TWI870471B - Pharmaceutical composition for treating systemic sclerosis - Google Patents

Abstract

As a novel technology for treating patients with systemic sclerosis accompanied by progressive skin sclerosis, the present invention provides a pharmaceutical composition for treating systemic sclerosis accompanied by progressive skin sclerosis, which contains an IL-17 pathway inhibitor as an active ingredient. The IL-17 pathway inhibitor can be any one or more selected from IL-17RA antagonists and IL-23R antagonists, and in particular, can be any one or more antibodies or fragments thereof selected from the group consisting of Brodalumab, Sukinumab, Isibetamab, Netakimab, Bimekizumab, Utekinumab, Tiltaximab, Risankizumab, Mirikizumab, Brazikumab and Guselkumab.

Description

Pharmaceutical composition for treating systemic sclerosis

The present invention relates to a pharmaceutical composition for treating systemic sclerosis containing an IL-17 pathway inhibitor as an active ingredient. The present invention relates to a method for treating systemic sclerosis using an IL-17 pathway inhibitor.

Systemic sclerosis is a chronic progressive disease characterized by hardening of the skin or internal organs. There are two types of systemic sclerosis: diffuse sclerosis (dcSSc), in which the sclerosis extends to the extremities (upper arms, thighs) or trunk in addition to the face, and localized sclerosis (lcSSc), in which the sclerosis is limited to the distal extremities (forearms, calves) or face. In patients with diffuse sclerosis, sclerosis develops within 6 years of onset, and as the sclerosis progresses, organ lesions or joint contractures in the lungs, digestive tract, kidneys, and heart also progress. In addition, it is reported that 70% of severe dermatosclerosis occurs within 3 years of onset.

Systemic sclerosis is a progressive disease whose pathogenesis is still unclear. There is no treatment for sclerosis of the skin, and long-term treatment is required. Therefore, under normal circumstances, the main treatment is symptomatic treatment or the use of drugs to inhibit the progression of the disease. Furthermore, since the site (organ) of the lesion will vary depending on the degree of disease progression of each patient, the treatment method is also selected according to the symptoms of each patient. Representative treatments for each organ include: small amounts of oral adrenocortical steroids (for sclerosis), cyclophosphamide (for pulmonary fibrosis), proton pump inhibitors (for reflux esophagitis), prostaglandin derivatives (for vascular lesions), angiotensin converting enzyme inhibitors (for scleroderma renal crisis), and endothelin receptor antagonists (for pulmonary hypertension). For sclerosis, drug therapy using adrenocortical steroids or immunosuppressants is usually used, but since there are concerns about side effects caused by long-term administration in these drug therapies, new treatments are expected to be established.

Regarding systemic sclerosis, it has been suggested that skin fibrosis and disease progression may be related to Th17 cells and IL-17A produced by Th17 cells. The number of Th17 cells and IL-17A concentration in the blood of patients with systemic sclerosis are higher than those in healthy adults, and it is believed that this is significantly related to skin sclerosis (non-patent documents 1-4). In the bleomycin-induced systemic sclerosis mouse model, it was also confirmed that the increase in the number of Th17 cells and IL-17A concentration is related to inflammation and sclerosis of the skin and lungs (non-patent documents 5, 6). It is known that the expression of IL-17RA mRNA and protein in the lesioned skin of patients with systemic sclerosis increases (non-patent document 7).

Brodalumab is an IgG2 monoclonal antibody that binds to human IL-17RA and blocks the biological activity of IL-17A, IL-17F, IL-17A/F heterodimers, and IL-17E (IL-25) (non-patent literature 8-10). In Japan, Brodalumab is approved as a treatment for common psoriasis, articular psoriasis, pustules and erythrodermic psoriasis for which existing treatments are inadequate. Prior Art Literature Patent Literature

Patent document 1: International Publication No. 2008/054603 [Non-patent document]

Non-patent document 1: Arthritis Rheum, 2000, Vol. 43, pp. 2455-2463 Non-patent document 2: Eur Cytokine Netw, 2012, Vol. 23, pp. 128-139 Non-patent document 3: Arthritis Res Ther, 2013, Vol. 15, R151 Non-patent document 4: Arthritis Res Ther, 2014, Vol. 16, R4 Non-patent document 5: Clin Exp Rheumatol, 2016, Vol. 34, Suppl 100, pp. 14-22 Non-patent document 6: Arthritis Rheum, 2012, Vol. 64, pp. 3726-3735 Non-patent document 7: Human Immunology, 2015, Vol. 76, pp. 22-29 Non-patent reference 8: Immunity, 2008, Vol. 28, No. 4, pp. 454-467 Non-patent reference 9: J Allergy Clin Immunol, 2007, Vol. 120, No. 6, pp. 1324-1331 Non-patent reference 10: J Immunol, 2005, Vol. 175, No. 1, pp. 404-412

[The problem the invention is trying to solve]

The main purpose of the present invention is to provide a novel technology for treating systemic sclerosis which may be accompanied by progressive skin sclerosis. [Technical means for solving the problem]

