3) 7 (58.3) 9 (75.0) - Good response 2 (15.4) 2 (18.2) 0 0 6 Patients with a major response, number (%) 8 (61.5) 9 (81.8) 10 (83.3) 10 (83.3) - Moderate response 5 (38.5) 8 (72.7) 10 (83.3) 8 (66.7) - Good response 3 (23.1) 1 (9.1) 0 2 (16.7) 14 Patients with a major response, Patients with a major response (%)11 (84.6)8 (82.7)9 (75.0)11 (91.7)- Moderate response8 (61.5)7 (63.6)6 (50.0)6 (50.0)- Good response3 (23.1)1 (9.1)3 (25.0)5 (41.7)22 Patients with a major response (%)10 (76.9)10 (90.9)10 (83.3)12 (100.0)- Moderate response6 (46.2)9 (81.8)6 (50.0)6 (50.0)- Good response4 (30.8)1 (9.1)4 (33.3)6 (50.0)30 Patients with a major response (%)12 (92.3)10 (90.9)10 (83.3)12 (100.0)- Severe response 7 (53.8) 6 (54.5) 8 (66.7) 4 (33.3) - Good response 5 (38.5) 4 (36.4) 2 (16.7) 8 (66.7) 54 Patients with a major response, number (%) 11 (84.6) 9 (81.8) 9 (75.0) 9 (75.0) - Severe response 9 (69.2) 8 (72.7) 7 (58.3) 5 (41.7) - Good response 2 (15.4) 1 (9.1) 2 (16.7) 5 (41.7)

[0330]

[0331] Proportion of patients achieving clinical response according to ACR20

[0332] The proportion of patients meeting the clinical response criteria according to the American College of Rheumatology 20% improvement (ACR20) classification criteria from weeks 14 to 54 was similar between the IV cohort (cohort 1) and the SC cohorts (cohorts 2, 3, and 4) (Table 10).

[0333]

[0334] Parameters Visit Cohort 1 IV 3 mg / kg (N=13) Cohort 2 SC 90 mg (N=11) Cohort 3 SC 120 mg (N=12) Cohort 4 SC 180 mg (N=12) ACR202 Week 4 (30.8) 3 (27.3) 4 (33.3) 6 (50.0) 6 Week 8 (61.5) 8 (72.7) 7 (58.3) 7 (58.3) 14 Week 10 (76.9) 8 (72.7) 8 (66.7) 11 (91.7) 22 Week 8 (61.5) 8 (72.7) 9 (75.0) 11 (91.7) 30 Week 11 (84.6) 10 (90.9) 10 (83.3) 12 (100.0) 54 Week 9 (69.2)9 (81.8)8 (66.7)10 (83.3)

[0335]

[0336] Example 2. Modeling of subcutaneous administration of infliximab in patients with rheumatoid arthritis (RA).

[0337]

[0338] Building a PK-PD model

[0339] A pharmacokinetic-pharmacodynamic (PK-PD) model for subcutaneous (SC) infliximab was established to simulate the PK of future doses and regimens, as well as for integration with a quantitative PK model to simulate the SC efficacy and safety of infliximab. The PK-PD model was based on data from intravenous infliximab in healthy subjects, patients with ankylosing spondylitis (AS), patients with rheumatoid arthritis (RA), and Crohn's disease (CD), and data from subcutaneous infliximab in patients with CD, RA, and healthy volunteers (Clinicaltrials.gov identifiers NCT01220518, NCT01217086, NCT02096861).

[0340] The PK-PD model constructed based on the above data can be used to simulate the results of subcutaneous administration of infliximab to patients with the indicated indications (rheumatoid arthritis, ulcerative colitis, Crohn's disease, plaque psoriasis, psoriatic arthritis, or ankylosing spondylitis).

[0341] PK-PD modeling analyses were performed using a nonlinear mixed-effects modeling approach. Data analysis began with a one-compartment model with proportional elimination of the proportional error model, and the final model was a two-compartment model with linear elimination from the central compartment. All pharmacokinetic models were parameterized in terms of clearance (CL) and volume of distribution.

[0342] The final PK model was the area under the concentration-time curve (AUC) of each infliximab clinical trial. tau ; area under the concentration-time curve) and trough blood concentration (C trough; minimum concentration immediately before the next application) parameters were applied to each actual dose, regimen, and route of administration to predict the profile, and the data were descriptively summarized with median and 90% confidence intervals. In addition, additional simulations were performed to evaluate the effects by body weight for each fixed dose, regimen, and route of administration. PK-PD modeling and simulation of the subcutaneous dose were performed with NONMEM v7.2.

[0343]

[0344] Dosage and regimen scenarios for modeling subcutaneous (SC) formulations in patients with rheumatoid arthritis (RA).

[0345] Based on the simulation scenario below, the pharmacokinetic aspects were predicted, and based on this, the efficacy and safety were predicted and compared with the intravenous (IV) injection regimen of infliximab administered at a maintenance dose of 3 mg / kg every 8 weeks (Table 11).

[0346]

[0347] Infliximab 120mg subcutaneously (SC) every 2 weeksInfliximab 120mg subcutaneously (SC) every 4 weeksInfliximab 180mg subcutaneously (SC) every 4 weeks

[0348]

[0349] Estimates of infliximab exposure parameters for body weight-specific infliximab SC dosing regimens in patients with rheumatoid arthritis.

[0350] Exposure pharmacokinetic parameters (AUC) for infliximab SC dosing regimen τ , C trough and C max ) was simulated in 10 kg increments for the body weight range of 50-130 kg, and the lowest blood concentration (C) of infliximab SC exposure by body weight was trough), area under the concentration-time curve (AUC) τ ) estimates showed a correlation with drug dosage (Table 12).

