AQUEOUS PHARMACEUTICAL COMPOSITION OF AN ANTI-IL17A ANTIBODY AND USE THEREOF

Abstract

The present disclosure relates to aqueous compositions for anti-IL17a antibodies, and more particularly to aqueous compositions for anti-IL17a antibodies with a V.sub.HH variable domain and a V.sub.L variable domain, and can be used as a medicinal agent for treating IL-17A-mediated diseases.

Claims

1. An aqueous pharmaceutical composition suitable for parenteral administration to a subject for inhibiting IL17a protein activity comprising: a pharmaceutically effective amount of an anti-IL17a antibody comprising a VHH-derivative domain and a variable VL domain; a histidine-based buffering agent; and an effective amount of a sugar-based alcohol as an osmotic agent.

2. The aqueous pharmaceutical composition as defined in claim 1, wherein said VHH-derivative domain of said anti-IL17a antibody comprises 3 hypervariable regions HCDR1, HCDR2 and HCDR3, wherein: HCDR1 comprises the amino acid sequence of SEQ ID NO: 1; HCDR2 comprises the amino acid sequence of SEQ ID NO: 2; HCDR3 comprises the amino acid sequence of SEQ ID NO: 3; and wherein the variable VL domain of said anti-IL17a antibody comprises the amino acid sequence of SEQ ID NO: 4.

3. The aqueous pharmaceutical composition as defined in claim 1, wherein said anti-IL17a antibody is Netakimab.

4. The aqueous pharmaceutical composition as defined in claim 1, wherein said Netakimab is of an amount of 5 mg/mL to 150 mg/mL.

5. The aqueous pharmaceutical composition as defined in claim 1, wherein said Netakimab is of an amount of 10 mg/mL to 100 mg/mL.

6. The aqueous pharmaceutical composition as defined in claim 1, wherein said Netakimab is of an amount of 40 mg/mL, 60 mg/mL or 70 mg/mL.

7-8. (canceled)

9. The aqueous pharmaceutical composition as defined in claim 1, wherein said sugar-based alcohol is Mannitol.

10. The aqueous pharmaceutical composition as defined claim 9, wherein said Mannitol is in an amount of 25-60 mg/mL.

11. The aqueous pharmaceutical composition as defined in claim 1, wherein a suitable amount of said histidine-based buffering agent is added to reach a pH of around 5.5 to around 6.5.

12. The aqueous pharmaceutical composition as defined in claim 11, wherein said buffering agent is composed of: an amount of 0.4 mg/mL to 1.6 mg/mL of L-histidine; and an amount of 0.4 mg/mL to 1.6 mg/mL of histidine hydrochloride monohydrate.

13. The aqueous pharmaceutical composition as defined in claim 1, further comprising a suitable solubilizer.

14. The aqueous pharmaceutical composition as defined in claim 13, wherein said solubilizer is Poloxamer 188.

15. The aqueous pharmaceutical composition as defined in claim 14, wherein said Poloxamer 188 is in an amount greater than 0 mg/mL but equal to or less than 1 mg/mL.

16. An aqueous pharmaceutical composition as defined in claim 15 comprising: Netakimab 40 mg/mL L-Histidine 0.4 mg/mL L-Histidine hydrochloride monohydrate 0.4 mg/mL Mannitol 54.5 mg/mL Poloxamer 188 0-1 mg/mL pH 6.0±0.5

17. The aqueous pharmaceutical composition as defined in claim 16, wherein a) said Poloxamer 188 is of an amount of 0.5 mg/mL; or b) said Poloxamer 188 is of an amount of 1 mg/mL.

18. An aqueous pharmaceutical composition suitable for parenteral administration to a subject for inhibiting IL17a protein activity comprising: a pharmaceutically effective amount of an anti-IL17a antibody comprising a VHH-derivative domain and a variable VL domain; an acetate-based buffering agent; and a disaccharide as an osmotic agent.

19. The aqueous pharmaceutical composition as defined in claim 18, wherein said VHH-derivative domain of said anti-IL17a antibody comprises 3 hypervariable regions HCDR1, HCDR2 and HCDR3, wherein: HCDR1 comprises the amino acid sequence of SEQ ID NO: 1; HCDR2 comprises the amino acid sequence of SEQ ID NO: 2; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 3; wherein the variable VL domain of said anti-IL17a antibody comprises the amino acid sequence of SEQ ID NO: 4.

20. The aqueous pharmaceutical composition as defined in claim 19, wherein said anti-IL17a antibody is Netakimab.

21. The aqueous pharmaceutical composition as defined in claim 18, wherein said Netakimab is of an amount of 5 mg/mL to 150 mg/mL.

22. The aqueous composition as defined in claim 18, wherein said Netakimab is of an amount of 10 mg/mL to 120 mg/mL.

23. The aqueous pharmaceutical composition as defined in claim 18, wherein said Netakimab is of an amount of 60 mg/mL, 100 mg/mL or 120 mg/mL.

24-25. (canceled)

26. The aqueous pharmaceutical composition as defined in claim 18, wherein said disaccharide is trehalose.

27. The aqueous pharmaceutical composition as defined in claim 26, wherein said trehalose is added to said composition as trehalose dihydrate in an amount of 50 mg/mL to 120 mg/mL.

28. The aqueous pharmaceutical composition as defined in claim 18, wherein said amount of acetate-based buffering agent is composed of: 0.4 mg/mL to 1.8 mg/mL of sodium acetate trihydrate; and a suitable amount of acetic acid to reach a pH of said composition inclusively between 4.0-6.0.

29. The aqueous pharmaceutical composition as defined in claim 18, further comprising a suitable solubilizer.

30. The aqueous pharmaceutical composition as defined in claim 29, wherein said solubilizer is Poloxamer 188.

31. The aqueous pharmaceutical composition as defined in claim 30, wherein said Poloxamer 188 is of an amount over 0 mg/mL to equal or under 1.0 mg/mL.

32. An aqueous pharmaceutical composition as defined in claim 30 comprising: Netakimab 60 mg/mL Sodium acetate trihydrate 1.74 mg/mL Trehalose dihydrate 80 mg/mL Acetic acid glac. to pH 5.0 pH 5.0±0.5, or Netakimab 60 mg/mL Sodium acetate trihydrate 1.74 mg/mL Trehalose dihydrate 80 mg/mL Poloxamer 188 0-1 mg/mL Acetic acid glac. to pH 5.0 pH 5.0±0.5.

33. (canceled)

34. The aqueous pharmaceutical composition as defined in claim 32, wherein a) said Poloxamer 188 is of an amount of 0.5 mg/mL; or b) said Poloxamer 188 is of an amount of 1 mg/mL.

35. An aqueous pharmaceutical composition as defined in claim 30 comprising: Netakimab 120 mg/mL Sodium acetate trihydrate 1.74 mg/mL Trehalose dihydrate 80 mg/mL Acetic acid glac. to pH 5.0 pH 5.0±0.5, or Netakimab 120 mg/mL Sodium acetate trihydrate 1.74 mg/mL Trehalose dihydrate 80 mg/mL Poloxamer 188 0-1 mg/mL Acetic acid glac. to pH 5.0 pH 5.0±0.5.

36. (canceled)

37. The aqueous pharmaceutical composition as defined in claim 35, wherein a) said Poloxamer 188 is of an amount of 0.5 mg/mL; or b) said Poloxamer 188 is of an amount of 1 mg/mL.

38. A method for treatment of an IL17a mediated disease comprising administering to a patient in need thereof the aqueous pharmaceutical composition as defined in claim 1.