To solve the above problems, the present invention provides the following [1] to [45]. [1] A pharmaceutical composition for treating systemic sclerosis, comprising an IL-17 pathway inhibitor as an active ingredient. [2] A pharmaceutical composition for treating systemic sclerosis associated with progressive skin sclerosis, comprising an IL-17 pathway inhibitor as an active ingredient. [3] The pharmaceutical composition of [1] or [2], wherein the IL-17 pathway inhibitor is selected from any one or more of an IL-17RA antagonist and an IL-23R antagonist. [4] The pharmaceutical composition of any one of [1] to [3], wherein the IL-17 pathway inhibitor is an antibody or an antibody fragment. [5] The pharmaceutical composition of [4], wherein the antibody is an anti-IL-17RA antibody, an anti-IL-17A antibody, an anti-IL-17A/F antibody, an anti-IL-23p40 subunit antibody and/or an anti-IL-23p19 subunit antibody, in particular, one or more selected from the group consisting of Brodalumab, Sukinumab, Isibetamab, Netakimab, Bimekizumab, Utekinumab, Tiltaximab, Risanzumab, Mirikizumab, Brazikumab and Guselkumab. [6] The pharmaceutical composition of [5], wherein the antibody is Brodalumab. [7] The pharmaceutical composition of any one of [1] to [6], wherein the systemic sclerosis is diffuse cutaneous sclerosis systemic sclerosis (dcSSc). [8] A pharmaceutical composition as described in any one of [1] to [7], which is used to reduce the patient's skin score (mRSS) by 3 or more before 12 weeks after the start of administration compared to before treatment. [9] A pharmaceutical composition as described in any one of [1] to [8], which is used to reduce the patient's skin score (mRSS) by 5 or more before 24 weeks after the start of administration compared to before treatment. [10] A pharmaceutical composition as described in any one of [1] to [9], which is used to reduce the patient's skin score (mRSS) by 7 or more before 52 weeks after the start of administration compared to before treatment. [11] A pharmaceutical composition as described in any one of [1] to [10], which is used for patients whose skin score (mRSS) before treatment is 20 or more and less than 30. [12] A pharmaceutical composition as described in any one of [1] to [11], wherein the single dose of the IL-17 pathway inhibitor is 70 mg, 140 mg, 210 mg, or 280 mg. [13] A pharmaceutical composition as described in any one of [1] to [12], wherein the single dose of the IL-17 pathway inhibitor is 210 mg, administered subcutaneously on day 1, 1 week later, 2 weeks later, and then once every 2 weeks. [14] A pharmaceutical composition as described in any one of [1] to [13], used in combination with a second therapeutic agent other than the IL-17 pathway inhibitor. [15] The pharmaceutical composition of [14], wherein the second therapeutic agent is at least one selected from the group consisting of adrenocortical steroids, antifibrotic drugs, immunosuppressants, proton pump inhibitors, prostate cyclin derivatives, angiotensin converting enzyme inhibitors, endothelin receptor antagonists and type II cannabinoid receptor antagonists. [16] A pharmaceutical composition for treating systemic sclerosis containing an IL-17 pathway inhibitor as an active ingredient, wherein the systemic sclerosis is diffuse cutaneous sclerosis (dcSSc), and the IL-17 pathway inhibitor is brodalumab, the single dose of which is 210 mg, administered subcutaneously on the first day, one week later, and two weeks later, and then once every two weeks.

[17] An IL-17 pathway inhibitor for use in treating systemic sclerosis. [18] An IL-17 pathway inhibitor for use in treating systemic sclerosis associated with progressive cutaneous sclerosis. [19] The IL-17 pathway inhibitor of [17] or [18], which is selected from any one or more of an IL-17RA antagonist and an IL-23R antagonist. [20] The IL-17 pathway inhibitor of any one of [17] to [19], which is an antibody or an antibody fragment. [21] The IL-17 pathway inhibitor of [20], which is an anti-IL-17RA antibody, an anti-IL-17A antibody, an anti-IL-17A/F, an anti-IL-23p40 subunit antibody and/or an anti-IL-23p19 subunit antibody or a fragment thereof, in particular, any one or more antibodies or fragments thereof selected from the group consisting of Brodalumab, Sukinumab, Isibetamab, Netakimab, Bimekizumab, Utekinumab, Tiltaximab, Risanzumab, Mirikizumab, Brazikumab and Guselkumab. [22] The IL-17 pathway inhibitor of [21], which is Brodalumab. [23] The IL-17 pathway inhibitor of any one of [17] to [22], wherein the systemic sclerosis is diffuse cutaneous sclerosis systemic sclerosis (dcSSc).

[24] A use of an IL-17 pathway inhibitor for the manufacture of a pharmaceutical composition for the treatment of systemic sclerosis. [25] A use of an IL-17 pathway inhibitor for the manufacture of a pharmaceutical composition for the treatment of systemic sclerosis associated with progressive skin sclerosis. [26] The use of [24] or [25], wherein the IL-17 pathway inhibitor is selected from any one or more of an IL-17RA antagonist and an IL-23R antagonist. [27] The use of any one of [24] to [26], wherein the IL-17 pathway inhibitor is an antibody or an antibody fragment. [28] The use as in [27], wherein the antibody is an anti-IL-17RA antibody, an anti-IL-17A antibody, an anti-IL-17A/F antibody, an anti-IL-23p40 subunit antibody and/or an anti-IL-23p19 subunit antibody, in particular, one or more selected from the group consisting of Brodalumab, Sukinumab, Isibetamab, Netakimab, Bimekizumab, Utekinumab, Tiltaximab, Risanzumab, Mirikizumab, Brazikumab and Guselkumab. [29] The use as in [28], wherein the antibody is Brodalumab. [30] The use as in any one of [24] to [29], wherein the systemic sclerosis is diffuse cutaneous sclerosis systemic sclerosis (dcSSc).