[0351]

[0352] Comparison (a) NParameterC trough AUC τ C max Geometric LS meanRatio of Geometric LS means90% CI of Ratio (%)Geometric LS meanRatio of Geometric LS means90% CI of Ratio (%)Geometric LS meanRatio of Geometric LS means90% CI of Ratio (%)Test: 120 mg SC at 2 weekly intervals vs Reference (b)All weight1125SC13.410.139.53;10.78224921.371.33;1.4018.80.250.25;0.26IV1.316467.274.850-60 kg100SC16.111.679.23;14.7626855.21.691.54;1.8522.40.330.31;0.35IV1.415893.16860-70 kg100SC15.49.147.31;11.4325450.41.441.32;1.5821.10.290.27;0.31IV1.717660.973.370-80 kg100SC13.38.657.01;10.67221431.251.15;1.3518.40.240.22;0.25IV1.517751.177.680-90 kg100SC11.98.166.61;10.0720002.31.111.02;1.2016.70.210.19;0.22IV1.5180378190-100 kg100SC117.255.91;8.9018518.30.990.91;1.0715.50.180.17;0.20IV1.518754.684100-110 kg100SC10.36.855.53;8.4917386.50.90.82;0.9814.50.160.15;0.18IV1.519379.788.3110-120 kg100SC10.15.744.57;7.22168730.820.75;0.89140.160.15;0.17IV1.820696.589.8120-130 kg100SC104.783.99;5.7216620.20.750.70;0.8113.80.150.14;0.16IV2.122191.794.1Test: 120 mg SC at 4 weekly intervals vs Reference (b)All weight1125SC4.33.243.04-3.4611280.70.690.67-0.7011.60.150.15;0.16IV1.316467.274.850-60 kg100SC5.13.83.09;4.6813169.40.860.79;0.9213.40.20.19;0.21IV1.315378.966.360-70 kg100SC4.33.572.81;4.5411414.30.730.67;0.7911.70.170.16;0.18IV1.215670.870.570-80 kg100SC4.22.932.31;3.7210878.80.630.58;0.6911.10.150.14;0.16IV1.417260.675.880-90 kg100SC42.492.02;3.0710230.80.550.51;0.6010.40.130.12;0.14IV1.618448.980.690-100 kg100SC3.22.562.05;3.198676.40.50.46;0.5490.110.11;0.12IV1.217419.880.7100-110 kg100SC3.52.011.61;2.529106.10.450.41;0.499.20.10.10;0.11IV1.820263.688.3110-120 kg100SC3.51.741.38;2.1989060.410.38;0.458.90.10.09;0.11IV22163389.4120-130 kg100SC3.21.671.34;2.0782000.380.35;0.418.30.090.08;0.09IV1.921756.994.1Test: 180 mg SC at 4 weekly intervals vs Reference (b)All weight1125SC6.44.864.55-5.1816904.61.031.00-1.0517.30.230.23;0.24IV1.316467.274.850-60 kg100SC7.85.774.48;7.4420079.11.281.17;1.4120.40.310.29;0.32IV1.315688.466.760-70 kg100SC6.84.944.04;6.05176381.081.01;1.16180.310.29;0.32IV1.416310.172.170-80 kg100SC5.94.663.63;5.9915874.10.940.86;1.0316.30.220.20;0.23IV1.3168127680-90 kg100SC5.63.973.24;4.8714770.10.830.77;0.9015.20.190.18;0.20IV1.417720.680.590-100 kg100SC5.93.112.52;3.8414659.70.750.69;0.8114.70.180.17;0.19IV1.919596.180.4100-110 kg100SC5.23.042.37;3.9113442.90.670.61;0.7413.60.160.15;0.17IV1.719982.385.1110-120 kg100SC4.43.042.42;3.8311861.80.610.57;0.6612.20.140.13;0.15IV1.519353.487.9120-130 kg100SC4.72.582.05;3.2412121.80.570.52;0.6212.30.130.12;0.14IV1.821419.993.4Note: (a) All patients were treated at week 6. Before starting maintenance therapy (crossover of test and reference), 3 mg / kg infliximab was administered via intravenous infusion over 2 hours at weeks 0 and 2.(b)Reference treatment was 3 mg / kg infliximab administered intravenously over 2 hours at 8-week intervals (maintenance therapy). (c) The ratio of geometric least squares means (LS means) was calculated as ratio = test / reference. CI: Confidence Interval, LS: Least Square, SD: Standard Deviation.

[0353]

[0354] Example 3. Evaluation of safety and therapeutic efficacy of subcutaneous infliximab in patients with Crohn's disease (CD) or ulcerative colitis (UC).

[0355]

[0356] This infliximab clinical trial is an open-label, randomized, multicenter, parallel-group, phase 1 trial designed to evaluate the pharmacokinetics, efficacy, and safety of infliximab SC and infliximab IV in patients with active Crohn's disease or active ulcerative colitis for up to 54 weeks. The trial consists of two parts.

[0357] Part 1 was designed to determine the optimal dose of infliximab SC in patients with Crohn's disease (CD) and to evaluate the steady-state area under the concentration-time curve (AUC) between weeks 22 and 30. τ ) to determine the optimal dose of infliximab SC equivalent to 5 mg / kg infliximab IV over the first 30 weeks. For Part 1, the trial duration is up to 65 weeks, including screening (up to 3 weeks) through the end-of-trial visit.

[0358] Part 2 was designed to confirm that infliximab SC is non-pharmacokinetically inferior to infliximab IV in patients with Crohn's disease (CD) or ulcerative colitis (UC), with baseline concentrations (C) at week 22. trough) will be demonstrated. The optimal SC infliximab dose and dosing interval corresponding to 5 mg / kg IV infliximab in Part 2 were determined by the independent Data Safety Monitoring Board (DSMB) based on pharmacokinetic, efficacy, pharmacodynamic, and safety data over the first 30 weeks of Part 1.

[0359] ● Patients weighing less than 80 kg: Infliximab SC 120 mg administered every 2 weeks

[0360] ● Patients weighing 80 kg or more: Infliximab SC 240 mg administered every 2 weeks

[0361]

[0362] Part 1

[0363] Patients were eligible for enrollment in this clinical trial if they met all of the following criteria:

[0364] * If you have active disease with a Crohn's Disease Activity Index (CDAI) score of 220 to 450 points

[0365] * If you were diagnosed with Crohn's disease at least 3 months prior to the first day of administration of the test drug

[0366] * If you have been treated for active Crohn's disease but have not responded to the full appropriate course of corticosteroid and / or immunosuppressant therapy, or if you are intolerant to or have a medical contraindication to such therapy.

[0367] Patients were not eligible for enrollment in the clinical trial if they met any of the following criteria:

[0368] * If you have previously received biological agents for the treatment of Crohn's disease or ulcerative colitis and / or TNFα inhibitors for the treatment of other diseases.

[0369] * Patients with allergy to infliximab, any other murine and / or human protein excipients, or hypersensitivity to immune globulin products.

[0370] * Active enterovaginal, retroperitoneal, enterocutaneous, or enterovaginal fistula within 6 months prior to the first dose of the study drug (Day 0). In the opinion of the investigator, enterovaginal fistulas without clinically significant symptoms and anal fistulas without drainage problems are acceptable.