39. The method as defined in claim 38, wherein the IL17A-mediated disease or disorder is selected from: rheumatoid arthritis, juvenile rheumatoid arthritis, systemic-onset juvenile rheumatoid arthritis, osteoarthritis, juvenile chronic arthritis, psoriatic arthritis, reactive arthritis, seronegative arthritis, polyarticular juvenile idiopathic arthritis, enthesitis-related arthritis; enthesitis; spondyloarthropathy, axial spondyloarthritis; Behcet' disease; inflammatory bowel disease, Crohn's disease, ulcerative colitis; asthma, allergic disorders, atopic allergy; ichthyosis; Pityriasis rubra pilaris; papulopustular rosacea; pyoderma gangrenosum; hidradenitis suppurativa; psoriasis, psoriatic arthropathy, type I psoriasis, type II psoriasis, plaque psoriasis; dermatitis, atopic dermatitis, autoimmune dermatitis, dermatological conditions; systemic sclerosis; grafting, graft-versus-host disease, graft rejection, acute or chronic immune disease associated with organ grafting, acute graft-associated immune disease, chronic graft-associated immune disease, small intestinal graft rejection, pancreatic graft rejection, any organ or tissue graft rejection, heart transplant rejection, cartilage graft rejection, renal transplant rejection, liver transplant rejection, allograft rejection, skin allograft rejection, heterograft rejection for any organ or tissue, bone graft rejection, bone marrow transplant (BMT) rejection, parathyroid graft rejection; bone erosion; sarcoidosis, atherosclerosis, Wegener's disease, microscopic polyangiitis with renal involvement, uveitis, phacogenic uveitis, noninfectious uveitis, cachexia, acute transverse myelitis, primary biliary cirrhosis, polyglandular autoimmune syndrome type I and type II, Schmidt's syndrome, acute respiratory distress syndrome; arthropathy, seronegative arthropathy, arthropathy associated with ulcerative colitis, Reiter's syndrome, enteropathic synovitis, atheromatosis disease/coronary sclerosis, autoimmune bullous disease, pemphigus, pemphigus foliaceus, linear IgA diseases, autoimmune hemolytic anemia, cranial giant arteritis, primary sclerosing hepatitis, cryptogenic autoimmune hepatitis, cryptogenic fibrosing alveolitis, systemic scleroderma associated with interstitial lung disease, rheumatoid arthritis associated with interstitial lung disease, systemic lupus erythematosus associated with lung disease, dermatomyositis/polymyositis associated with lung disease, Sjogren disease associated with lung disease, ankylosing spondylitis associated with lung disease, vasculitis, diffuse pulmonary vasculitis, primary vasculitis, fibrosis, lung disease with lymphocyte infiltration, autoimmune hepatitis, autoimmune hepatitis type I (classic autoimmune or lupoid hepatitis), autoimmune hepatitis type II (associated with anti-LKM antibody), autoimmune hypoglycemia, osteoarthrosis, primary sclerosing cholangitis, erythematosus; systemic lupus erythematosus, discoid lupus erythematosus, lupus nephritis; multiple sclerosis (all types), sympathetic ophthalmia, pulmonary hypertension secondary to connective tissue disease, Goodpasture syndrome, pulmonary manifestations of polyarteritis nodosa, acute rheumatic fever, rheumatoid spondylitis, Still's disease, systemic scleroderma, scleroderma disease, scleroderma, Sjogren's Syndrome, Takayasu disease/arthritis; autoimmune thrombocytopenia, idiopathic thrombocytopenia; autoimmune thyroid disorders, hyperthyroid, autoimmune hypothyroidism (Hashimoto disease), atrophic autoimmune hypothyroidism; vitiligo, acute hepatic disease, chronic hepatic disease, cholestasis, Th1- and Th2-mediated disease; malignancies such as lung cancer, breast cancer, stomach cancer, bladder cancer, colorectal cancer, pancreatic cancer, pancreatic carcinoma, ovarian cancer, prostate cancer and hematopoietic malignancies (leukemia and lymphomas), acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, adenocarcinoma, B-cell lymphoma, Burkitt lymphoma, inflammatory response to bypass, chronic myelocytic leukemia (CML), chronic inflammatory pathologies, chronic lymphatic leukemia (CLL), rectocolic carcinoma, cystic fibrosis, malignant lymphoma, malignant histiocytosis, malignant melanoma, multiple myeloma, non-Hodgkin's lymphomas, nasopharyngeal cancer, solid tumors, hairy-cell leukemia, Hodgkin disease, sarcoma, myelodysplastic syndrome, cytokine therapy-induced disorders, demyelinating disease, inflammatory demyelinating disease, pulmonary fibrosis, idiopathic pulmonary fibrosis, usual interstitial pneumonia, iridocyclitis/uveitis/optic neuritis, lymphoedema, mixed connective-tissue disease, monoclonal gammapathy, neonatal chronic lung disease, nephritis, nephrotic, neurodegenerative disorders, osteoporosis, paraneoplastic disease/tumor-related hypercalcemia, Raynaud's phenomenon and disease, skin changes, a comprehensive systemic inflammatory response syndrome, thrombocytopenia, toxicity, urticaria, acute coronary syndrome, adult-onset Stills disease, aplastic anemia, coronary sclerosis, atopic eczema; autoimmune disorder associated with streptococcus infection, autoimmune enteropathy, autoimmune hearing loss, autoimmune lymphoproliferative syndrome (ALPS), autoimmune myocarditis, autoimmune premature ovarian failure; celiac disease, cervical spondylosis, clinically isolated syndrome (cis) with the risk for multiple sclerosis, erythema multiform, severe erythema multiform, pemphigoid, bullous pemphigoid, cicatrical pemphigoid, mucosal pemphigoid, gestational pemphigoid, iritis, keratitis, motor neuron disease, non-A, non-B hepatitis, optic neuritis, oligoarticular JIA, polyarteritis nodosa, polychondritis, poliosis, polymyositis, relapsing neuromyelitis optica, rheumatic heart disease, SAPHO (synovitis, acne, pustulosis, hyperostosis and osteitis), secondary amyloidosis, ankylosing spondylitis, systemic inflammation response syndrome, cranial arteritis, and Yersinia- or Salmonella-associated arthropathy.

40-43. (canceled)

44. A method for treatment of an IL17a mediated disease comprising administering to a patient in need thereof the aqueous pharmaceutical composition as defined in claim 18.

45. The method as defined in claim 34, wherein the IL17A-mediated disease or disorder is selected from: rheumatoid arthritis, juvenile rheumatoid arthritis, systemic-onset juvenile rheumatoid arthritis, osteoarthritis, juvenile chronic arthritis, psoriatic arthritis, reactive arthritis, seronegative arthritis, polyarticular juvenile idiopathic arthritis, enthesitis-related arthritis; enthesitis; spondyloarthropathy, axial spondyloarthritis; Behcet' disease; inflammatory bowel disease, Crohn's disease, ulcerative colitis; asthma, allergic disorders, atopic allergy; ichthyosis; Pityriasis rubra pilaris; papulopustular rosacea; pyoderma gangrenosum; hidradenitis suppurativa; psoriasis, psoriatic arthropathy, type I psoriasis, type II psoriasis, plaque psoriasis; dermatitis, atopic dermatitis, autoimmune dermatitis, dermatological conditions; systemic sclerosis; grafting, graft-versus-host disease, graft rejection, acute or chronic immune disease associated with organ grafting, acute graft-associated immune disease, chronic graft-associated immune disease, small intestinal graft rejection, pancreatic graft rejection, any organ or tissue graft rejection, heart transplant rejection, cartilage graft rejection, renal transplant rejection, liver transplant rejection, allograft rejection, skin allograft rejection, heterograft rejection for any organ or tissue, bone graft rejection, bone marrow transplant (BMT) rejection, parathyroid graft rejection; bone erosion; sarcoidosis, atherosclerosis, Wegener's disease, microscopic polyangiitis with renal involvement, uveitis, phacogenic uveitis, noninfectious uveitis, cachexia, acute transverse myelitis, primary biliary cirrhosis, polyglandular autoimmune syndrome type I and type II, Schmidt's syndrome, acute respiratory distress syndrome; arthropathy, seronegative arthropathy, arthropathy associated with ulcerative colitis, Reiter's syndrome, enteropathic synovitis, atheromatosis disease/coronary sclerosis, autoimmune bullous disease, pemphigus, pemphigus foliaceus, linear IgA diseases, autoimmune hemolytic anemia, cranial giant arteritis, primary sclerosing hepatitis, cryptogenic autoimmune hepatitis, cryptogenic fibrosing alveolitis, systemic scleroderma associated with interstitial lung disease, rheumatoid arthritis associated with interstitial lung disease, systemic lupus erythematosus associated with lung disease, dermatomyositis/polymyositis associated with lung disease, Sjogren disease associated with lung disease, ankylosing spondylitis associated with lung disease, vasculitis, diffuse pulmonary vasculitis, primary vasculitis, fibrosis, lung disease with lymphocyte infiltration, autoimmune hepatitis, autoimmune hepatitis type I (classic autoimmune or lupoid hepatitis), autoimmune hepatitis type II (associated with anti-LKM antibody), autoimmune hypoglycemia, osteoarthrosis, primary sclerosing cholangitis, erythematosus; systemic lupus erythematosus, discoid lupus erythematosus, lupus nephritis; multiple sclerosis (all types), sympathetic ophthalmia, pulmonary hypertension secondary to connective tissue disease, Goodpasture syndrome, pulmonary manifestations of polyarteritis nodosa, acute rheumatic fever, rheumatoid spondylitis, Still's disease, systemic scleroderma, scleroderma disease, scleroderma, Sjogren's Syndrome, Takayasu disease/arthritis; autoimmune thrombocytopenia, idiopathic thrombocytopenia; autoimmune thyroid disorders, hyperthyroid, autoimmune hypothyroidism (Hashimoto disease), atrophic autoimmune hypothyroidism; vitiligo, acute hepatic disease, chronic hepatic disease, cholestasis, Th1- and Th2-mediated disease; malignancies such as lung cancer, breast cancer, stomach cancer, bladder cancer, colorectal cancer, pancreatic cancer, pancreatic carcinoma, ovarian cancer, prostate cancer and hematopoietic malignancies (leukemia and lymphomas), acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, adenocarcinoma, B-cell lymphoma, Burkitt lymphoma, inflammatory response to bypass, chronic myelocytic leukemia (CML), chronic inflammatory pathologies, chronic lymphatic leukemia (CLL), rectocolic carcinoma, cystic fibrosis, malignant lymphoma, malignant histiocytosis, malignant melanoma, multiple myeloma, non-Hodgkin's lymphomas, nasopharyngeal cancer, solid tumors, hairy-cell leukemia, Hodgkin disease, sarcoma, myelodysplastic syndrome, cytokine therapy-induced disorders, demyelinating disease, inflammatory demyelinating disease, pulmonary fibrosis, idiopathic pulmonary fibrosis, usual interstitial pneumonia, iridocyclitis/uveitis/optic neuritis, lymphoedema, mixed connective-tissue disease, monoclonal gammapathy, neonatal chronic lung disease, nephritis, nephrotic, neurodegenerative disorders, osteoporosis, paraneoplastic disease/tumor-related hypercalcemia, Raynaud's phenomenon and disease, skin changes, a comprehensive systemic inflammatory response syndrome, thrombocytopenia, toxicity, urticaria, acute coronary syndrome, adult-onset Stills disease, aplastic anemia, coronary sclerosis, atopic eczema; autoimmune disorder associated with streptococcus infection, autoimmune enteropathy, autoimmune hearing loss, autoimmune lymphoproliferative syndrome (ALPS), autoimmune myocarditis, autoimmune premature ovarian failure; celiac disease, cervical spondylosis, clinically isolated syndrome (cis) with the risk for multiple sclerosis, erythema multiform, severe erythema multiform, pemphigoid, bullous pemphigoid, cicatrical pemphigoid, mucosal pemphigoid, gestational pemphigoid, iritis, keratitis, motor neuron disease, non-A, non-B hepatitis, optic neuritis, oligoarticular JIA, polyarteritis nodosa, polychondritis, poliosis, polymyositis, relapsing neuromyelitis optica, rheumatic heart disease, SAPHO (synovitis, acne, pustulosis, hyperostosis and osteitis), secondary amyloidosis, ankylosing spondylitis, systemic inflammation response syndrome, cranial arteritis, and Yersinia- or Salmonella-associated arthropathy.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0668] The invention will be better understood by way of the following detailed description of embodiments of the invention with reference to the appended drawings, in which:

[0669] FIG. 1 is a graph illustrating the dependence of the optical density of solutions at 400 nm as a function of PEG concentration in exemplary anti-IL17a antibody compositions with different buffering agents;

[0670] FIG. 2 is a graph illustrating the dependence of the optical density of solutions at 400 nm as a function of PEG concentration in exemplary anti-IL17a antibody compositions with different concentrations of Histidine and/or different pH;

[0671] FIG. 3 is a graph illustrating the dependence of the optical density of solutions at 400 nm as a function of PEG concentration in exemplary anti-IL17a antibody compositions with different osmotic agents; and

[0672] FIG. 4 is a graph illustrating the dependence of the optical density of solutions at 400 nm as a function of PEG concentration in exemplary anti-IL17a antibody compositions with different solubilizers and/or concentrations of solubilizers.

[0673] FIG. 5 is a graph illustrating the proportion of patients in each study arm who achieved a PASI 75 at Week 12 of treatment (BCD-085-2 Study).