[31] A method for treating systemic sclerosis, comprising the following steps: administering to a subject a pharmaceutical composition containing an IL-17 pathway inhibitor as an active ingredient. [32] A method for treating systemic sclerosis associated with progressive skin sclerosis, comprising the following steps: administering to a subject a pharmaceutical composition containing an IL-17 pathway inhibitor as an active ingredient. [33] The treatment method of [31] or [32], wherein the IL-17 pathway inhibitor is selected from any one or more of an IL-17RA antagonist and an IL-23R antagonist. [34] The treatment method of any one of [31] to [33], wherein the IL-17 pathway inhibitor is an antibody or an antibody fragment. [35] The treatment method of [34], wherein the above-mentioned antibody is an anti-IL-17RA antibody, an anti-IL-17A antibody, an anti-IL-17A/F antibody, an anti-IL-23p40 subunit antibody and/or an anti-IL-23p19 subunit antibody or a fragment thereof, in particular, one or more selected from the group consisting of Brodalumab, Sukinumab, Isibetumab, Netakimab, Bimekizumab, Utekinumab, Tiltaximab, Risankizumab, Mirikizumab, Brazikumab and Guselkumab. [36] The treatment method of [35], wherein the above-mentioned antibody is Brodalumab. [37] The treatment method of any one of [31] to [36], wherein the systemic sclerosis is diffuse cutaneous sclerosis systemic sclerosis (dcSSc). [38] The treatment method of any one of [31] to [37], wherein the subject's mRSS score is reduced by 3 or more points 12 weeks after the start of treatment compared to before treatment. [39] The treatment method of any one of [31] to [38], wherein the subject's mRSS score is reduced by 5 or more points 24 weeks after the start of treatment compared to before treatment. [40] The treatment method of any one of [31] to [39], wherein the mRSS of the subject is reduced by 7 or more 52 weeks after the start of treatment compared to before treatment. [41] The treatment method of any one of [31] to [40], wherein the mRSS of the subject before treatment is 20 or more and less than 30. [42] The treatment method of any one of [31] to [41], wherein the single administration dose of the IL-17 pathway inhibitor is 70 mg, 140 mg, 210 mg, or 280 mg. [43] The treatment method of any one of [31] to [42], wherein the IL-17 pathway inhibitor is administered subcutaneously at a dose of 210 mg on day 1, 1 week later, and 2 weeks later, and then once every 2 weeks. [44] The treatment method of any one of [31] to [43], further comprising the following step: administering a second therapeutic agent other than the IL-17 pathway inhibitor. [45] The treatment method of [44], wherein the second therapeutic agent is selected from at least one of the group consisting of adrenocortical steroids, antifibrotic drugs, immunosuppressants, proton pump inhibitors, prostaglandin derivatives, angiotensin converting enzyme inhibitors, endothelin receptor antagonists and type II cannabinoid receptor antagonists. [Effect of the invention]

According to the present invention, a novel technology is provided for effectively treating systemic sclerosis which may be accompanied by progressive skin sclerosis.

The following describes a preferred embodiment of the present invention. The embodiments described below are representative embodiments of the present invention and are not intended to limit the scope of the present invention.

The present invention relates to a pharmaceutical composition for treating patients with systemic sclerosis accompanied by progressive skin sclerosis, which contains an IL-17 pathway inhibitor as an active ingredient.

Furthermore, the present invention also includes a method for treating patients with systemic sclerosis, comprising the following steps: administering an IL-17 pathway inhibitor to patients with systemic sclerosis accompanied by progressive skin sclerosis.

Systemic sclerosis is a chronic, progressive disease characterized by hardening of the skin or internal organs. There are two types of systemic sclerosis: diffuse sclerosis (dcSSc), in which the hardening of the skin extends to the extremities (upper arms, thighs) or trunk in addition to the face, and localized sclerosis (lcSSc), in which the hardening of the skin is limited to the distal extremities (forearms, lower legs) or face.

The systemic sclerosis targeted by the pharmaceutical composition or treatment method of the present invention is not limited to diffuse cutaneous sclerosis systemic sclerosis and localized cutaneous sclerosis systemic sclerosis, but diffuse cutaneous sclerosis systemic sclerosis is preferred.

The systemic sclerosis patient who is the subject of the pharmaceutical composition or treatment method of the present invention may also be a patient who, in addition to the symptoms of skin sclerosis, also has symptoms of organ lesions of the lungs, digestive tract, kidneys or heart, or symptoms of joint flexion and contraction.