[0371] * If you have undergone small bowel resection more than 3 times before the first administration of the test drug (day 0)

[0372] This clinical trial consisted of three clinical trial periods: screening, dosing, and end-of-trial period. Screening was conducted between days -21 and -1 before the first dose of the study drug to assess the patients' eligibility for the study. All tests were performed, including tests for hepatitis B, hepatitis C, and human immunodeficiency virus (HIV-1, HIV-2) infection, urine and serum pregnancy tests for women of childbearing potential, colonoscopy, CRP, 12-lead ECG, and clinical laboratory tests. In addition, interferon-gamma release assay (IGRA) tests and chest X-rays were performed to rule out patients with tuberculosis.

[0373] At week 0, day 0, patients who met all inclusion criteria and did not meet any of the exclusion criteria were enrolled in the trial and all enrolled patients received IV infliximab in two single doses, at weeks 0 and 2. Patients had the option of receiving any of the following premedications, selected at the investigator's discretion, 30 to 60 minutes prior to the start of study drug administration to prevent hypersensitivity reactions to the study drug (e.g., antihistamine [2 to 4 mg chlorpheniramine equivalents], hydrocortisone, paracetamol, and / or non-sedating antihistamine [10 mg cetirizine equivalents]).

[0374] Patients who received two full doses and had no safety concerns at the investigator's discretion were randomly assigned to SC infliximab or IV infliximab prior to the 6-week, 42-day predose. Randomization was stratified by region (European or non-European), current use of azathioprine, 6-mercaptopurine, or methotrexate (MTX) therapy, clinical response at week 6 as assessed by the CDAI-70, and week 6 body weight (≤70 kg or >70 kg). A total of 45 patients with active Crohn's disease were enrolled, of whom 44 patients were randomly assigned 1:1:1:1 to four study cohorts and continued to receive study drug for up to week 54 (Table 13).

[0375]

[0376] Cohort number Dosage Clinical trial drug Administration method Number of patients Cohort 15 mg / kg Infliximab IV 100 mg / vial 2-hour IV infusion 13 Cohort 2 120 mg Infliximab SC 120 mg / PFS Single SC injection 11 Cohort 3 180 mg Infliximab SC 90 mg / PFS 2 SC injections 12 Cohort 4 240 mg Infliximab SC 120 mg / PFS 2 SC injections 8

[0377] PFS, prefilled syringe

[0378]

[0379] For patients assigned to Cohort 1, an additional 7 doses of IV infliximab will be administered at 6 weeks and then every 8 weeks (Weeks 14, 22, 30, 38, 46, and 54). For patients assigned to Cohorts 2, 3, and 4, the first SC infliximab dose will be administered at Week 6, and further SC infliximab doses will be administered every 2 weeks until Week 54. For all patients in Cohorts 2, 3, and 4, the initially assigned dose will be adjusted to the optimal dose after dose confirmation. Further SC injections using the optimal dose will be administered until Week 54. Infliximab SC will be injected by a healthcare provider at each study site visit (weeks 6, 8, 10, 14, 22, 24, 26, 28, 30, 38, 46, and 54). At all other weeks (weeks 12, 16, 18, 20, 32, 34, 36, 40, 42, 44, 48, 50, and 52), patients may self-inject infliximab SC if determined appropriate by the investigator after training in appropriate injection technique.

[0380] Patients will return to the study site at predefined intervals for clinical evaluation and blood sampling. At each visit, patients will be questioned about adverse events (AEs) and concomitant medications and monitored for clinical signs and symptoms of TB. The primary pharmacokinetic endpoint will be assessed during the maintenance phase between weeks 22 and 30, and secondary pharmacokinetic endpoints will be assessed throughout the treatment period up to week 54. Blood samples for analysis, efficacy, PD, and safety assessments will be collected and performed at time points specified in the assessment schedule.

[0381] The end-of-clinic visit will be conducted eight weeks after the end of the maintenance phase. However, if a patient discontinues the clinical trial prematurely, the visit will be conducted eight weeks after the last dose. For patients who drop out, all clinical trial procedures will be conducted on the day of dropout or the day after, and every effort will be made to complete all end-of-clinic assessments by eight weeks after the patient's last dose.

[0382]

[0383] Part 2

[0384] Part 2 will be initiated based on the Independent Data and Safety Monitoring Board's review of the PK modeling report data, which includes the first 30 weeks of PK, efficacy, PD, and safety data identified in Part 1.

[0385] Patients must meet all of the following criteria to be enrolled in Part 2 of this clinical trial:

[0386] patients with active Crohn's disease

[0387] * If you have active disease with a Crohn's Disease Activity Index (CDAI) score of 220 to 450 points

[0388] * If you were diagnosed with Crohn's disease at least 3 months prior to the first day of administration of the test drug

[0389] * If you have been treated for active Crohn's disease but have not responded to the full appropriate course of corticosteroid and / or immunosuppressant therapy, or if you are intolerant to or have a medical contraindication to such therapy.

[0390] * If one or more of the following items are satisfied:

[0391] - If the serum CRP (C-reactive protein) concentration exceeds 0.5 mg / dL

[0392] - If the fecal calprotectin concentration exceeds 100 μg / g

[0393] - In patients with ileo-colonic Crohn's disease, the colonoscopy examination (SES-CD) score is 6 or more, or in patients with ileo-colonic Crohn's disease, the score is 4 or more and there is an ulcer score in at least one area.

[0394] Patients with active ulcerative colitis

[0395] * If the total Mayo score is 6 to 12 points and the endoscopic examination score is 2 or higher, indicating active disease.

[0396] * If you have been diagnosed with ulcerative colitis at least 3 months prior to the first day of administration of the test drug

[0397] * If you have been treated for active ulcerative colitis but have not responded to, are intolerant to, or have medical contraindications to common treatment drugs such as corticosteroids and / or 6-mercaptopurine or azathioprine

[0398] Patients cannot be enrolled in Part 2 of the clinical trial if they meet any of the following criteria:

[0399] * If you have previously received biological agents for the treatment of Crohn's disease or ulcerative colitis and / or TNFα inhibitors for the treatment of other diseases.

[0400] * Patients with allergy to infliximab, any other murine and / or human protein excipients, or hypersensitivity to immune globulin products.

[0401] * Patients with Crohn's disease with active enterovaginal, retroperitoneal, enterocutaneous, or enterovaginal fistula within 6 months prior to the first dose of the study drug (Day 0). In the opinion of the investigator, enterovaginal fistulas without clinically significant symptoms and anal fistulas without drainage problems are permitted.