[0674] FIG. 6 is a graph illustrating the proportion of patients in each study arm who achieved a PASI 75 at Weeks 4, 8 and 12 of treatment (BCD-085-2 study).

[0675] FIG. 7 is a graph illustrating the mean percent improvement in the PASI score from baseline at Weeks 4, 8 and 12 of treatment (BCD-085-2 study).

[0676] FIG. 8 is a graph illustrating the mean percent improvement in the NAPSI score from baseline at Week 12 of treatment (BCD-085-2 Study).

[0677] FIG. 9 is a graph illustrating Netakimab concentration profile after the first injection and shows medians and interquartile ranges, min and max values (BCD-085-2 Study).

[0678] FIG. 10 is a graph illustrating Netakimab concentration profile after multiple injections and shows medians and interquartile ranges, min and max values (BCD-085-2 Study).

[0679] FIG. 11 is a graph illustrating study design (BCD-085-2ext Study).

[0680] FIG. 12 is a graph illustrating the proportion of patients who achieved PASI 75 after one year of treatment (week 38 of the BCD-085-2ext study).

[0681] FIG. 13 is a graph illustrating the proportion of patients who achieved PASI 90 after 52 weeks of treatment (38 weeks of BCD-085-2ext study).

[0682] FIG. 14 is a graph illustrating the proportion of patients who achieved PASI 100 after 52 weeks of treatment (38 weeks of BCD-085-2ext study).

[0683] FIG. 15 is a graph illustrating the proportion of patients who achieved sPGA score 0-1 after 52 weeks of treatment (38 weeks of BCD-085-2ext study).

[0684] FIG. 16 is a graph illustrating the proportion of patients who achieved sPGA score 0 (clean skin) after 52 weeks of treatment (38 weeks of BCD-085-2ext study).

[0685] FIG. 17 is a graph illustrating the study design (BCD-085-7 study).

[0686] FIG. 18 is a graph illustrating the assessment of the PASI 75/90/100 and sPGA 0-1 (ITT population, n=213), (BCD-085-7 study).

[0687] FIG. 19 is a graph illustrating the relative change in PASI at Weeks 8 and 12 (Visits 6 and 8) in ITT population (n=213) (BCD-085-7 study).

[0688] FIG. 20 is a graph illustrating the mean change from baseline in itch severity (VAS) at Weeks 1 and 12 (Visits 2 and 8) in ITT population (n=213) (BCD-085-7 study).

[0689] FIG. 21 is a graph illustrating the mean change in DLQI score at Weeks 8 and 12 (Visits 6 and 8) in ITT population (n=213) (BCD-085-7 study).

[0690] FIG. 22 is a graph illustrating the mean change from baseline in NAPSI score at Week 12 (N=131) (the figure shows median value) (BCD-085-7 study).

[0691] FIG. 23 is a graph illustrating the proportion of patients who achieved ACR 20/50/70 (among those with psoriatic arthritis, n=15) (BCD-085-7 study).

[0692] FIG. 24 is a graph illustrating the proportion of patients with ASAS20 Response during the study (BCD-085-3 Study).

[0693] FIG. 25 is a graph illustrating the proportion of patients with ASAS20, ASAS40, and ASAS5/6 response during the study (BCD-085-3 Study).

[0694] FIG. 26 is a graph illustrating pharmacokinetcs after single dose administration (Study BCD-085-3).

[0695] FIG. 27 is a graph illustrating pharmacokinetcs after multiple dose administration (Study BCD-085-3).

[0696] FIG. 28 is a graph illustrating study design (BCD-085-3ext Study).

[0697] FIG. 29 is a graph illustrating ASAS20/40 response rate (Week 16).

[0698] FIG. 30 is a graph illustrating main secondary endpoints (mean change from baseline at Week 16).

[0699] FIG. 31 is a graph illustrating the mean change from baseline in MRI scores.

[0700] FIG. 32 is a graph illustrating total back pain score within 16 weeks of ASTERA study (means) (* P<0.05 for the comparison with placebo).

[0701] FIG. 33 is a graph illustrating Change in BASDAI, BASFI and QoL at Week 16 (means).

DETAILED DESCRIPTION

Definitions

[0702] “Monoclonal antibody” as used herein relates to an antibody obtained from llama, chimeric antibody, humanized antibody or fully human antibody, unless otherwise stated in the present application. Monoclonal antibodies according to the disclosure can be produced using, for example, recombinant technology, phage display technology, synthetic technology or the combinations of these or other technologies well known from the prior art.

[0703] “Monoclonal antibody” refers to an antibody obtained from a single copy or a clone including, for example, any eukaryotic, prokaryotic or phage clone, rather than to production method thereof. “Monoclonal antibody” can be an intact antibody (with full or full-length Fc-region), actually intact antibody, an antibody part or fragment comprising an antigen-binding region, for example, Fab-fragment, Fab′-fragment or F(ab′)2-fragment from llama or chimeric, humanized or human antibody. “Fab”-fragment comprises a variable light chain domain and a constant light chain domain as well as a variable heavy chain domain and first constant heavy chain domain (CH1). “F(ab′)2” antibody fragment contains a pair of Fab-fragments which are mostly covalently bound by hinged cysteine residues at C-terminal regions. Other chemical bonds between antibody fragments are also well known from the state of art.

[0704] In addition, “monoclonal antibody” as used herein can be a single-chain Fv that can be obtained by binding to DNA encoding VHH and VL with a linker sequence. As long as the protein keeps its ability of specific or preferable binding to the target (for example, epitope or antigen), it is covered by the term “antibody”. Antibodies can be either glycosylated or not and are within the frames of the disclosure.

[0705] The term “derivative” or antibody “variant”, as used herein, refers to a molecule the amino acid sequence of which differs from the parental sequence by adding, deletion and/or, substitution of one or more amino acid residues in the sequence of parental antibody. In the preferred embodiment, an antibody contains at least one (for example, from one to about ten preferably 2, 3, 4, 5, 6, 7 or 8) amino acid substitutions in FR- or CDR-regions of the parental antibody. This application defines the identity or homology regarding the sequence of a variant antibody as the percentage of amino acid residues in a variant antibody sequence that are identical to residues in parental antibody after aligning the sequences and, if needed, cutting in order to achieve the maximum percentage identical sequence.

[0706] An antibody derivative (from parental one) keeps its ability to bind the same antigen or, preferably, an epitope as that with which the parental antibody binds, or, preferably, exhibits at least one property or biological activity exceeding that of the parental antibody. For example, the antibody preferably has a better aggregation stability, more strong affinity, improved pharmacokinetics or increased ability to inhibit the antigen biological activity, compared to parental antibody.

[0707] The term “VHH-derivative”, as used herein, refers to the derivatives of VHH antibodies the amino acid sequence of which differs from the sequence of parental VHH antibody by substitution of one or more amino acid residues in the sequence of parental antibody. In the preferred embodiment, VHH antibody contains at least one (for example, from one to about ten preferably 2, 3, 4, 5, 6, 7 or 8) amino acid substitutions in FR- or CDR-regions of the parental antibody.

[0708] An antibody derivative keeps its ability to bind the same antigen or, preferably, epitope as that with which the parental antibody binds, or, preferably, exhibits at least one property or biological activity exceeding that of the parental antibody. For example, the antibody preferably has a better aggregation stability, more strong affinity, improved pharmacokinetics or increased ability to inhibit the antigen biological activity, compared to parental antibody.

[0709] “Parental VHH antibody” or “initial VHH antibody”, or “wild VHH antibody” as used herein refers to VHH antibody isolated from an immunized or non-immunized Camelidae animal encoded with amino acid sequence that is used to produce a VHH variant. Parental antibody can have a framework sequence originating from Camelidae (with respect to VHH variable domain), but preferably the frame sequence of the light chain variable domain is of completely or substantially human origin.

[0710] “Parental”, “initial”, or “wild” antibody as used herein refers to an antibody encoded with amino acid sequence that is used to produce a variant. Parental antibody can have a framework sequence originating from Camelidae (with respect to VHH variable domain), but preferably the frame sequence of the light chain variable domain is of completely or substantially human origin.

[0711] As used herein, the term “specifically binds” refers to such a situation in that one party involved in the process of specific binding does not significantly bind molecules other than its specific binding partner (partners). This term also applies if, for example, an antigen-binding site of the antibody according to the disclosure is specific for particular epitope that is carried by a number of antigens; in this case, the specific antibody with an antigen-binding site will be able to bind specifically with various epitope-carrying antigens. Thus, the monoclonal antibody according to the disclosure specifically binds to human IL17 (IL17A), while it does not specifically bind human IL17B, IL17C, IL17D or IL17E. Moreover, a monoclonal antibody of the disclosure specifically binds human IL17 and IL17 from cynomolgus monkey, but does not specifically bind neither rat IL17 nor murine IL17.

[0712] As used herein, the term “preferably binds” refers to such a situation in that an antibody binds a specific antigen at least by 20% more, preferably by about 50%, or 2-fold, 20-fold, 50-fold or 100-fold more than it binds any other antigen, as measured according to the procedures known from the prior art (for example, competitive ELISA or KD measurements obtained using Octet apparatus). An antibody can preferably bind one epitope within an antigen but not bind another epitope of the same antigen. Thus, an antibody of the disclosure preferably binds human IL17 but not rabbit IL17.

[0713] As used herein, the term “epitope” refers to the molecule part that can be recognized by and bind an antibody via one or several antigen-binding sites of an antibody. Epitopes often comprise the chemically surface-active groups of molecules such as amino acids or sugar side chains, and have specific 3-D structural characteristics “Inhibiting epitope” and/or “neutralizing epitope” means an epitope that, as in the context of an intact antigen molecule and binding an antibody specific to said epitope, causes in vivo or in vitro loss or reduction of activity of the molecule or organism that contains the molecule.

[0714] As used herein, the term “epitope” also refers to a polypeptide fragment, having antigenic and/or immunogenic activity in animals, preferably in mammals such as mice and humans. The term “antigenic epitope” as used herein is a polypeptide fragment which can specifically bind the antibody and can be detected by any technique well known from the prior art (for example, by means of the standard immunoassay). Antigen epitopes are not necessary immunogenic, but they can possess immunogenicity. “Immunogenic epitope” as used herein is defined as a polypeptide fragment that evokes an antibody response in animals, as determined by any method of the prior art. “Nonlinear epitope” or “conformational epitope” contains nonadjacent polypeptides (amino acids) within the antigen protein, which binds with epitope-specific antibody.