The severity of skin sclerosis in systemic sclerosis can be evaluated using known methods. For example, the modified Rodnan total skin thickness score (mRSS) can be evaluated using the following method listed in the guidelines of the Japanese Dermatological Society. The body was divided into 17 parts (two fingers, two backs of hands, two forearms, two upper arms, face, front chest, abdomen, two thighs, two calves, two backs of feet), and the degree of hardening of the skin was evaluated on a 4-point scale of 0 to 3 for each part (0 = normal, 1 = mild, 2 = moderate, 3 = high, and the total score was 0 to 51. When evaluating, the skin was pinched with two thumbs to observe the thickness of the skin and the mobility of the subcutaneous tissue. The complete lack of skin and the mobility of the subcutaneous tissue were judged as 3, and the lack of skin and the mobility of the subcutaneous tissue were judged as 5. The case where the skin feels slightly thick even though there is no obvious hardening of the skin is judged as 1, and the case in between is judged as 2. Regarding the severity of hardening of the skin, in Japan, the total mRSS is classified as: 0 (normal: 0), 1-9 (mild: 1), 10-19 (moderate: 2), 20-29 (severe: 3), and 30 or more (very severe: 4) (Journal of the Dermatological Society of Japan, 126(10), 1831-1896, 2016). The mRSS measurement method is also disclosed in J Rheumatol, 1993; 20(11): pp. 1892-1896 and J Rheumatol, 1995; 22: pp. 1281-1285.

The severity of skin sclerosis targeted by the pharmaceutical composition or treatment method of the present invention is not particularly limited, but mRSS is preferably 10 or more, more preferably 20 or more, and most preferably 20 or more and less than 30. That is, the severity of skin sclerosis is preferably moderate or more, more preferably severe or more, and most preferably moderate to severe.

The pharmaceutical composition or treatment method of the present invention may also be used for patients with systemic sclerosis who have not been adequately treated with existing treatments. The pharmaceutical composition or treatment method of the present invention may also be used for patients with systemic sclerosis who have skin sclerosis and have not been adequately treated with existing treatments. The pharmaceutical composition or treatment method of the present invention may also be used for patients with systemic sclerosis who have moderate to severe skin sclerosis. The pharmaceutical composition or treatment method of the present invention may also be used for patients with systemic sclerosis who have skin sclerosis in the early stages of the disease. The so-called early stages of the disease refer to within 6 years after the onset of the disease. The pharmaceutical composition or treatment method of the present invention may also be used for patients with systemic sclerosis who have reversible skin sclerosis. The so-called reversible skin sclerosis refers to the condition of the skin showing swelling and hardening, but not reaching atrophy.

Improvement of skin sclerosis can be confirmed by known methods. For example, after administration of the pharmaceutical composition of the present invention, mRSS is measured over time to confirm that mRSS is reduced compared to before treatment, thereby confirming improvement of skin sclerosis.

The so-called improvement of the symptoms of skin sclerosis means that after a specific period of time has passed since the administration of the pharmaceutical composition or the start of the treatment method, the mRSS is reduced by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more than before the treatment. With respect to mRSS, after the administration of the pharmaceutical composition of the present invention or the start of the treatment method, the mRSS may be reduced by 2 or more before 8 weeks, by 3 or more before 12 weeks, by 3 or more before 16 weeks, by 4 or more before 20 weeks, by 5 or more before 24 weeks, by 6 or more before 40 weeks, and by 7 or more before 52 weeks.

In addition to improving or treating the symptoms of sclerosis, the pharmaceutical composition and treatment method of the present invention can also improve or treat at least one symptom selected from organ lesions of the lungs, digestive tract, kidneys or heart, or symptoms of joint flexion and contracture. In addition, the pharmaceutical composition and treatment method of the present invention can improve or treat various symptoms based on systemic or local fibrosis. The improvement of each symptom can be evaluated using known methods. For example, the improvement of lung function related to fibrosis in the lungs can be evaluated by scoring the lung function using a spirometer. The improvement of the symptoms of reflux esophagitis in the digestive tract can be evaluated by scoring the patient's symptoms using the FSSG (Frequency Scale for the Symptoms of GERD) specific questionnaire.

The term "administration" used in this specification refers to single administration or multiple administrations (hereinafter also described as "continuous administration").

The dosage of the IL-17 pathway inhibitor used in the present invention is not particularly limited. It can be used in a dosage that can be used in clinical applications by referring to the instructions of each inhibitor. Specifically, when the IL-17 pathway inhibitor is brodalumab, the dosage for a single dose is preferably 70 mg or more, more preferably 140 mg or more, and most preferably 210 mg. The dosage can also be appropriately increased or decreased during the continuous administration of the above-mentioned therapeutic agent. Typically, the dosage for a single dose is 70 mg, 140 mg, 210 mg, or 280 mg.

The administration interval of the pharmaceutical composition is not particularly limited, for example, it is administered on the 1st day (hereinafter also recorded as the 0th week), the 1st week and the 2nd week, and then administered once every 2 weeks or once every 4 weeks. The administration interval can be appropriately extended or shortened. The administration interval is preferably administered on the 1st day, the 1st week, the 2nd week, and then administered once every 2 weeks. The dosage and the administration interval are particularly preferably administered once at a single dosage of 210 mg, administered once on the 1st day, after 1 week, after 2 weeks, and then administered once every 2 weeks.

The administration period of the pharmaceutical composition is not particularly limited, and can be, for example, 8, 10, 12, 16, 20, 24, 36, 48, or 52 weeks after the start of administration, or can be longer than 52 weeks. The administration period is preferably longer than 52 weeks. A drug-free period may also be included in the administration period.