[0402] * Patients with Crohn's disease who underwent small bowel resection more than three times before the first administration of the test drug (day 0)

[0403] * Patients with ulcerative colitis who received corticosteroids or 5-aminosalicylic acid within 2 weeks prior to screening

[0404] Part 2 will consist of three clinical trial periods: screening, dosing, and the end of the trial. Screening will be conducted between days -42 and 0 before the first dose of study drug and will assess patients' eligibility for the study. All tests will be performed, including tests for hepatitis B, C, and human immunodeficiency virus (HIV-1, HIV-2) infection, urine and serum pregnancy tests for women of childbearing potential, colonoscopy (for Crohn's disease patients), proctosigmoidoscopy (for ulcerative colitis patients), C-reactive protein (CRP), 12-lead ECG, and clinical laboratory tests. In addition, interferon-gamma release assay (IGRA) tests and chest X-rays will be performed to rule out tuberculosis patients.

[0405] At week 0, day 0, patients who meet all inclusion criteria and do not meet any of the exclusion criteria will be enrolled in the trial and will receive IV infliximab in two single doses, at weeks 0 and 2. Patients may receive premedication, selected at the investigator's discretion, 30 to 60 minutes prior to the start of study drug administration to prevent hypersensitivity reactions to the study drug, including but not limited to: an antihistamine [2 to 4 mg chlorpheniramine equivalents], hydrocortisone, paracetamol, and / or a non-sedating antihistamine [10 mg cetirizine equivalents].

[0406] Patients who have received two full doses and have no safety concerns at the investigator's discretion will be randomly assigned to SC infliximab or IV infliximab prior to the 42-day, 6-week dosing regimen. Randomization will be stratified by current use of azathioprine, 6-mercaptopurine, or methotrexate (MTX), disease (Crohn's disease or ulcerative colitis), clinical response to Crohn's disease by CDAI-70 at week 6 or clinical response to ulcerative colitis by partial Mayo score at week 6, and body weight (<80 kg or ≥80 kg) at week 6. A minimum of 130 patients with active Crohn's disease or active ulcerative colitis will be randomly assigned 1:1 to the two study arms and will be treated with study drug for up to week 54 (Table 14).

[0407]

[0408] Group number Dosage Clinical trial drug Administration method Number of patients Group 1 5 mg / kg Infliximab IV 100 mg / vial 2-hour IV infusion Minimum 65 people Group 2 120 mg (<80 kg) Infliximab SC 120 mg / PFS Single SC injection Minimum 65 people Group 3 240 mg (≥80 kg) Infliximab SC 120 mg / PFS 2 SC injections

[0409] PFS, prefilled syringe

[0410]

[0411] For patients assigned to Arm 1, additional IV infliximab is administered at week 6 and every 8 weeks thereafter (weeks 14 and 22) through week 22, and then transitions to SC infliximab at week 30, at a SC dose determined based on body weight at week 30. This dose is administered every 2 weeks through week 54. For patients assigned to Arm 2, SC infliximab is administered at a SC dose determined based on body weight at week 6, at week 6 through week 54, every 2 weeks. Dose escalation is permitted after week 30 at the discretion of the investigator. SC infliximab is administered by a healthcare provider at each site visit (weeks 6, 14, 22, 24, 26, 28, 30, 38, 46, and 54). For all other weeks, patients may self-inject SC infliximab if determined appropriate by the investigator after training in appropriate injection technique.

[0412] The primary pharmacokinetic endpoint assessment will be conducted at week 22, and secondary pharmacokinetic endpoint assessments will be conducted during the maintenance phase between weeks 22 and 30 and throughout the treatment period up to week 54. Blood samples for analysis, efficacy, PD, and safety assessments will be collected and conducted at the time points specified in the assessment schedule.

[0413] The end-of-clinic visit will be conducted two weeks after the end of the maintenance phase. However, if the patient discontinues the clinical trial after receiving SC administration, the visit will be conducted two weeks after the last dose. If the patient discontinues the clinical trial after receiving IV administration, the visit will be conducted eight weeks after the last dose. For patients who drop out, all clinical trial procedures will be conducted on the day of dropout or the day after dropout. Every effort will be made to complete all end-of-clinic assessments at the designated time after the patient receives the last dose.

[0414] Part 2 clinical assessments, blood draws and clinical trial type visits are conducted in the same manner as Part 1 and are collected and performed at the times specified in the assessment schedule.

[0415]

[0416] conclusion

[0417] 3-1. Safety Assessment

[0418] Summary of adverse events

[0419] Safety was assessed as a secondary endpoint in Part 1 and included immunogenicity, hypersensitivity monitoring (including delayed hypersensitivity monitoring), vital signs (including blood pressure, heart rate, and respiratory rate, and body temperature), body weight, interferon-gamma release assay, chest X-ray, HIV-1, HIV-2, and hepatitis B virus infection status, physical examination findings, 12-lead ECG, adverse events (including serious adverse events), adverse events of special interest (infusion-related / hypersensitivity / anaphylactic reactions [drug-related reactions], delayed hypersensitivity reactions, injection site reactions, infections, and malignancies), signs and symptoms of tuberculosis, clinical laboratory analyses, pregnancy testing, previous and concomitant medications, and local pain using a 100-mm visual analogue scale (VAS).

[0420] Cumulative safety data from this study were included up to week 30, and an overall summary of treatment-emergent adverse events (AEs) during the maintenance phase (weeks 6 to 30) is presented in Table 15. Overall, 70 treatment-emergent AEs occurred in 28 (63.6%) patients, with 8 (61.5%) in the IV cohort (cohort 1) and 20 (64.5%) in the overall SC cohort (cohorts 2-4), showing similar rates in both groups. In addition, the severity of most treatment-emergent AEs was grade 1 or 2, and 9 (20.5%) of all treatment-emergent AEs were considered drug-related.

[0421] Treatment-related serious adverse events (SAEs) occurred in 8 (18.2%) patients: 2 (15.4%) in the IV cohort (cohort 1) and 6 (19.4%) in the overall SC cohort (cohorts 2-4). All SAEs were considered unrelated to the drug.

[0422] Among the treatment-related adverse events due to medication-related reactions, infusion-related reactions, hypersensitivity, or anaphylaxis were reported in 1 patient in the IV cohort (cohort 1) on the day of the 30-week dosing and in 1 patient in the SC cohort (cohort 4) 2 days after the 6-week dosing. Since infliximab medication-related reactions are related to anti-adhesive antibodies (ADAs) (Remsima SmPC 2017), patients who showed medication-related reactions were investigated for the presence of anti-adhesive antibodies (ADAs). Only 1 patient (IV cohort [cohort 1]) tested positive for anti-adhesive antibodies (ADAs) and neutralizing antibodies (NAbs) after receiving IV preparations at weeks 6 and 14 during the maintenance phase following the loading phase. The positive result was confirmed from week 22, and the medication-related reaction occurred at week 30.