[0715] Expressed “functional activity” or “functional characteristics” or the terms “biological activity” or “activity” referring to an antibody according to the disclosure are interchangeable as used herein, and include but not limited to: epitope/antigen affinity and specificity; ability to neutralize or be an antagonist to IL17 in vivo or in vitro; IC50; antibody stability and in vivo immunogenicity of the antibody. Other biological properties or antibody characteristics identified from the prior art include, for example, the cross-reactivity (i.e. reaction with non-human homologs of the target peptide or with other proteins or targets) and ability to retain high levels of protein expression in mammal cells. Aforementioned properties or characteristics may be observed, measured or evaluated using the procedures recognized in the prior art, including but not limited to ELISA, competitive ELISA, Octet analysis, neutralization assay in vitro or in vivo without limitation, receptor binding, production and/or release of cytokine or growth factor, signal transduction and immune histochemical study of tissue sections obtained from various sources including humans, primates or any other source.

[0716] The population of “monoclonal antibodies” as used herein refers to a homogenous or essentially homogeneous antibody population (i.e. at least or 96%, but more preferably no less than about 97 or 98%, or further preferably at least 99% of antibodies in the population will compete for the same antigen/epitope in ELISA, or further preferably antibodies are identical regarding their amino acid sequences).

[0717] A native full-size antibody is represented by immunoglobulin molecule comprising four polypeptide chains (two heavy H chains of about 50-70 KDa for the full length, and two light L chains of about 25 KDa for the full length) linked via disulfide bonds. Amino-terminal part of each chain comprises a variable domain of about 100-110 or more amino acids that are responsible for binding an antigen. Carboxyl-terminal domain of each chain determines the constant region that is mostly responsible for the effector function. Light chains are classified as kappa and lambda and have specific constant regions. Each light chain is characterized in comprising a variable N-terminal light chain region (hereafter referred to as VL or VK) and a constant light chain region that consists of a single domain (CL or CK). Heavy chains are classified as γ, δ, α, μ, and ε and define classes of immunoglobulins: IgG, IgM, IgA, IgD and IgE, respectively; some of them can be additionally divided into sub-classes (isotypes) such as IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2. Each heavy chain type is characterized by a specific constant region Fc. Each heavy chain comprises a variable N-terminal region (hereafter referred to as VH) and constant region CH. Constant heavy chain region consists of three domains (CH1, CH2 and CH3) for IgG, IgD and IgA, and of 4 domains (CH1, CH2, CH3 and CH4) for IgM and IgE. VH, VHH and VL can also be divided into so-called hypervariable regions (complementarity determining regions, CDR) interspersing with more conservative framework regions (FR). Each variable domain comprises three CDRs and FRs located in the following order from N-terminus to C-terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4.

[0718] In the present application, 3 heavy chain CDRs are referred to as “HCDR1, HCDR2 and HCDR3”, while 3 light chain CDR are referred to as “LCDR1, LCDR2 and LCDR3”. CDRs contain the majority of amino acid residues specifically interacting with an antigen. CDR-residues are numbered and positioned in compliance with Kabat Numbering Scheme.

[0719] The term “antigen” refers to an antigen target against which an antibody can be reactive; it is used herein in the same way as specialists use it in the technical field, and includes but is not limited to, polypeptides, peptides, polysaccharides, glycoproteins, polynucleotides (for example, DNA), or chemical antigens, receptors or interleukins. Interleukins can include interleukins of various groups, such as interleukin 1 (alfa and beta), interleukin 2, interleukin 3, interleukin 4, interleukin 5, interleukin 6, interleukin 7, interleukin 8, interleukin 9, interleukin 10, interleukin 11, interleukin 17, interleukin 18 and interleukin 33.

[0720] The term “antigen” can also be used to describe the material that is used for immunization of animals (for example, llama) with the purpose of production of antibodies as described in the present disclosure. In that context, “antigen” can have a broader meaning and may cover purified forms of an antigen as well as non-purified or not fully isolated, or purified antigen products such as cells, cell lysates, or supernatants, cell fractions, for example, cell membranes etc. with added haptens conjugated with a protein-carrier. Antigen used for immunization does not necessarily mean an antigen structurally identical to an antigen target to which, finally, an antibody of the disclosure is able to bind. Usually, antigen used for immunization is a downsized version of an antigen target, for example, a fragment comprising an immunogenic epitope. More details about antigens used for immunization are described in the literature and may be familiar to the specialist in this technical field.

[0721] Variable regions of each light/heavy chain pair form antigen-binding sites of an antibody. Thus, an intact IgG antibody has two binding sites. Except for bi-functional or bi-specific antibodies, two binding sites are identical. According to the present application, “antigen-binding region” or “antigen-binding site”, or “antigen-binding domain”, are interchangeable, as used herein, with refer to an antibody region comprising amino acid residues interacting with an antigen and giving the antibody its specificity and affinity to an antigen. This antibody fragment includes the frame amino acid residues necessary for maintaining the proper conformation of antigen-binding residues.

[0722] Preferably, CDR of VHH antigen-binding region or the entire antigen-binding region of an antibody of the present disclosure fully originates from Camelidae family or is substantially of Camelidae origin, and comprises specific amino acid residues changed, for example, substituted with various amino acid residues (for example, refer to Table 6) in order to improve the particular properties of an antibody (for example, KD, koff or IC50). Preferably, the antibody framework regions in accordance with the present disclosure are of Camelidae origin or of human origin, or substantially of a human origin (at least by 80, 85, 90, 95, 96, 97, 98 or 99% of human origin), and comply with Kabat numbering.

[0723] “Antibody fragment” may be represented by an antibody fragment or antibody fragment that has the activity of a full-size antibody. Said antibody fragment may be represented by F(ab′)2, F(ab)2, Fab′, Fab Fv and scFv.

[0724] “Interleukin 17”, also referred to as “IL17” or “IL17A”, is a 20-30 kD homo-dimeric glycoprotein. The gene of human IL17 encodes the protein consisting of 155 amino acids and having a 19 amino acid signal sequence and 136 amino acid mature segment. Amino acid sequence of human IL17A is by 80%, 63% and 58% similar to amino acid sequences of rabbit, mouse and rat, respectively Amino acid sequence of human IL17A is by 97% identical to IL17A of cynomolgus monkey.

[0725] The term “antibody” when applied in relation to anti-IL17 monoclonal antibody of the present disclosure (hereafter referred to as an “antibody of the present disclosure”), as used herein, means a monoclonal antibody.

[0726] As used herein, the terms “inhibit” or “neutralize” regarding to the activity of an antibody of the present disclosure shall mean the ability to block, prevent, restrict, slow down, stop, reduce or reverse significantly, for example, the development or severity of inhibition subject, including but not limited to biological activity (such as activity of IL17) or property, disease or condition. Binding of an antibody according to the present disclosure with IL17 results in the inhibition or neutralization of IL17 activity preferably of at least 20, 30, 40, 50, 60, 70, 80, 90, 95% or higher.

[0727] The term “separated” or “isolated” with regard to nucleic acids or protein products (such as an antibody) refers to the nucleic acid molecule or protein molecule that is identified and separated from at least one of contaminating substances to which it is usually combined in the natural source. Preferably, an “isolated antibody” is an antibody that substantially contains no other antibodies that have particular antigenic specificity (for example, pharmaceutical compositions of the present disclosure contain an isolated antibody that specifically binds IL17A and substantially contain no antibodies that specifically bind antigens other than IL17A).

[0728] The term “Kabat numbering scheme” or “numbering according to Kabat” as used herein refers to the system for numbering of amino acid residues that are more variable (i.e. hypervariable) than other amino acid residues in variable regions of heavy and light chains of an antibody (Kabat et al. Ann. N.Y. Acad. Sci., 190:382-93 (1971); Kabat et al. Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242 (1991)).

[0729] Polynucleotide is “functionally bound” if it has functional linkages to other polynucleotide. For example, promoter or enhancer is functionally bound to the coding sequence if it affects the sequence transcription. Polypeptide is “functionally bound” to another polypeptide if polynucleotides coding thereof is functionally bound, preferably if they are located in the same open reading frame.

[0730] The term “Specific binding” between an antibody and an antigen target (antigen) refers to immunological specificity. Antibody can specifically bind an antigen target if it binds an antigen epitope stronger than other antigen epitopes. Specific binding does not exclude the cross-reactivity with other antigens that carry similar antigen epitopes.

[0731] VL domains in antibodies of the disclosure can be either VL lambda type or VL kappa type. The term “VL domain” covers both VL lambda and VL kappa isotypes that contain one or more amino acid substitutions, insertions or deletions.

[0732] The term “pharmaceutical composition” covers the formulation and/or composition containing a therapeutically effective amount of an antibody of the present disclosure plus excipients (carriers, diluents, vehicles, solvents and other excipients such as).

[0733] The term “use” or “treatment” applies to the ability of using an antibody of the present disclosure or a pharmaceutical composition containing thereof to treat, relief the course of the disease, expedite the remission or reduce the recurrence rate for the disease or disorders mediated by receptors with which an antibody of the present disclosure can bind.

Exemplary Embodiments

[0734] The present disclosure relates to suitable aqueous pharmaceutical compositions for an anti-IL17a antibody including a VHH-derivative domain and a variable V.sub.L domain, such as Netakimab. One aqueous pharmaceutical composition may have a histidine-based buffer and mannitol as an osmotic agent. Poloxamer 188 may be added as a solubilizer. Another aqueous pharmaceutical composition may have an acetate-based buffer and trehalose as an osmotic agent. Poloxamer 188 may be added as a solubilizer.

[0735] The histidine-based buffer may be the result of combining L-histidine with histidine hydrochloride monohydrate or, additionally, with hydrochloric acid, or other acids. It will be understood that even though histidine hydrochloride monohydrate may be used as a salt for the histidine-based buffer, any other histidine-based salt may be used for the histidine-based buffer without departing from the present teachings.

[0736] The acetate-based buffer may be the result of combining acetic acid with sodium acetate trihydrate. It will be understood that even though sodium acetate trihydrate may be used as a salt for the acetate-based buffer, any other acetate salt, such as potassium acetate, may be used for the acetate-based buffer without departing from the present teachings.

[0737] The composition of the present disclosure may, in addition, additionally include one or more other suitable excipients that are well known to specialists in this field.

[0738] The above compositions are suitable for parenteral administration, such as intravenous, subcutaneous, intradermal, intra-arterial, intrathecal, intraperitoneal, intra-articular and/or intramuscular administration.

[0739] In some embodiments, the implementation of the liquid pharmaceutical composition is stable during storage in the sense that it does not occur any further processes of protein aggregation or its modifications in comparison with the indicator of stability at zero time point.