The IL-17 pathway inhibitors of the present invention include various substances that can block the interaction between IL-17RA and IL-17RA ligands (IL-17A, IL-17F, IL-17A/F, IL-17E, etc.) and block physiologically active signals. Hereinafter, substances that block the interaction between IL-17RA and IL-17RA ligands and block physiologically active signals are referred to as "IL-17RA antagonists." IL-23 is known to induce Th17 cells that produce IL-17RA ligands and is located upstream of the IL-17 pathway (Nature Reviews Drug Discovery 2015, Vol. 14, pp. 11-12). Therefore, the IL-17 pathway inhibitor of the present invention also includes substances that can block the interaction between IL-23 and IL-23R and block physiologically active signals. Hereinafter, substances that block the interaction between IL-23 and IL-23R and block physiologically active signals are referred to as "IL-23R antagonists". IL-17RA antagonists may be, for example, antagonists that have the activity of blocking the binding of IL-17RA to IL-17RA ligands, antagonists that have the activity of blocking the activation of IL-17RA initiated by the binding of IL-17RA ligands, or antagonists that have the activity of blocking the binding between IL-17RA and receptors that form heterodimers. The IL-23R antagonist may be, for example, an antagonist having the activity of inhibiting the binding of IL-23R and IL-23, or an antagonist having the activity of inhibiting the binding of p19 and p40, which are subunits of IL-23.

IL-17RA antagonists and IL-23R antagonists may be, for example, low molecular weight drugs, antibodies or antibody fragments, siRNA, and antisense oligonucleotides. IL-17RA antagonists and IL-23R antagonists are preferably antibodies or antibody fragments.

Specific examples of antibodies that are IL-17RA antagonists include anti-IL-17RA antibodies, anti-IL-17A antibodies, anti-IL-17F antibodies, anti-IL-17A/F antibodies, anti-IL-17E antibodies, and fragments thereof.

As a low molecular weight IL-17RA antagonist, specific examples thereof include: dihydroorotate dehydrogenase inhibitor. As a dihydroorotate dehydrogenase inhibitor, specific examples thereof include: Vidofludimus.

Specific examples of antibodies that are IL-23R antagonists include anti-IL-23p40 subunit antibodies and anti-IL-23p19 subunit antibodies.

Specific examples of anti-IL-23p40 subunit antibodies include Utekinumab. Specific examples of anti-IL-23p19 subunit antibodies include Tiltaxizumab, Risankizumab, Mirikizumab, Brazikumab, and Guselkumab.

The IL-17 pathway inhibitor is preferably an IL-17RA antagonist and an IL-23R antagonist, and more preferably an IL-17RA antagonist. The IL-17RA antagonist is preferably brodalumab as an anti-IL-17RA antibody, netakimab, sukinumab or isixitumab as an anti-IL-17A antibody, and bimekizumab as an anti-IL-17A/F antibody, and the most preferred is brodalumab.

The pharmaceutical composition or treatment method of the present invention can be used in combination with a second treatment agent or a second treatment method. The second treatment agent is, for example, an adrenal cortical steroid, an antifibrotic drug, an immunosuppressant, a proton pump inhibitor, an angiotensin converting enzyme inhibitor, an endothelin receptor antagonist prostaglandin derivative, or a type II cannabinoid receptor antagonist. As an adrenal cortical steroid, for example, prednisolone can be listed. As an antifibrotic drug, for example, pirfenidone and nintedanib can be listed. As immunosuppressants, for example, cyclophosphamide, mycophenolate mofetil, cyclosporine, tacrolimus, azathioprine, imidazolipide, and methotrexate can be listed. As proton pump inhibitors, for example, omeprazole, lansoprazole, rabeprazole, and esomeprazole can be listed. As angiotensin-converting enzyme inhibitors, for example, captopril, enalapril, alacepril, imidapril, and temocapril can be listed. As endothelin receptor antagonists, for example, bosentan, ambrisentan, and macitentan can be listed. As prostaglandin derivatives, for example, iloprost, belastat, treprostinil, epoprostenol, or clinprost can be listed. As a type II cannabinoid receptor antagonist, for example, Lenabasum can be cited. As a second treatment method, for example, a large amount of intravenous immunoglobulin therapy (IVIG) or light therapy can be cited. In the pharmaceutical composition or treatment method of the present invention, IL-17 pathway inhibitors can also be used in combination of two or more. In the pharmaceutical composition and treatment method of the present invention, when an IL-17 pathway inhibitor and a second treatment agent are used, they can be administered to the patient simultaneously or at different times. Therefore, the pharmaceutical composition or treatment method of the present invention also includes the mode of using it in combination with a second treatment agent.

The antibody used in the present invention may be a monoclonal antibody or a polyclonal antibody, and is preferably a monoclonal antibody that binds to a single epitope.

The antibody may be a monoclonal antibody produced by a fusion tumor, or may be a recombinant antibody produced by gene recombination technology. Examples of recombinant antibodies include: mouse antibodies, rat antibodies, human chimeric antibodies (hereinafter referred to as "chimeric antibodies"), humanized antibodies (also known as human complementarity determining region (CDR) transplanted antibodies), and human antibodies. For humans, in order to reduce immunogenicity, it is preferred to use chimeric antibodies, humanized antibodies, or human antibodies.