[0423] Adverse events due to injection site reactions occurred in 4 (12.9%) patients in the SC cohort (cohorts 2-4), but all were Grade 1 or 2 in severity. Patients with injection site reactions were also evaluated for the presence of anti-drug antibodies (ADAs), and 2 of the 4 tested positive for ADAs and neutralizing antibodies (NAbs) during the trial.

[0424] Posttreatment adverse events due to infection occurred in 2 (15.4%) patients in the IV cohort (cohort 1) and 7 (22.6%) patients in the SC cohort (cohorts 2-4).

[0425] There were 1 (7.7%) patient in the IV cohort (Cohort 1) and 4 (12.9%) in the SC cohorts (Cohorts 2-4) who discontinued treatment due to adverse reactions after treatment. Of these, only 1 patient in Cohort 3 discontinued treatment due to an adverse reaction considered to be related to the drug, which was grade 1 latent tuberculosis.

[0426] There were two deaths reported during the clinical trial (one each in Cohort 1 and Cohort 3). In the IV cohort (Cohort 1), one patient died at home of sudden cardiac death approximately one month after completing Week 6 of dosing, but the death was reported to be unrelated to the drug. The patient had comorbidities of hypertension and chronic heart failure. In the SC cohort (Cohort 3), one patient died at home of sudden death the night after Week 30 of dosing, but the death was reported to be unrelated to the drug. The patient had comorbidities of chronic aortic calcification, diabetes, obesity, and metabolic syndrome.

[0427]

[0428] Cohort 1IV 5 mg / kg (N=13) Cohort 2SC 120 mg (N=11) Cohort 3SC 180 mg (N=12) Cohort 4SC 240 mg (N=8) SC Total (N=31) Number of patients experiencing at least 1 treatment-related adverse event (%)8 (61.5)8 (72.7)7 (58.3)5 (62.5)20 (64.5)Related4 (30.8)1 (9.1)1 (8.3)3 (37.5)5 (16.1)Unrelated6 (46.2)7 (63.6)7 (58.3)4 (50.0)18 (58.1) Number of patients experiencing at least 1 treatment-related serious adverse event (%)2 (15.4)2 (18.2)1 (8.3)3 (37.5)6 (19.4)Related00000Unrelated2 (15.4)2 (18.2)1 (8.3)3 (37.5)6 (19.4)Number of patients who experienced at least one treatment-related adverse event due to medication-related reactions (%)1 (7.7)001 (12.5)1 (3.2)Number of patients who experienced at least one treatment-related adverse event due to injection site reactions (%)01 (9.1)2 (16.7)1 (12.5)4 (12.9)Number of patients who experienced at least one treatment-related adverse event due to infection (%)2 (15.4)4 (36.4)1 (8.3)2 (25.0)7 (22.6)Related1 (7.7)01 (8.3)1 (12.5)2 (6.5)At least one treatment-related adverse event Number of patients who discontinued clinical trial drug administration among patients who experienced adverse events (%)1 (7.7)1 (9.1)2 (16.7)1 (12.5)4 (12.9)

[0429] * In each summary section, if more than one patient was reported, only the most severe case was counted. Cases were considered relevant only if the relationship was defined as "Possible," "Probable," or "Definite."

[0430]

[0431] Immunogenicity

[0432] In general, the proportion of patients positive for ADA was low in the SC cohort, and most patients were ADA-negative at week 30. The number of patients positive for ADA at week 30 was 8 (61.5%), 0 (0.0%), 3 (25.0%), and 1 (12.5%) in cohorts 1 to 4, respectively (Table 16).

[0433]

[0434] Visit Cohort 1IV 5 mg / kg (N=13) Cohort 2SC 120 mg (N=11) Cohort 3SC 180 mg (N=12) Cohort 4SC 240 mg (N=8) SC Total (N=31) 0 Weekly ADA Positive 0001 (12.5) 1 (3.2) NAb Positive 000006 Weekly ADA Positive 1 (7.7) 003 (37.5) 3 (9.7) NAb Positive 1 (7.7) 002 (25.0) 2 (6.5) 14 Weekly ADA Positive 4 (30.8) 01 (8.3) 2 (25.0) 3 (9.7) NAb Positive 2 (15.4) 01 (8.3) 1 (12.5) 2 (6.5) 22 Weekly ADA Positive 7 (53.8) 01 (8.3) 2 (25.0) 3 (9.7) NAb positive 5 (38.5) 01 (8.3) 2 (25.0) 3 (9.7) 30 weeks ADA positive 8 (61.5) 03 (25.0) 1 (12.5) 4 (12.9) NAb positive 4 (30.8) 01 (8.3) 1 (12.5) 2 (6.5) 6 weeks ADA positive at least once after medication * 7 (58.3)03 (25.0)03 (9.7)6 weeks after administration of NAb at least once * 5 (41.7)01 (8.3)01 (3.2)

[0435] Abbreviations: ADA, drug-resistant antibody; NAb, neutralizing antibody

[0436] * Percentage by visit was calculated using the number of randomly assigned patients as the denominator.

[0437] *Denominator: Number of patients who were ADA-negative at weeks 0 and 6; Numerator: Number of patients who were ADA- or NAb-positive at any time at weeks 14 and 30.

[0438]

[0439] Local pain assessment using a visual analog scale (VAS)

[0440] The visual analog scale (VAS) ranges from 0 to 100 mm, with higher scores indicating more severe pain. Cohorts 3 and 4, which required two injections per visit, reported slightly higher levels of localized pain than the other cohorts. Overall, low levels of localized pain were observed in all cohorts (mean ≤21.05 mm) (Table 17).

[0441]

[0442] Visit Statistics Cohort 1 IV 5 mg / kg (N=13) Cohort 2 SC 120 mg (N=11) Cohort 3 SC 180 mg (N=12) Cohort 4 SC 240 mg (N=8) Weeks 6 Number of Weeks 13 11 128 Mean (Standard Deviation) 16.32 (18.929) 8.43 (7.807) 21.87 (26.124) 19.31 (18.676) Median 77 11.85 11.5 Minimum, Maximum 0, 670, 250, 79.26, 63 14 Weeks 12 10 126 Mean (Standard Deviation) 6.38 (8.742) 5.60 (4.203) 11.93 (13.145) 18.75 (22.018)Median2.2566.658.5Minimum, maximum0, 280, 130, 393, 5922 Weeks1110117Mean (Standard Deviation)4.23 (5.574)10.10 (12.838)14.15 (13.828)12.07 (10.675)Median26910Minimum, maximum0, 150, 45.50, 403, 34.530 Weeks109115Mean (Standard Deviation)4.69 (6.872)9.08 (8.851)21.05 (21.887)12.60 (10.158)Median2.79128Minimum, maximum0, 23.50, 29.11, 713.5, 29

[0443]

[0444] 3-2. Evaluation of therapeutic efficacy

[0445] Disease activity measured by CDAI

[0446] Analysis of the Crohn's Disease Activity Index (CDAI) scores at weeks 2, 6, 14, 22, and 30 compared to baseline as a secondary efficacy endpoint revealed a trend toward a decrease in actual values ​​over time in each cohort. At week 6, one of the randomization stratification variables, the proportion of patients who responded to the CDAI-70 criteria was slightly higher in Cohort 2 than in the other cohorts, requiring caution in interpreting the efficacy results.