[0740] Methods of Treatment and Use of the Aqueous Composition

[0741] In another embodiment, the present disclosure relates to a method of treating a mammal, comprising administering to the mammal a therapeutically effective amount of the pharmaceutical compositions of the present disclosure, wherein the mammal may have a disease or disorder that can be effectively treated with the anti-IL17a antibodies of the disclosure an anti-IL17a antibody of the disclosure.

[0742] In a preferred embodiment, the mammal is a human.

[0743] Diseases or disorders that can be treated with the compositions provided include, but are not limited to, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic-onset juvenile rheumatoid arthritis, osteoarthritis, juvenile chronic arthritis, psoriatic arthritis, reactive arthritis, seronegative arthritis, polyarticular juvenile idiopathic arthritis, enthesitis-related arthritis; enthesitis; spondyloarthropathy, axial spondyloarthritis; Behcet' disease; inflammatory bowel disease, Crohn's disease, ulcerative colitis; asthma, allergic disorders, atopic allergy; ichthyosis; Pityriasis rubra pilaris; papulopustular rosacea; pyoderma gangrenosum; hidradenitis suppurativa; psoriasis, psoriatic arthropathy, type I psoriasis, type II psoriasis, plaque psoriasis; dermatitis, atopic dermatitis, autoimmune dermatitis, dermatological conditions; systemic sclerosis; grafting, graft-versus-host disease, graft rejection, acute or chronic immune disease associated with organ grafting, acute graft-associated immune disease, chronic graft-associated immune disease, small intestinal graft rejection, pancreatic graft rejection, any organ or tissue graft rejection, heart transplant rejection, cartilage graft rejection, renal transplant rejection, liver transplant rejection, allograft rejection, skin allograft rejection, heterograft rejection for any organ or tissue, bone graft rejection, bone marrow transplant (BMT) rejection, parathyroid graft rejection; bone erosion; sarcoidosis, atherosclerosis, Wegener's disease, microscopic polyangiitis with renal involvement, uveitis, phacogenic uveitis, noninfectious uveitis, cachexia, acute transverse myelitis, primary biliary cirrhosis, polyglandular autoimmune syndrome type I and type II, Schmidt's syndrome, acute respiratory distress syndrome; arthropathy, seronegative arthropathy, arthropathy associated with ulcerative colitis, Reiter's syndrome, enteropathic synovitis, atheromatosis disease/coronary sclerosis, autoimmune bullous disease, pemphigus, pemphigus foliaceus, linear IgA diseases, autoimmune hemolytic anemia, cranial giant arteritis, primary sclerosing hepatitis, cryptogenic autoimmune hepatitis, cryptogenic fibrosing alveolitis, systemic scleroderma associated with interstitial lung disease, rheumatoid arthritis associated with interstitial lung disease, systemic lupus erythematosus associated with lung disease, dermatomyositis/polymyositis associated with lung disease, Sjogren disease associated with lung disease, ankylosing spondylitis associated with lung disease, vasculitis, diffuse pulmonary vasculitis, primary vasculitis, fibrosis, lung disease with lymphocyte infiltration, autoimmune hepatitis, autoimmune hepatitis type I (classic autoimmune or lupoid hepatitis), autoimmune hepatitis type II (associated with anti-LKM antibody), autoimmune hypoglycemia, osteoarthrosis, primary sclerosing cholangitis, erythematosus; systemic lupus erythematosus, discoid lupus erythematosus, lupus nephritis; multiple sclerosis (all types), sympathetic ophthalmia, pulmonary hypertension secondary to connective tissue disease, Goodpasture syndrome, pulmonary manifestations of polyarteritis nodosa, acute rheumatic fever, rheumatoid spondylitis, Still's disease, systemic scleroderma, scleroderma disease, scleroderma, Sjogren's Syndrome, Takayasu disease/arthritis; autoimmune thrombocytopenia, idiopathic thrombocytopenia; autoimmune thyroid disorders, hyperthyroid, autoimmune hypothyroidism (Hashimoto disease), atrophic autoimmune hypothyroidism; vitiligo, acute hepatic disease, chronic hepatic disease, cholestasis, Th1- and Th2-mediated disease; malignancies such as lung cancer, breast cancer, stomach cancer, bladder cancer, colorectal cancer, pancreatic cancer, pancreatic carcinoma, ovarian cancer, prostate cancer and hematopoietic malignancies (leukemia and lymphomas), acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, adenocarcinoma, B-cell lymphoma, Burkitt lymphoma, inflammatory response to bypass, chronic myelocytic leukemia (CML), chronic inflammatory pathologies, chronic lymphatic leukemia (CLL), rectocolic carcinoma, cystic fibrosis, malignant lymphoma, malignant histiocytosis, malignant melanoma, multiple myeloma, non-Hodgkin's lymphomas, nasopharyngeal cancer, solid tumors, hairy-cell leukemia, Hodgkin disease, sarcoma, myelodysplastic syndrome, cytokine therapy-induced disorders, demyelinating disease, inflammatory demyelinating disease, pulmonary fibrosis, idiopathic pulmonary fibrosis, usual interstitial pneumonia, iridocyclitis/uveitis/optic neuritis, lymphoedema, mixed connective-tissue disease, monoclonal gammopathy, neonatal chronic lung disease, nephritis, nephrotic, neurodegenerative disorders, osteoporosis, paraneoplastic disease/tumor-related hypercalcemia, Raynaud's phenomenon and disease, skin changes, a comprehensive systemic inflammatory response syndrome, thrombocytopenia, toxicity, urticaria, acute coronary syndrome, adult-onset Stills disease, aplastic anemia, coronary sclerosis, atopic eczema; autoimmune disorder associated with streptococcus infection, autoimmune enteropathy, autoimmune hearing loss, autoimmune lymphoproliferative syndrome (ALPS), autoimmune myocarditis, autoimmune premature ovarian failure; celiac disease, cervical spondylosis, clinically isolated syndrome (cis) with the risk for multiple sclerosis, erythema multiform, severe erythema multiform, pemphigoid, bullous pemphigoid, cicatrical pemphigoid, mucosal pemphigoid, gestational pemphigoid, iritis, keratitis, motor neuron disease, non-A, non-B hepatitis, optic neuritis, oligoarticular JIA, polyarteritis nodosa, polychondritis, poliosis, polymyositis, relapsing neuromyelitis optica, rheumatic heart disease, SAPHO (synovitis, acne, pustulosis, hyperostosis and osteitis), secondary amyloidosis, ankylosing spondylitis, systemic inflammation response syndrome, cranial arteritis, and Yersinia- or Salmonella-associated arthropathy.

[0744] Additional diseases or disorders that can be treated with the compositions of the present disclosure include the diseases described in in Patent Application No. PCT/RU2015/000163, the relevant parts of which are incorporated herein by reference.

[0745] Provided pharmaceutical compositions can be administered to an individual in need of treatment through a systemic injection, for example, by intravenous or subcutaneous or intramuscular injection; or by injection or application to an appropriate site, for example, by direct injection or direct application to the site, when the site is available for surgery; or through topical use.

[0746] In one embodiment, the present disclosure relates to a method of treating and/or preventing axial spondylitis, comprising administering to a mammal in need thereof a therapeutically effective amount of one of the provided an anti-IL17a antibodies of the disclosure compositions.

[0747] In one embodiment, the present disclosure relates to a method of treating and/or preventing ankylosing spondylitis, comprising administering to a mammal in need thereof a therapeutically effective amount of one of the provided an anti-IL17a antibodies of the disclosure compositions.

[0748] In one embodiment, the present disclosure relates to a method of treating and/or preventing psoriasis, comprising administering to a mammal in need thereof a therapeutically effective amount of one of the provided an anti-IL17a antibodies of the disclosure compositions.

[0749] In one embodiment, the present disclosure relates to a method of treating and/or preventing psoriasis vulgaris or plaque psoriasis, comprising administering to a mammal in need thereof a therapeutically effective amount of one of the provided an anti-IL17a antibodies of the disclosure compositions.

[0750] In one embodiment, the present disclosure relates to a method of treating and/or preventing nail psoriasis, comprising administering to a mammal in need thereof a therapeutically effective amount of one of the provided an anti-IL17a antibodies of the disclosure compositions.

[0751] In one embodiment, the present disclosure relates to a method of treating and/or preventing genital psoriasis, comprising administering to a mammal in need thereof a therapeutically effective amount of one of the provided an anti-IL17a antibodies of the disclosure compositions.

[0752] In one embodiment, the present disclosure relates to a method of treating and/or preventing scalp psoriasis, comprising administering to a mammal in need thereof a therapeutically effective amount of one of the provided an anti-IL17a antibodies of the disclosure compositions.

[0753] In one embodiment, the present disclosure relates to a method of treating and/or preventing palmoplanar psoriasis, comprising administering to a mammal in need thereof a therapeutically effective amount of one of the provided an anti-IL17a antibodies of the disclosure compositions.

[0754] In one embodiment, the present disclosure relates to a method of treating and/or preventing pustular psoriasis, comprising administering to a mammal in need thereof a therapeutically effective amount of one of the provided an anti-IL17a antibodies of the disclosure compositions.

[0755] In one embodiment, the present disclosure relates to a method of treating and/or preventing psoriatic arthritis, comprising administering to a mammal in need thereof a therapeutically effective amount of one of the provided an anti-IL17a antibodies of the disclosure compositions.

[0756] In one embodiment, the present disclosure relates to a method of treating and/or preventing bullous pemphigoid, comprising administering to a mammal in need thereof a therapeutically effective amount of one of the provided an anti-IL17a antibodies of the disclosure compositions.

[0757] In one embodiment, the present disclosure relates to a method of treating and/or preventing pyoderma gangrenosum, comprising administering to a mammal in need thereof a therapeutically effective amount of one of the provided an anti-IL17a antibodies of the disclosure compositions.

[0758] The therapeutically effective amount of anti-IL17a antibodies of the disclosure, and of the aqueous compositions including the anti-IL17a antibodies of the disclosure, in the formulations provided depends on the condition being treated, the severity of the condition, the previous therapy and the patient's history and response to the therapeutic agent. A suitable dose can be adjusted by the decision of the attending physician so that it can be administered to the patient once or through several injections.

[0759] In one of the embodiments, the effective amount of anti-IL17a antibodies of the disclosure per dose for a patient is from about 0.01 to 10 mg per kilogram body weight, or about 0.01 to 5 mg per kilogram body weight, or about 0.01 to 4 mg per kilogram body weight, or approximately 0.05-3 mg per kilogram body weight, or approximately 0.05 mg per kilogram body weight, or approximately 0.25 mg per kilogram body weight, or approximately 0.825 mg per kilogram body weight, or approximately 1.25 mg per kilogram body weight, or approximately 1.75 mg per kilogram body weight, or approximately 2.25 mg per kilogram body weight or approximately 3 mg per kilogram body weight.