Specifically, the monoclonal antibody used in the present invention can be selected from the following antibodies (A) to (F) and the antibody fragments. (A) CDR1, CDR2, and CDR3 of the heavy chain variable region (denoted as VH) of the antibody respectively comprise the amino acid sequences shown in sequence numbers 1, 2, and 3, and CDR1, CDR2, and CDR3 of the light chain variable region (denoted as VL) of the antibody respectively comprise the amino acid sequences shown in sequence numbers 4, 5, and 6; (B) VH of the antibody comprises the amino acid sequence shown in sequence number 7, and VL of the antibody comprises the amino acid sequence shown in sequence number 8; (C) The heavy chain (H chain) of the antibody comprises the amino acid sequence shown in sequence number 9. sequence, and the L chain of the antibody comprises a monoclonal antibody of the amino acid sequence shown in sequence number 10; (D) an antibody that competes with any of the antibodies selected from (A) to (C) above and binds to IL-17RA; (E) an antibody that binds to an epitope present in IL-17RA, and the IL-17RA binds to any of the antibodies selected from (A) to (C) above; and (F) an antibody that has a sequence identity of more than 90% with the amino acid sequence of any of the antibodies selected from (A) to (C) above, and has the same binding specificity and binding activity as the antibody.

In the present invention, regarding a monoclonal antibody in which CDR1, CDR2, and CDR3 of VH of the antibody comprise the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and CDR1, CDR2, and CDR3 of VL of the antibody comprise the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively, or a monoclonal antibody in which VH of the antibody comprises the amino acid sequence of SEQ ID NO: 7, and VL of the antibody comprises the amino acid sequence of SEQ ID NO: 8, one embodiment of which is the anti-human IL-17RA human monoclonal antibody _AMH14 / _AML14 (Patent Document 1) and the recombinant anti-human IL-17RA human antibody brodalumab.

In the present invention, the so-called "monoclonal antibody" refers to an antibody secreted by monoclonal antibody-forming cells, which recognizes only one epitope (antigenic determinant) and has a relatively uniform amino acid sequence (primary structure) constituting the monoclonal antibody.

The so-called "epitope" refers to a single amino acid sequence recognized by a monoclonal antibody for binding; a stereostructure containing an amino acid sequence; an amino acid sequence bound to a modified residue such as a sugar chain, glycolipid, polysaccharide lipid, amine, carboxyl, phosphate and sulfate; and a stereostructure containing an amino acid sequence bound to the modified residue. The so-called "stereostructure" refers to the stereostructure of naturally occurring proteins, and refers to the stereostructure formed by proteins expressed in cells or on cell membranes.

In the present invention, antibody molecules are also referred to as immunoglobulins (hereinafter referred to as Ig). Based on the differences between molecular structures, human antibodies are classified into the following isotypes: IgA1, IgA2, IgD, IgE, IgG1, IgG2, IgG3, IgG4, and IgM. IgG1, IgG2, IgG3, and IgG4, which have relatively high homology of amino acid sequences, are also collectively referred to as IgG. As the antibody type used in the present invention, the IgG type is preferred, and the IgG type selected from IgG1, IgG2, IgG4, and Fc variants in which one or more amino acid residues in the Fc region of the isotype antibody are replaced is more preferred.

In the present invention, the antibody molecule comprises polypeptides called heavy chain (H chain) and light chain (L chain).

Furthermore, the H chain includes VH and an H chain constant region (also referred to as CH) from the N-terminal side, and the L chain includes VL and an L chain constant region (also referred to as CL) from the N-terminal side.

The so-called "chimeric antibody" refers to an antibody that contains VH and VL of an antibody derived from an animal other than human, and CH and CL of a human antibody. There is no particular limitation on the type of animal from which the variable region is derived, as long as it is an animal that can be used to produce a fusion tumor, such as mouse, rat, hamster, rabbit, etc.

The so-called "humanized antibody" refers to an antibody obtained by transplanting the CDRs of VH and VL derived from non-human animal antibodies to the appropriate positions of VH and VL of human antibodies (human CDR-grafted antibodies).

The so-called "human antibodies" refer to antibodies that exist naturally in the human body or antibodies that contain amino acid sequences encoded by human genes. Human antibodies also include antibodies produced based on methods of genetic engineering, cell engineering, and developmental engineering, obtained from human antibody phage libraries or transgenic animals that produce human antibodies.

In the present invention, the type of antibody fragment is not particularly limited, and examples thereof include: Fab, Fab', F(ab') ₂ , scFv, diabody, dsFv, peptide containing CDR, and the like.

The pharmaceutical composition of the present invention may contain only the IL-17 pathway inhibitor as an active ingredient. Generally, it is preferably provided in the form of a pharmaceutical preparation mixed with one or more pharmacologically acceptable carriers and produced by any method known in the art of pharmaceutical preparation. Specific examples of pharmaceutical preparations include: pharmaceutical preparations containing 140 mg/mL of the recombinant anti-human IL-17RA human antibody brodalumab as an active ingredient, and prepared using 10 mmol/L of L-glutamine, 3% (w/v) of L-proline, and 0.010% (w/v) of polysorbate 20 as additives. In addition, the pharmaceutical preparation also includes: a pharmaceutical preparation with a pH value of 4.8, comprising 140 mg/mL of the recombinant anti-human IL-17RA human antibody brodalumab, and further comprising 30 mmol/L of L-glutamine, 2.4% (w/v) of L-proline, and 0.01% (w/v) of polysorbate 20 as additives. The pharmaceutical preparation can be produced, for example, by the method described in International Publication No. 2011/088120.