[0447] The actual values ​​and changes from baseline in disease activity as measured by the CDAI are summarized in Table 18.

[0448]

[0449] IV 5mg / kg (N=12) SC 120mg (N=11) SC 180mg (N=12) SC 240mg (N=7) Visit Statistics Actual Value Change from Baseline Actual Value Change from Baseline Actual Value Change from Baseline Actual Value Change from Baseline Actual Value Change from Baseline Change Baseline Number of people 1211127 Mean 310.13298.16302.38324.36 Standard deviation 73.35356.49073.63347.866 Minimum 221.8228.8229.1249.9 Median 279.35290.10266.75317.40 Maximum 433.5409.2422.5394.92 Weeks Number of people 12121111121277 Mean 243.01-67.13219.88-78.28266.96-35.43254.59-69.77 Standard deviation 97.7 5759.87599.37072.81152.40167.36990.91569.656Minimum48.8-173.0120.9-169.6175.0-163.4117.5-199.9Median227.05-57.10174.70-77.70269.75-39.25228.90-42.00Maximum394.172.0457.848.6357.886.0381.0-7.86Number of weeks12121111121277Average212.20-97.93172.58-1 25.58 216.43-85.96 220.34-104.01 Standard deviation 92.0 1998.599 105.719 115.90 970.50 782.38 879.04 161.204 Minimum 56.2-211.1 47.6-268.0 28.6-209.4 103.5-213.9 Median 230.65-145.40 149.20-141.70 240.20-88.25 215.30-88.40 Maximum 371.7 102.2 365.4 102.3 280.5 42.03 40.5-3 4.614 Weeks12121010121277 Average192.33-117.81138.86-156.55188.41-113.98216.24-108.11 Standard Deviation96.466103.05397.259128.87382.635109.633108.773105.399 Minimum5.0-259.049.0-360.227.0-328.354.8-252.4 Median203.55-101.9589.40-151.00206.10-101.70258.40-85.30Maximum 346.076.5334.661.3276.523.4355.817.622 Weekly number 11111010111177Average 145.25-168.58126.86-168.55155.41-136.05159.67-164.69Standard deviation 103.340107.22578.765109.10166.51290.717124.519117.773Minimum -1 1.8-369.6 35.6-312.2 23.6-314.0 22.6-293.2 Median 154.40-133.00 107.20-164.15 164.00-106.40 158.20-198.40 Maximum 348.1-32.3 304.24 1.12 52.9-0.23 17.27.3 30 weeks lifespan 101099111166 average 138.10-178.9283.37-215.63 121.38-170.08 136.12-191.07 standard deviation 109.844 105.11740.11262.24 170.64679.50 196.74987.759 minimum -16.0- 355.621.4-299.017.8-265.019.6-297.8Median125.40-156.9573.40-199.50125.80-178.40135.65-211.70Maximum397.4-36.1138.5-107.9274.121.0306.6-68.4.

[0450]

[0451] Response assessment according to CDAI-70 and CDAI-100 response criteria

[0452] Based on CDAI scores, the proportion of patients who responded to the CDAI-70 response criterion (patients with a decrease of 70 or more points in CDAI score from baseline) was similar across treatment groups (Table 19). The proportion of patients who responded to the CDAI-100 response criterion (patients with a decrease of 100 or more points in CDAI score from baseline) was also similar across treatment groups (Table 20).

[0453]

[0454] Visit statistics IV 5 mg / kg (N=12) SC 120 mg (N=11) SC 180 mg (N=12) SC 240 mg (N=7) 2 Patients with a major response, number (%) 5 (41.7) 7 (63.6) 3 (25.0) 3 (42.9) 6 Patients with a major response, number (%) 7 (58.3) 9 (81.8) 7 (58.3) 5 (71.4) 14 Patients with a major response, number (%) 8 (66.7) 8 (72.7) 8 (66.7) 4 (57.1) 22 Patients with a major response, number (%) 9 (75.0) 9 (81.8) 9 (75.0) 5 (71.4) 30 Patients with a major response, number (%) 8 (66.7) 9 (81.8) 10 (83.3) 5 (71.4)

[0455]

[0456] Visit statistics IV 5 mg / kg (N=12) SC 120 mg (N=11) SC 180 mg (N=12) SC 240 mg (N=7) 2 Patients with a major response, number of patients (%) 3 (25.0) 5 (45.5) 2 (16.7) 3 (42.9) 6 Patients with a major response, number of patients (%) 7 (58.3) 6 (54.5) 5 (41.7) 3 (42.9) 14 Patients with a major response, number of patients (%) 6 (50.0) 6 (54.5) 6 (50.0) 3 (42.9) 22 Patients with a major response, number of patients (%) 8 (66.7) 7 (63.6) 7 (58.3) 4 (57.1) 30 Patients with a major response, number of patients (%) 7 (58.3) 9 (81.8) 10 (83.3) 5 (71.4)

[0457]

[0458] Clinical remission evaluation

[0459] The proportion of patients achieving clinical remission (absolute CDAI score less than 150) was similar across treatment groups. A relatively high proportion of patients in Cohort 2 achieved clinical remission during the maintenance period (Weeks 6 to 30); however, 6 (54.5%) patients in Cohort 2 had already achieved clinical remission at Week 6, and most patients maintained clinical remission through Week 30 (Table 21).

[0460]

[0461] Visit statistics IV 5 mg / kg (N=12) SC 120 mg (N=11) SC 180 mg (N=12) SC 240 mg (N=7) 2 Weeks achieved, patients (%) 2 (16.7) 2 (18.2) 0 1 (14.3) 6 Weeks achieved, patients (%) 3 (25.0) 6 (54.5) 2 (16.7) 1 (14.3) 14 Weeks achieved, patients (%) 3 (25.0) 6 (54.5) 4 (33.3) 2 (28.6) 22 Weeks achieved, patients (%) 5 (41.7) 7 (63.6) 4 (33.3) 3 (42.9) 30 Weeks achieved, patients (%) 7 (58.3) 9 (81.8) 7 (58.3) 5 (71.4)

[0462]

[0463] Example 4. Modeling of subcutaneous administration of infliximab in patients with Crohn's disease (CD).