[0760] The frequency of dosing may be normally about twice per week, or once per week, or about once every 2 weeks, or about once every 4 to 8 weeks, or about once every 10 weeks, or about once per month or about once every 3 months.

[0761] If the dose should be administered more than once a week, the illustrative dose range is the same as the dose ranges indicated above or less, and it is preferably administered two or more times a week with a dose range of 5-240 mg/dose.

[0762] In another embodiment, an acceptable dose for administration by injection may contain 5-300 mg/dose, or may contain 40 mg, or 50 mg, or 60 mg per dose; or may contain 70 mg, or 80 mg, or 90 mg, or 100 mg per dose; or may contain 110 mg, or 120 mg, or 130 mg, or 140 mg per dose; or may contain 150 mg, or 160 mg, or 170 mg, or 180 mg per dose; or may contain 190 mg, or 200 mg, or 210 mg, or 220 mg per dose; or may contain 230 mg, or 240 mg, or 250 mg, or 260 mg per dose; or may contain 270 mg, or 280 mg, or 290 mg per dose.

[0763] A dose may be delivered as one or more than one injection. A dose may be delivered as one, two or three injection. One injection may contain 1 mL or 2 mL of the disclosure composition.

[0764] In one embodiment, anti-IL17a antibodies of the disclosure may be administered at a dose of 40 mg by a single (sc) injection.

[0765] In one embodiment, anti-IL17a antibodies of the disclosure may be administered at a dose of 60 mg by a single injection.

[0766] In one embodiment, anti-IL17a antibodies of the disclosure may be administered at a dose of 70 mg by a single injection.

[0767] In one embodiment, anti-IL17a antibodies of the disclosure may be administered at a dose of 80 mg by a single injection.

[0768] In one embodiment, anti-IL17a antibodies of the disclosure may be administered at a dose of 80 mg as two injections of 40 mg.

[0769] In one embodiment, anti-IL17a antibodies of the disclosure may be administered at a dose of 100 mg by a single injection.

[0770] In one embodiment, anti-IL17a antibodies of the disclosure may be administered at a dose of 120 mg by a single injection.

[0771] In one embodiment, anti-IL17a antibodies of the disclosure may be administered at a dose of 120 mg as two injections of 60 mg.

[0772] In some cases, to achieve the desired degree of improvement, treatment may be necessary for long periods. For incurable chronic conditions, the treatment regimen may be continued indefinitely.

[0773] In another embodiment, the pharmaceutical compositions of the present disclosure may be prepared as a bulk formulation, and in essence, the components of the pharmaceutical composition are present in amounts higher than may be required for administration, and are diluted accordingly before administration.

[0774] Alternatively, a pharmaceutical composition may be frozen, spray-dried or lyophilizated and reconstituted before application in an appropriate sterile carrier. Lyophilization can be performed using techniques in the art which includes various steps like freezing, annealing, primary and secondary drying.

[0775] The pharmaceutical compositions may be administered as a single therapeutic agent or in combination with additional therapeutic agents as needed. Thus, in one embodiment, the methods of treatment and/or prophylaxis provided are used in combination with the administration of a therapeutically effective amount of another active agent. Another active agent can be administered before, during or after the administration of the pharmaceutical compositions of the present disclosure. The other active agent may be administered as part of the provided composition or, alternatively, as a separate formulation.

[0776] The introduction provides a pharmaceutical composition can be carried out by various means, including parenteral, oral, buccal, nasal, rectal and local introduction. Parenteral administration may include, but not limited, transdermal, subcutaneous, intravenous, intra-arterial, intraperitoneal, intradermal, intracardiac, intraventricular, intracranial, intratracheal, intrathecal, intramuscular injection, intravitreal injection.

[0777] The pharmaceutical compositions of the present disclosure are particularly suitable for parenteral administration, i.e. subcutaneously, intramuscularly, intravenously, intraperitoneally, into the spinal cord, into the joints, intrasynovially and/or intrathecally. Parenteral administration may be by bolus injection or continuous infusion. Pharmaceutical compositions for injection can be in the standard dosage form, for example, in ampoules, vials, prefilled syringes or in multi-dose containers with an added preservative, but not limited to this. In addition, a number of recent approaches to drug delivery have been developed, and the pharmaceutical compositions of the present disclosure are suitable for administration by these new methods, for example, BD Physioject™, Inject-ease®, Genject®, pen-injectors such as GenPen®, and needleless devices such as like MediJector® and BioJector®. The pharmaceutical composition of the present disclosure can also be adapted for not yet open routes of administration.

[0778] See also Langer, 1990, Science, 249: 1527-1533.

[0779] The provided pharmaceutical compositions can also be formulated as a depot preparation. Such long-acting formulations can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compositions can be modified using suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil), or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0780] The pharmaceutical compositions, if desired, may be provided in a vial, package, or in a dispenser device, which may contain one or more unit dosage forms containing the active ingredient. In one embodiment, the dispenser device may comprise a syringe containing a single dose of the liquid composition ready for injection. The syringe may be accompanied by instructions for administration.

[0781] In another embodiment, the present disclosure relates to a kit or container containing the aqueous pharmaceutical composition according to the disclosure. The concentration of the polypeptide in the aqueous pharmaceutical composition may vary over a wide range, but, as a rule, within the range of from about 1 to about 200 mg/ml of aqueous composition. The kit may also be accompanied by instructions for use.

[0782] The method of obtaining the above compositions includes adding to the aqueous phase acetate buffer agents, followed by adding, in any sequence, the following components: osmolytic agent selected from disaccharides (such as trehalose, sucrose, or their combination), an anti-IL17a antibody comprising a VHH-derivative domain and a variable VL domain, and/or solubilizer selected from the group: polysorbate 20, polysorbate 80, poloxamer 188, or combinations thereof.

[0783] The method of obtaining the above compositions includes adding to the aqueous phase histidine buffer agents, followed by adding, in any sequence, the following components: osmolytic agent selected from sugar-based alcohols (such as mannitol, sorbitol, or their combination), an anti-IL17a antibody comprising a VHH-derivative domain and a variable VL domain, and/or solubilizer selected from the group: polysorbate 20, polysorbate 80, poloxamer 188, or combinations thereof.

[0784] Exemplary Study:

[0785] The following represents an exemplary study for determining reagents and concentrations of same for making an aqueous composition of the anti-IL17a antibodies of the present disclosure, such as Netakimab.

[0786] It will be understood that the experiments and methods described herein refer to an anti-IL17a antibody of the disclosure, such as Netakimab, with a variable V.sub.HH domain and a variable V.sub.L domain. Exemplary suitable antibodies are described in Patent Application No. PCT/RU2015/000163.

[0787] It will be understood that even though the exemplary studies and examples presented herein refer to Netakimab as an exemplary antibody, the exemplary studies and examples may apply to another antibody of the disclosure without departing from the present teachings (e.g. namely due to the structural similarities of the antibodies of the present disclosure, a V.sub.HH variable domain joined to a V.sub.L variable domain).

[0788] The examples and studies presented herein are for illustrative purposes, demonstrating the suitability of certain of the constituents used in the anti-IL17a antibody aqueous compositions of the present disclosure. It will be understood that other methods and techniques may be used by a person of ordinary skill in the art without departing from the present teachings.

[0789] The suitability of the aqueous compositions of the present disclosure were tested using the exemplary methods described herein.

[0790] Method 1: Preparing Stable Anti-IL17 Antibody Formulations

[0791] Antibody samples (10 mg/ml) were prepared in Stirred Cell (Millipore) under pressure. To this end, the initial antibody formulation was placed in a cell, the protein was concentrated under a compressed air stream to 10 mg/ml under continuous stirring, at least 10-fold volume of an aqueous solution with the target formulation comprising buffering agents, osmotic agents and, if necessary, additional water-soluble stabilizers was then added to the cell. After diafiltration the antibody was concentrated to about 12-20 mg/ml, unloaded from the cell, and the exact protein concentration was measured by UV spectroscopy. An appropriate placebo solution was then added to the sample to prepare a solution comprising protein at a target concentration of 10±0.5 mg/ml.

[0792] Protein samples at 40 mg/ml or higher were prepared in Pellicon cassettes (Millipore) in a tangential flow mode. To this end, the initial antibody formulation was placed in a diafiltration tank, the protein was concentrated to 40-100 mg/ml, at least 10-fold volume of the solution with the target formulation comprising buffering agents, osmotic agents and, if necessary, additional water-soluble stabilizers was then supplied to the system. The concentrate of osmotic agents and water-soluble stabilizers may alternatively be added after diafiltration. After diafiltration the antibody was concentrated to a concentration exceeding the target one, unloaded from the system, and the exact protein concentration was measured. An appropriate placebo solution was then added to the sample to prepare a solution with protein at the target concentration.

[0793] When obtaining formulations comprising solubilizers, the surfactant concentrates were added to the antibody after diafiltering and concentrating, with the final dilution of the antibody to the target concentration with a placebo solution.

[0794] Before aseptic filling in the final container (for example, a glass/plastic vessel, vial or syringe), the antibody solution was filtered using a 0.22 μm membrane.

[0795] Method 2: Protein Concentration Assay in Test Samples

[0796] The protein concentration was measured by UV spectroscopy at a wavelength of 280 nm in UV transparent plates.

[0797] Each sample was diluted with a solution of appropriate placebo to around 0.5 mg/mL; 150 μl of the diluted sample was placed to a UV spectroscopy plate well. Optical density of solutions in the plate wells was measured using a plate spectrophotometer at a wavelength of 280 nm. An appropriate placebo solution was used as a reference solution.

[0798] Concentration (mg/ml) of protein (C) was calculated using the following formula:

[00001]$C=\frac{A\left(280\right)*b}{\epsilon *l}$

[0799] A.sub.280 is a value of optical density at a wavelength of 280 nm;

[0800] ε is an extinction coefficient of test protein;

[0801] b is a total dilution factor for a sample;

[0802] l is layer thickness in a plate well; for 150 μl, l=0.42 cm.

[0803] Method 3: PEG Aggregation

[0804] The solution of PEG 6000 with a mass concentration of 20-25% in a test excipient composition was prepared. The resulting solutions were filtered through a Durapore 0.45 μm filter.