The administration route of the IL-17 pathway inhibitor in the pharmaceutical composition or treatment method of the present invention is preferably the most effective route when the treatment is performed. Specific examples of the administration route include: oral administration, or non-oral administration such as oral, intratracheal, intrarectal, subcutaneous, intramuscular or intravenous administration, preferably subcutaneous or intravenous administration, and more preferably subcutaneous administration. Examples of administration forms include: sprays, capsules, tablets, powders, granules, syrups, emulsions, suppositories, injections, ointments, patches, etc., and injections are preferred.

The administration device of the therapeutic agent of the present invention can be appropriately selected during the treatment. Examples of administration devices include prefilled syringes and automatic syringes, but are not limited thereto. Examples

[Trial Example 1: Phase I clinical trial of recombinant anti-human IL-17RA human antibody brodalumab in systemic sclerosis patients] (1) Trial overview The overview of a phase I clinical trial of recombinant anti-human IL-17RA human antibody brodalumab in systemic sclerosis patients with moderate to severe skin sclerosis (hereinafter referred to as the "clinical trial") is shown in Table 1. Systemic sclerosis patients who met the conditions shown in Table 2 were selected as subjects for the clinical trial, and the safety and efficacy of brodalumab were evaluated. Each subject was subcutaneously administered 210 mg of brodalumab on day 1, week 1, and week 2, and then every 2 weeks until week 50.

Brodalumab was prepared according to conventional practice in the form of a recombinant human antibody derived from CHO (Chinese hamsters ovary) cells having the variable region amino acid sequence of the antibody described in Patent Document 1.

[Table 1] Adaptation, design Dosage, duration Number of registered subjects Indication: Systemic sclerosis Design: Open-label trial, uncontrolled study Dosage: 210 mg Evaluation period: 52 weeks 8 people

[Table 2] Clinical trial eligibility age: 18 years old and above Clinical trial eligibility gender: Male/Female Acceptance of healthy volunteers: None Benchmark 1) Admission Criteria 1) Patients who have obtained written consent to participate in this clinical trial voluntarily (if the patient is under 20 years old at the time of obtaining consent, written consent must be obtained from an authorized representative) 2) Patients aged 18 to 70 years old at the time of consent 3) Patients who meet the diagnostic criteria, severity classification, and treatment guidelines for systemic sclerosis during pre-examination 4) Patients who have developed symptoms of sclerosis other than Raynaud's syndrome within 60 months of the time of registration 5) Patients with moderate to severe skin sclerosis with progressive skin sclerosis and mRSS of 10 or more and less than 30 at the time of the pre-examination and this registration (patients who meet any of the following criteria): ・Patients newly diagnosed with diffuse skin sclerosis type systemic sclerosis within 1 year ・Patients whose mRSS at the time of the pre-examination increased by 3 or more compared to the most recent examination 1 to 6 months before the pre-examination ・Patients whose mRSS at the time of the pre-examination increased by at least 2 and had 1 new lesion site compared to the most recent examination 1 to 6 months before the pre-examination ・Patients whose mRSS at the time of the pre-examination increased by at least 1 and had 2 new lesions site compared to the most recent examination 1 to 6 months before the pre-examination 2) Exclusion criteria 1) Patients with any of the following complications ・Type 1 diabetes ・Poorly controlled type 2 diabetes (HbAlc over 8.5%) ・Depressive heart failure (New York Heart Association functional score II to IV) ・Patients with symptoms of myocardial infarction, unstable angina, or stroke within 12 months before the first administration of the clinical trial drug ・Poorly controlled hypertension (systolic blood pressure over 150 mmHg or diastolic blood pressure over 90 mmHg during pre-examination) ・Severe chronic lung disease (%FVC less than 60%, %DLco less than 40% (calculated based on the "New Standard Value of Japanese Vital Measurement Using the LMS Method (Japan Respiratory Society)")) ・Major chronic inflammatory diseases or connective tissue diseases other than sclerosis 2) Patients with a history or current illness of mental illness, alcohol and/or drug abuse, or other mental illness who, in the judgment of the investigator or co-investigator, may endanger the safety of the subjects or may interfere with the evaluation, procedures, or completion of the clinical trial. 3) Patients who, at the time of this registration, are identified in the C-SSRS assessment as having had suicidal thoughts (severity level 4 or 5) or some suicidal behaviors in the past or currently 4) Patients with severe depression who have a PHQ-8 score of 15 or above at the time of this registration (if the PHQ-8 score is 10-14, a psychiatric specialist should be consulted)

(2) Trial results For the subjects participating in the clinical trial, the skin rating score (mRSS) indicating the degree of skin hardening was measured over time from the first administration of brodalumab. The results obtained are shown in Figures 1 and 2. Regarding mRSS, doctors used their thumbs to pinch the skin of 17 parts of the body and evaluated the degree of skin hardening of each part on a 4-point scale of 0 to 3 (0 = normal, 1 = mild, 2 = moderate, 3 = severe, total 0 to 51 points). The mRSS skin severity is classified as 0 = normal, 1 to 9 = mild, 10 to 19 = moderate, 20 to 29 = severe, and 30 or above = very severe.