[0464]

[0465] Building a PK-PD model

[0466] It was performed in the same manner as Example 2.

[0467]

[0468] Dosage and regimen scenarios for modeling subcutaneous (SC) formulations in patients with Crohn's disease (CD).

[0469] Based on the simulation scenario below, the pharmacokinetic aspects were predicted, and based on this, the efficacy and safety were predicted and compared with the intravenous (IV) injection regimen of infliximab administered at a maintenance dose of 5 mg / kg every 8 weeks (Table 22).

[0470]

[0471] Infliximab 120 mg subcutaneously (SC) every 2 weeksInfliximab 180 mg subcutaneously (SC) every 2 weeksInfliximab 240 mg subcutaneously (SC) every 2 weeks

[0472]

[0473] Estimates of infliximab exposure parameters for body weight-specific infliximab SC dosing regimens in patients with Crohn's disease (CD)

[0474] The exposure pharmacokinetic parameters for the SC infliximab dose regimen were simulated in 10 kg increments for body weights of 50–130 kg, and the trough plasma concentration (C) of SC exposure was calculated. trough ), area under the concentration-time curve (AUC) τ ) estimates showed a correlation with drug dosage (Table 23).

[0475]

[0476] Comparison (a) NParameterC trough AUC τ C max Geometric LS meanRatio of Geometric LS means90% CI of Ratio (%)Geometric LS meanRatio of Geometric LS means90% CI of Ratio (%)Geometric LS meanRatio of Geometric LS means90% CI of Ratio (%)Test: 120 mg SC at 2 weekly intervals vs Reference (b)All weight265SC12.87.766.57;9.1621591.70.90.84;0.95180.180.17;0.18IV1.724093.4102.350-60 kg100SC15.88.146.39;10.3626409.11.050.96;1.1521.90.190.18;0.21IV1.925184.2112.460-70 kg100SC12.88.436.60;10.7521721.40.880.80;0.9618.20.150.14;0.16IV1.524685.5119.670-80 kg100SC12.36.685.26;8.4820668.20.760.70;0.8317.20.130.13;0.14IV1.827245.112980-90 kg100SC11.36.184.75;8.0319046.90.670.61;0.7415.90.120.11;0.13IV1.828287.6134.390-100 kg100SC11.24.933.82;6.3718698.20.60.55;0.6615.50.110.10;0.12IV2.330916.4139.7100-110 kg100SC10.34.643.59;5.9917331.10.540.49;0.6014.40.10.09;0.10IV2.231999.9149110-120 kg100SC9.94.173.20;5.4216654.40.50.45;0.5513.90.090.08;0.10IV2.433437.4152.6120-130 kg100SC94.433.33;5.9015388.50.460.41;0.5112.90.080.07;0.09IV233509.7161.9Test: 180 mg SC at 2 weekly intervals vs Reference (b)All weight265SC19.211.629.85;13.7232367.41.341.26;1.4326.90.260.25;0.28IV1.724093.4102.350-60 kg100SC23.712.199.57;15.5139576.41.571.44;1.7232.80.290.27;0.31IV1.925184.2112.460-70 kg100SC19.212.629.90;16.1132541.41.321.20;1.4527.20.230.21;0.24IV1.524685.5119.670-80 kg100SC18.410.017.88;12.72309811.141.05;1.2425.80.20.19;0.21IV1.827245.112980-90 kg100SC16.99.267.13;12.0428541.71.010.92;1.1123.80.180.16;0.19IV1.828287.6134.390-100 kg100SC16.77.395.72;9.5428000.40.910.82;0.9923.20.170.15;0.18IV2.330916.4139.7100-110 kg100SC15.46.955.38;8.98259590.810.74;0.8921.60.140.14;0.16IV2.231999.9149110-120 kg100SC14.96.254.80;8.1324932.80.750.68;0.8220.70.140.13;0.15IV2.433437.4152.6120-130 kg100SC13.56.644.98;8.84230250.690.62;0.7619.30.120.11;0.13IV233509.7161.9Test: 240 mg SC at 2 weekly intervals vs Reference (b)All weight265SC25.615.4913.12;18.2843143.11.791.68;1.9135.90.350.33;0.37IV1.724093.4102.350-60 kg100SC31.616.2312.75;20.6652743.52.091.91;2.2943.70.390.36;0.42IV1.925184.2112.460-70 kg100SC25.516.8113.18;21.4443361.11.761.60;1.9336.30.30.28;0.33IV1.524685.5119.670-80 kg100SC24.513.3410.50;16.9441293.81.521.39;1.6534.40.270.25;0.28IV1.827245.112980-90 kg100SC22.512.349.49;16.0438036.31.341.22;1.4831.70.240.22;0.25IV1.828287.6134.390-100 kg100SC22.39.857.62;12.72373021.211.10;1.32310.220.21;0.24IV2.330916.4139.7100-110 kg100SC20.69.267.17;11.9634586.71.080.98;1.1928.80.190.18;0.21IV2.231999.9149110-120 kg100SC19.88.336.40;10.8333210.90.990.90;1.1027.60.180.17;0.19IV2.433437.4152.6120-130 kg100SC18.08.846.64;11.7830661.10.910.83;1.0125.70.160.15;0.17IV233509.7161.9Note: (a) All patients received 5 mg / kg infliximab via intravenous infusion over 2 hours at weeks 0 and 2, prior to maintenance therapy (crossover of test and reference) starting at week 6.(b)Reference treatment was 5 mg / kg infliximab administered intravenously over 2 hours at 8-week intervals (maintenance therapy). (c) The ratio of geometric least squares means (LS means) was calculated as ratio = test / reference. CI: Confidence Interval, LS: Least Square, SD: Standard Deviation.

[0477]

Claims

1. A method for treating a TNFα-related disease, comprising administering to a patient a pharmaceutical composition comprising an anti-TNFα antibody or an antigen-binding fragment thereof. A method comprising administering to a patient subcutaneously an anti-TNFα antibody or an antigen-binding fragment thereof at a dose of 60 to 300 mg at intervals of 1 to 8 weeks.

2. In paragraph 1, A method wherein the TNFα-related disease is selected from the group consisting of rheumatoid arthritis, ulcerative colitis, Crohn's disease, plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis.