[0805] The estimated amount of the sample, excipient solution, and 20-25% PEG 6000 solution was transferred to 96 well UV plates so that the concentration of PEG 6000 in a number of wells ranged from 0% to 18% and protein concentration in each well was 1 mg/ml. All solutions obtained in wells were thoroughly mixed by pipetting.

[0806] Turbidity of solutions was then evaluated visually, and optical density of solutions at a wavelength of 400 nm was measured.

[0807] Protein precipitation in the presence of PEG is associated with the effect of volume substitution, i.e. protein is sterically excluded from regions of solvent by the polymer. This results in an increase of protein concentration until its solubility will be exceeded and it will be precipitated. The less stable is a sample, the lower is PEG 6000 concentration, at which the sample will form visible aggregates (opalescence).

[0808] Method 4: Evaluation of Colloidal Stability by Shake Test

[0809] Test samples were divided into 2 portions of 200 μl each and placed into glass vials, 1 vial per formulation was stored in a refrigerator at 2-8° C., the rest vials were shaken at 800 rpm at 2-8° C. for the specified period. After the stress, the vials were then vortexed and transferred for analysis.

[0810] Method 5: Evaluation of Colloidal Stability by Cryoconcentration

[0811] Test samples were divided into 2 portions and placed into plastic vials: 1 vial per formulation was stored in a refrigerator at 2-8° C., the rest vials were stored in a freezer at minus 16-20° C. for the specified period of time. After the stress, the vials were removed from the freezer, kept at room temperature until the content was completely thawed; the solutions were then mixed using a vortex and transferred for analysis.

[0812] Method 6: Evaluation of Thermal Stability by Thermostress

[0813] Test samples were divided into 2 portions and placed into separate glass vials: 1 vial per composition was stored in a refrigerator at 2-8° C., the rest vials were incubated in a thermostat at a required temperature for the specified period of time. After heating, the vials were removed from the thermostat, kept at room temperature for about 15 minutes, and transferred for analysis.

[0814] Method 7: Determination of Homogeneity and Protein Aggregation Point by Dynamic Light Scattering (DLS)

[0815] Homogeneity of test samples was evaluated on Zetasizer Nano ZSP (measurement mode: Size). To this end, 0.5 ml of a solution was placed in a dust-free plastic disposable cuvette. [0816] Analytical model: Protein analysis. [0817] Keeping for 30 seconds at temperature before starting the measurement. [0818] At each point, average value from 13 measurements in 3 replications.

[0819] The aggregation point of test proteins was determined on Zetasizer Nano ZSP. To this end, a solution was placed in a dust-free quartz cuvette, the cuvette was gradually heated in the device with constant measurement of the intensity of scattered light in the “Temperature trend” measurement mode. [0820] Analytical model: Protein analysis. [0821] Mode: Temperature trend, mod: Protein aggregation point. 50 to 85° C. at a heating increment of 1° C. [0822] Keeping for 60 seconds at temperature before starting the measurement. [0823] At each point, average value from 15 measurements in 1 replication.

[0824] The temperature trend was built using the device software that also automatically calculates the protein aggregation point.

[0825] Method 8: Determination of Samples Homogeneity by Size-Exclusion High-Performance Liquid Chromatography (SEC HPLC)

[0826] Sample homogeneity was then determined by performing high performance liquid chromatography (SEC HPLC) with the following specifications: [0827] Tosoh column TSK-GelG3000SWXL 7.8 mm ID×30 cm, cat. N° 08541. [0828] Column temperature: 25° C. [0829] Mobile phase flow rate: 0.7 ml/min. [0830] Injection volume: 10 μl. [0831] Sample concentration: 5 mg/ml. [0832] Detector wavelength: 220 nm. [0833] Elution time: 25 min. [0834] Mobile phase: Disodium hydrogen phosphate anhydrous 7.1 mg/ml. [0835] Sodium chloride 17.54 mg/ml.

[0836] The mobile phase pH was adjusted to 7.0 with orthophosphoric acid.

[0837] The change in purity after stress was calculated using the following formula:

Δ=(fracture of main peak after stress−fracture of main peak before stress)

[0838] Method 9: Evaluation of Acid-Base Profile of Samples Using Ion-Exchange (IE) HPLC

[0839] The acid-base profile of samples was then determined by performing ion-exchange (IE) HPLC in accordance with the following specifications: [0840] ProPac WCX-10 Analytical column, 4×250 mm [0841] ProPac WCX-10G guard column, 4×50 mm [0842] Column temperature: 25° C. [0843] Mobile phase flow rate: 0.7 ml/min [0844] Injection volume: 50 μl [0845] Sample concentration: 1 mg/ml [0846] Detector wavelength: 280 nM [0847] Elution time: 60 min [0848] Mobile phase: [0849] Eluent A: 20 mM 2-(N-morpholino)ethanesulfonic acid (MES), pH=6.0 [0850] Eluent B: 20 mM 2-(N-morpholino)ethanesulfonic acid (MES), 400 mM NaCl, pH=6.0 [0851] Phase A gradient: 87-0-90%.

[0852] Absolute change in the acid-base profile after stress was calculated with the following formula:

Δ=|acidic fraction amount before stress−acidic fraction amount after stress|+|dominant fraction amount before stress−dominant fraction amount after stress|+|alkaline fraction amount before stress−alkaline fraction amount after stress|

[0853] Method 10: Determination of Low Molecular Weight Impurities by Reducing and Non-Reducing Polyacrylamide Gel Electrophoresis (SDS-PAGE)

[0854] Polyacrylamide gel (PAAG) was prepared in glass plates in the presence of sodium dodecyl sulfate, said plates consisting of a concentrating layer of 4% PAAG and a separating layer of 12.5% PAAG (under reducing conditions)/8% PAAG (under non-reducing conditions).

[0855] An electrophoresis chamber was assembled and installed in accordance with a vertical electrophoresis apparatus user manual. Probes were prepared by diluting samples with purified water to a final concentration of 1 mg/ml. A volume equivalent of 40 μg was taken, and the prepared probes of the test sample were mixed in a ratio of 3:1 (volume/volume) with a 4× sample buffer solution containing 2-mercaptoethanol (reducing conditions) and not containing 2-mercaptoethanol (non-reducing conditions), and stirred. The resulting solutions were incubated at (99±1) ° C. for 3 min (samples containing 2-mercaptoethanol) and at (99±1) ° C. for 1 min (samples without 2-mercaptoethanol). The solutions were cooled to room temperature, mixed, and transferred to PAAG wells under an electrode buffer solution layer.

[0856] Electrophoresis was performed in constant current mode using a water-cooling system. Parameters of power supply were set: the voltage was 110 V during passing of the dye front through the concentrating gel. After moving of the dye front to the lower separation gel at the level of 5-7 mm, the voltage was increased to 180 V. The power supply was turned off when the dye front reached the bottom line of the gel.

[0857] After electrophoresis, the gels were detached from the glasses, and the proteins were fixed in a fixing solution for 16-18 hours at room temperature. The gels were then stained (in an Acid Blue 83 solution) and washed to obtain a clear visualization of the bands. The gels were scanned. The purity and impurities in the test samples were evaluated using GelPro software.

[0858] Method 11: Specific Activity Determination

[0859] The specific activity of monoclonal anti-IL17 antibody samples was evaluated by their ability to specifically bind IL17a protein and neutralize IL17a-dependent production of IL6 by HT1080 cells. The suspension of HT1080 cells was added to culture plates in a volume of 50 μl/well. The plates were incubated for 5-6 hours at 37° C., 5% CO.sub.2. Using a Freedom Evo robot, serial dilutions of the standard and test samples were prepared, mixed with IL17a+TNFα solution, incubated for 1 hour at room temperature. After incubation, the mixture was transferred to culture plates in a volume of 50 μl/well. The plates were incubated for 16-18 hours at 37° C., 5% CO2. All the procedures described above were performed under aseptic conditions.

[0860] The level of IL17a-dependent production of IL6 was detected by ELISA using an ELISA kit for measuring IL6 concentration: Human IL-6 DuoSet ELISA, R&D System, USA, cat. no. DY206.

[0861] Magellan 7.2 software was employed to plot four-parameter logistic curves (average optical density vs. protein concentration) for the standard sample/test sample solutions in the same plate.

[0862] The relative specific activity of the test sample as % (RP) was calculated by the following formula:

[00002]$\mathrm{RP}=\frac{{\mathrm{ED}}_{50}\mathrm{st}}{{\mathrm{ED}}_{50}\mathrm{test}}100\%,$

[0863] where ED.sub.50st—the value of half effective dose of a standard sample, ng/ml;

[0864] ED.sub.50test—the value of half effective dose of a test sample, ng/ml.

[0865] The average value of relative specific activity was taken as the final result, said average value was calculated from 3 independent measurements (determined from 3 different culture plates).

EXAMPLES

Example 1. Selecting the Buffer Solution

[0866] The present exemplary study covers two four typical buffer solutions for the antibodies of the present disclosure suitable for, e.g., parenteral administration, including subcutaneous administration.

[0867] Test Formulations (Per ml):

TABLE-US-00015 Name Composition 5 mM Acet, Netakimab 10 mg pH 5.0 Sodium acetate 0.44 mg trihydrate (t/h) Acetic acid glac. to pH 5.0 4.5 mM His, Netakimab 10 mg pH 6.0 L-Histidine 0.4 mg L-Histidine 0.4 mg hydrochloride monohydrate (m/h) 5 mM PB, Netakimab 10 mg pH 6.0 Sodium 0.59 mg dihydrogenphosphate monohydrate (m/h) Sodium hydrogen 0.10 mg phosphate anhydrous (anhyd.) 5 mM Cit, Netakimab 10 mg pH 5.0 Sodium citrate 0.93 mg dihydrate (d/h) Citric acid anhydrous 0.35 mg (anhyd.)

[0868] Determination of Colloidal Stability by PEG Aggregation

[0869] The results are present in Table 1 and in FIG. 1.

TABLE-US-00016 TABLE 1 Average optical density at 400 nm of solutions after preparation. PEG 6000, % 0% 2% 4% 6% 8% 10% 12% 14% 16% 18% Acet, 0.0540 0.0584 0.0728 0.0793 0.0990 0.1123 0.1272 0.1520 0.1747 0.2023 pH 5.0 His, 0.0411 0.0489 0.0490 0.0492 0.0599 0.0602 0.0623 0.0660 0.0906 0.0733 pH 6.0 PB, 0.0502 0.0523 0.0549 0.0559 0.0601 0.0665 0.1275 0.4731 1.1599 1.4772 pH 6.0 Cit, 0.0584 0.0598 0.0600 0.0561 0.0934 0.0958 0.5840 1.8051 2.4373 2.4714 pH 5.0 In bold: Visible aggregation is being observed.