The information of the subjects participating in the clinical trial is shown in Table 3. As shown in the table, among 8 systemic sclerosis patients with moderate to severe skin sclerosis, 7 had severe (mRSS: 20-29) skin sclerosis.

[Table 3] Patient ID mRSS at the start of treatment Illness duration (months) gender Age Disease Type 4827-007-01 20 4 female 47 dc 4827-007-03 29 10 female 60 dc 4827-007-04 25 27 female 64 dc 4827-007-05 29 12 male 47 dc 4827-007-06 20 59 female 47 dc 4827-007-08 26 56 female 35 dc 4827-007-09 twenty two 5 female 55 dc 4827-007-10 14 35 female 55 dc

As shown in Figure 1, the mRSS of 8 systemic sclerosis patients with moderate to severe skin sclerosis decreased by more than 3 from the baseline (mRSS at the start of treatment) at 12 weeks after the start of administration. Similarly, at 24 weeks after the start of administration, the mRSS decreased by more than 5 from the baseline, and at 52 weeks after the start of administration, the mRSS decreased by more than 7 from the baseline. It can be seen that for systemic sclerosis patients with moderate to severe skin sclerosis, by using brodalumab treatment, a significant reduction in skin scores can be obtained at the earlier stage of 12 weeks, 24 weeks or 52 weeks after the start of treatment.

Previous treatment with adrenocortical steroids (dexamethasone intravenous pulse therapy) for cutaneous sclerosis in systemic sclerosis required 6 months to achieve a mean mRSS decrease of 4.5 from baseline (Rhcumatol lnt, 1994, 14, 91-94). In addition, it was reported that even in the treatment with cyclophosphamide as an immunosuppressant, the reduction of mRSS from the baseline stopped at 3.6 12 months after the start of treatment (N Engl J Med, 2006, 354, 2655-66). Similarly, in the treatment with azathioprine as an immunosuppressant, no improvement of skin sclerosis was observed even 18 months after the start of treatment (C in Rhcumatol, 2006, 25, 205-212). On the other hand, in the treatment with brodalumab, all systemic sclerosis patients with moderate to severe skin sclerosis, including 7 patients with severe skin sclerosis, achieved a significant reduction in mRSS at 12 weeks, 24 weeks, or 52 weeks after the start of treatment. The results indicate that brodalumab is suitable for systemic sclerosis with moderate to severe skin sclerosis, and can exert a therapeutic effect at a very early stage compared with previous drugs. [Sequence Listing Non-Keywords]

Sequence number 1: Brodatumab_HCDR1 amino acid sequence Sequence number 2: Brodatumab_HCDR2 amino acid sequence Sequence number 3: Brodatumab_HCDR3 amino acid sequence Sequence number 4: Brodatumab_LCDR1 amino acid sequence Sequence number 5: Brodatumab_LCDR2 amino acid sequence Sequence number 6: Brodatumab_LCDR3 amino acid sequence Sequence number 7: Brodatumab_VH amino acid sequence Sequence number 8: Brodatumab_VL amino acid sequence Sequence number 9: Brodatumab_H chain amino acid sequence Sequence number 10: Brodatumab_L chain amino acid sequence

Figure 1 is a curve chart showing the changes in the skin score (mRSS: modified Rodnan total skin thickness score) of each patient after the start of treatment. The vertical axis represents mRSS (0 at the start of treatment). The horizontal axis represents the time (weeks) since the first administration of brodalumab. Figure 2 is a curve chart showing the average value of the changes in mRSS of each patient after the start of treatment. The vertical axis represents mRSS (0 at the start of treatment). The horizontal axis represents the time (weeks) since the first administration of brodalumab.

Claims (7)

A use of brodalumab, which is used to prepare a pharmaceutical composition for treating systemic sclerosis, wherein the pharmaceutical composition for treating systemic sclerosis reduces the patient's skin score (mRSS) by more than 3 points 12 weeks after the start of administration compared to before treatment, and contains brodalumab as an active ingredient. In the pharmaceutical composition, the single dose of brodalumab is 210 mg, and it is subcutaneously administered on the first day, one week later, and two weeks later, and then subcutaneously administered once every two weeks. For use as claimed in claim 1, wherein the systemic sclerosis is diffuse cutaneous sclerosis systemic sclerosis (dcSSc). For use as claimed in claim 1 or 2, the pharmaceutical composition reduces the patient's skin score (mRSS) by more than 5 points 24 weeks after the start of administration compared to before treatment. For use as claimed in claim 1 or 2, the pharmaceutical composition reduces the patient's skin score (mRSS) by more than 7 points before treatment 52 weeks after the start of administration. For use as claimed in claim 1 or 2, the pharmaceutical composition is used for patients whose skin score (mRSS) before treatment is greater than 20 and less than 30. For use as claimed in claim 1 or 2, the above-mentioned pharmaceutical composition is used in combination with a second therapeutic agent other than brodalumab. For use as claimed in claim 6, the second therapeutic agent is at least one selected from the group consisting of adrenocortical steroids, antifibrotic drugs, immunosuppressants, proton pump inhibitors, prostate cyclin derivatives, angiotensin converting enzyme inhibitors, endothelin receptor antagonists and type II cannabinoid receptor antagonists.