3. In paragraph 2, TNFα-related diseases include rheumatoid arthritis.

4. In paragraph 3, A method of administering to a patient an anti-TNFα antibody or antigen-binding fragment thereof in a dose of 90 to 180 mg.

5. In paragraph 2, A method wherein the TNFα-related disease is selected from the group consisting of ulcerative colitis, Crohn's disease, plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis.

6. In paragraph 5, A method comprising administering to a patient a dose of 120 to 240 mg of an anti-TNFα antibody or antigen-binding fragment thereof.

7. In paragraph 1, A method comprising administering to a patient a dose of 80 to 100 mg, 110 to 130 mg, 170 to 190 mg or 230 to 250 mg of an anti-TNFα antibody or antigen-binding fragment thereof.

8. In paragraph 7, A method comprising administering to a patient a dose of 90 mg, 120 mg, 180 mg or 240 mg of an anti-TNFα antibody or antigen-binding fragment thereof.

9. In paragraph 1, A method further comprising a step of determining the dosage according to the patient's weight, wherein the anti-TNFα antibody or antigen-binding fragment thereof is administered in a dosage of 90 to 180 mg when the patient's weight is less than 80 kg, and in a dosage of 190 to 270 mg when the patient's weight is 80 kg or more.

10. In paragraph 1, A method comprising administering an anti-TNFα antibody or an antigen-binding fragment thereof to a patient at intervals of 1, 2, 3, 4, 5, 6, 7 or 8 weeks.

11. In paragraph 10, A method of administering an anti-TNFα antibody or an antigen-binding fragment thereof to a patient at intervals of 2 or 4 weeks.

12. In paragraph 1, A method wherein an anti-TNFα antibody or an antigen-binding fragment thereof is administered in combination with a disease-modifying antirheumatic drug (DMARD).

13. In paragraph 12, A method wherein the disease-modifying antirheumatic drug (DMARD) is selected from the group consisting of methotrexate, leflunomide, sulfasalazine, and hydroxychloroquine.

14. In paragraph 1, A method wherein the patient has received intravenous administration of an anti-TNFα antibody or an antigen-binding fragment thereof at least once prior to subcutaneous administration.

15. In paragraph 14, A method wherein the patient is a patient who has been administered an anti-TNFα antibody or antigen-binding fragment thereof at a dose of 1 to 10 mg / kg per dose.

16. In paragraph 14, A method wherein the first subcutaneous administration is performed 2 to 8 weeks after the last intravenous administration.

17. In paragraph 1, After subcutaneous administration to patients, the trough blood concentration (C) of anti-TNFα antibody or its antigen-binding fragment trough ) is maintained at 3 to 16 μg / mL.

18. In paragraph 1, After subcutaneous administration to patients, the trough blood concentration (C) of anti-TNFα antibody or its antigen-binding fragment trough ) is maintained at 9 to 32 μg / mL.

19. In paragraph 1, After subcutaneous administration, the patient has one or more of the following characteristics: a) a decrease in DAS28 (Disease Activity Score in 28 joints) of at least 2.0; or b) CDAI (Crohn's disease activity index) decreases by at least 70.

20. In paragraph 1, Prior to subcutaneous administration, the patient had one or more of the following characteristics: a) Patients with an inadequate response to disease-modifying anti rheumatic drugs (DMARDs), including methotrexate; b) Patients who have not previously been treated with methotrexate or other DMARDs; c) Patients with severe inflammatory symptoms and elevated serum markers associated with inflammation who do not respond adequately to conventional treatment; or d) Patients who have not responded to, are contraindicated in, or are intolerant to systemic therapy, including methotrexate, cyclosporine, or psoralen ultraviolet A therapy (PUVA).

21. In paragraph 1, Prior to subcutaneous administration, the patient had one or more of the following characteristics: a) Patients who have not responded adequately to treatment with corticosteroids, 6-mercaptopurine, azathioprine, or immunosuppressants, are intolerant to them, or for whom these treatments are contraindicated; or b) Patients who do not respond to conventional treatment, including antibiotics, drainage methods, or immunosuppressive therapy.

22. In paragraph 1, Anti-TNFα antibody or antigen-binding fragment thereof, A light chain variable region comprising a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 1, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 2, and a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3; and A method comprising a heavy chain variable region comprising a CDR1 domain comprising an amino acid sequence of SEQ ID NO: 4, a CDR2 domain comprising an amino acid sequence of SEQ ID NO: 5, and a CDR3 domain comprising an amino acid sequence of SEQ ID NO:

6.

23. In paragraph 1, Anti-TNFα antibody or antigen-binding fragment thereof, A light chain variable region comprising the amino acid sequence of SEQ ID NO: 7; and A method comprising a heavy chain variable region comprising an amino acid sequence of sequence number 8.

24. In paragraph 1, Anti-TNFα antibody or antigen-binding fragment thereof, A light chain comprising the amino acid sequence of sequence number 9; and A method comprising a heavy chain comprising an amino acid sequence of sequence number 10.

25. In paragraph 1, The anti-TNFα antibody is infliximab, the method.

26. In paragraph 1, A method comprising a composition comprising an anti-TNFα antibody or an antigen-binding fragment thereof, comprising: (A) 90 to 180 mg / ml of an anti-TNFα antibody or an antigen-binding fragment thereof; (B) 0.02 to 0.1% (w / v) of polysorbate; (C) 1 to 10% (w / v) of sorbitol; and (D) 1 to 50 mM of a buffer comprising acetate.

27. In paragraph 1, A method wherein a composition comprising an anti-TNFα antibody or an antigen-binding fragment thereof is filled into a pre-filled syringe or an auto-injector and administered to a patient.

28. A pharmaceutical composition for treating a TNFα-related disease comprising an anti-TNFα antibody or an antigen-binding fragment thereof, A pharmaceutical composition for treating a TNFα-related disease, wherein an anti-TNFα antibody or an antigen-binding fragment thereof is administered subcutaneously at intervals of 1 to 8 weeks in a dose of 60 to 300 mg. 29.(a) a pharmaceutical composition comprising an anti-TNFα antibody or an antigen-binding fragment thereof; and (b) A kit comprising instructions directing subcutaneous administration of an anti-TNFα antibody or antigen-binding fragment thereof at a dose of 60 to 300 mg at intervals of 1 to 8 weeks for the treatment of a patient with a TNFα-related disease.

30. In the manufacture of a pharmaceutical composition for administering to a patient to treat a TNFα-related disease, use of an anti-TNFα antibody or an antigen-binding fragment thereof, For use in which anti-TNFα antibody or antigen-binding fragment thereof in a dose of 60 to 300 mg is administered subcutaneously at intervals of 1 to 8 weeks.

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