[0870] The samples in histidine and acetate buffer solutions showed the highest colloidal stability in the presence of PEG. The phosphate- and citrate-based composition were excluded from further research, since aggregation at 12 BEG is an unsatisfying indicator when developing concentrated finished dosage forms for subcutaneous administration. Based on the obtained results, the acetate and histidine buffer solutions were selected for further development.

Example 2. Development of Anti-IL17 Excipient Composition Based on Histidine Buffer Solution

[0871] Buffer Solution pH/Ionic Strength Optimization

[0872] Test Formulations (Per ml):

TABLE-US-00017 4.5 mM His, Netakimab 10 mg pH 6.0 L-Histidine 0.4 mg L-Histidine 0.4 mg hydrochloride m/h  10 mM His, Netakimab 10 mg pH 6.0 L-Histidine 0.9 mg L-Histidine 0.9 mg hydrochloride m/h  20 mM His, Netakimab 10 mg pH 6.0 L-Histidine 1.8 mg L-Histidine 1.8 mg hydrochloride m/h  10 mM His, Netakimab 10 mg pH 5.5 L-Histidine 0.46 mg L-Histidine 1.48 mg hydrochloride m/h  10 mM His, Netakimab 10 mg pH 6.5 L-Histidine 1.16 mg L-Histidine 0.54 mg hydrochloride m/h

[0873] Determination of Colloidal Stability by PEG Aggregation

[0874] The results are given in Table 2 and in FIG. 2. Changing pH and histidine concentration does not affect the colloidal stability and theoretical solubility of protein.

TABLE-US-00018 TABLE 2 Solutions average optical density data. Sample name/ PEG concentration 0% 6% 8% 10% 12% 14% 16% 18% 4.5 mM His, pH 6.0 0.0528 0.0690 0.0576 0.0611 0.0576 0.0625 0.0572 0.0651  10 mM His, pH 6.0 0.0596 0.0665 0.0610 0.0663 0.0616 0.0662 0.0597 0.0673  20 mM His, pH 6.0 0.0576 0.0595 0.0624 0.0673 0.0649 0.0658 0.0676 0.0626  10 mM His, pH 5.5 0.0573 0.0584 0.0623 0.0637 0.0683 0.0638 0.0686 0.0619  10 mM His, pH 6.5 0.0586 0.0534 0.0629 0.0655 0.0683 0.0619 0.0643 0.0677

[0875] Evaluation of Thermal Stability and Temperature of Protein Aggregation

TABLE-US-00019 TABLE 3 Results summary Total change Change in in acid-base Change Aggregation purity, % profile, % in pH temperature, Thermostress 50° C., 48 h ° C. Test samples SEC IEC DLS 4.5 mM His, pH 6.0 −0.42 13.28 6.16 76  10 mM His, pH 6.0 −0.74 14.33 6.14 75  20 mM His, pH 6.0 −1.24 16.70 6.08 72  10 mM His, pH 5.5 −0.75 14.62 5.55 74  10 mM His, pH 6.5 −0.79 15.83 6.53 74 Bold: positive, best result; italic: negative, worst result; no bold or italic: average result

[0876] It was experimentally confirmed that an increase in the buffer capacity of the histidine buffer solution leads to a decrease in the thermal stability of anti-IL17 antibody. At the same time, a decrease in the histidine/histidine hydrochloride ratio to 0.4 mg/ml/0.4 mg/ml does not lead to a detectable pH shift after diafiltration and thermostress. Increasing the buffer solution pH to 6.5 slightly reduces the thermal stability of protein; the stability of anti-IL17 antibody in the pH range of 5.5-6.0 does not have significant differences.

[0877] The following placebo formulation is acceptable for further development (per ml):

TABLE-US-00020 L-Histidine 0.4 mg L-Histidine hydrochloride m/h 0.4 mg pH 6.0 ± 0.5

[0878] Selecting an Osmotic Agent

[0879] Four typical excipients were selected to be used as an osmolytic. Parenteral restrictions are taken into account when selecting their concentration.

[0880] Test Formulations (Per ml)

TABLE-US-00021 Hisbuf. + TRE Netakimab 10 mg pH 6.0 L-Histidine 0.4 mg L-Histidine 0.4 mg hydrochloride monohydrate Trehalose dihydrate 100 mg Hisbuf. + SUC Netakimab 10 mg pH 6.0 L-Histidine 0.4 mg L-Histidine 0.4 mg hydrochloride monohydrate Sucrose 100 mg Hisbuf. + MAN Netakimab 10 mg pH 6.0 L-Histidine 0.4 mg L-Histidine 0.4 mg hydrochloride monohydrate Mannitol 54.5 mg Hisbuf. + SORB Netakimab 10 mg pH 6.0 L-Histidine 0.4 mg Histidine 0.4 mg hydrochloride monohydrate Sorbitol 54.5 mg

[0881] Determination of Colloidal Stability by BEG Aggregation

[0882] The results are given in Table 4 and in FIG. 3.

TABLE-US-00022 TABLE 4 Solutions average optical density data. Sample name/ PEG concentration 0% 6% 8% 10% 12% 14% 16% 18% His + TRE 0.0574 0.0633 0.0636 0.0676 0.0714 0.0741 0.0794 0.0868 His + SUC 0.0527 0.0607 0.0643 0.0687 0.0742 0.0816 0.0914 0.0946 His + MAN 0.0485 0.0535 0.0597 0.0622 0.0676 0.074 0.0799 0.0847 His + SORB 0.0515 0.0610 0.0639 0.0705 0.0818 0.0893 0.0953 0.0935

[0883] Evaluation of Thermal Stability and Temperature of Protein Aggregation

[0884] The results of the evaluation of thermal stability and temperature of the protein aggregations are presented in Table 5.

TABLE-US-00023 TABLE 5 Results summary Total change Change in in acid-base Aggregation purity, % profile, % temperature, Thermostress 50° C., 48 h ° C. Test samples SEC IEC DLS His + TRE −0.73 16.31 72 His + SUC −0.54 16.21 71 His + MAN 74 His + SORB −1.48 19.46 71 Bold: positive, best result; italic: negative, worst result; no bold or italic: average result

[0885] All the above formulations provide sufficient thermal and colloidal stability of protein. However, the formulation that comprises mannitol has good thermostabilizing properties, as its formulation showed an increase in protein impurities after 48 hours of thermostress, as demonstrated by SEC, as well as the total change in isoform profile showed the minimum value as compared to other formulations obtained.

[0886] Based on the obtained data, the following placebo formulation is acceptable to be used as a pharmaceutical composition:

TABLE-US-00024 L-Histidine 0.4 mg/mL L-Histidine hydrochloride m/h 0.4 mg/mL Mannitol 54.5 mg/mL pH 6.0 ± 0.5

[0887] Choosing a Solubilizer and Optimizing its Content

[0888] To reduce the level of aggregation of the concentrated form of the monoclonal anti-IL17 antibody, the use of Polysorbate 80 and Poloxamer 188 solubilizers has been considered.

[0889] Test Formulations (Per ml)

TABLE-US-00025 His + MAN Netakimab 10 mg pH 6.0 L-Histidine 0.4 mg L-Histidine 0.4 mg hydrochloride m/h Mannitol 54.5 mg His + MAN + 0.1 PS80 Netakimab 10 mg pH 6.0 L-Histidine 0.4 mg L-Histidine 0.4 mg hydrochloride m/h Mannitol 54.5 mg Polysorbate 80 0.1 mg His + MAN + 0.2 PS80 Netakimab 10 mg pH 6.0 L-Histidine 0.4 mg L-Histidine 0.4 mg hydrochloride m/h Mannitol 54.5 mg Polysorbate 80 0.2 mg His + MAN + 0.5 PS80 Netakimab 10 mg pH 6.0 L-Histidine 0.4 mg L-Histidine 0.4 mg hydrochloride m/h Mannitol 54.5 mg Polysorbate 80 0.5 mg His + MAN + 1.0 PS80 Netakimab 10 mg pH 6.0 L-Histidine 0.4 mg L-Histidine 0.4 mg hydrochloride m/h Mannitol 51.5 mg Polysorbate 80 1.0 mg His + MAN + 0.1 Poloxamer Netakimab 10 mg pH 6.0 L-Histidine 0.4 mg L-Histidine 0.4 mg hydrochloride m/h Mannitol 54.5 mg Poloxamer 188 0.1 mg His + MAN + 1.0 Poloxamer Netakimab 10 mg pH 6.0 L-Histidine 0.4 mg L-Histidine 0.4 mg hydrochloride m/h Mannitol 54.5 mg Poloxamer 188 1.0 mg

[0890] Determination of Colloidal Stability by PEG Aggregation

[0891] The colloidal stability by PEG aggregation of the solutions was then determined. The results are given in Table 6 and in FIG. 4.

TABLE-US-00026 TABLE 6 Solutions average optical density data. Sample name/ PEG concentration 0% 6% 8% 10% 12% 14% 16% 18% His + MAN 0.0494 0.0517 0.0529 0.0549 0.0680 0.0612 0.0649 0.0746 His + MAN + 0.0483 0.0520 0.0537 0.0552 0.0635 0.0603 0.0628 0.0687 0.1 PS80 His + MAN + 0.0524 0.0551 0.0578 0.0591 0.0583 0.0642 0.0736 0.0802 0.2 PS80 His + MAN + 0.0526 0.0551 0.0557 0.0570 0.0710 0.0692 0.0701 0.0721 0.5 PS80 His + MAN + 0.0512 0.0576 0.0583 0.0572 0.0638 0.0653 0.0687 0.0734 1.0 PS80 His + MAN + 0.0534 0.0539 0.0576 0.0582 0.0639 0.0663 0.0658 0.0740 0.1 Poloxamer His + MAN + 0.0514 0.0534 0.0581 0.0522 0.0611 0.0678 0.0619 0.0730 1.0 Poloxamer

[0892] Evaluation of Thermal Stability and Temperature of Protein Aggregation

[0893] The thermal stability and temperature of protein aggregation was then determined, the results presented in Table 7.

TABLE-US-00027 TABLE 7 Results summary Change Total change in purity, in acid-base Aggregation % profile, % temperature, Thermostress 50° C., 48 h ° C. Test samples SEC IEC DLS His + MAN −0.30% 15.67 74 His + MAN + 0.1 PS80 −0.53% 15.91 72 His + MAN + 0.2 PS80 −2.72% 15.92 72 His + MAN + 0.5 PS80 −3.03% 15.78 71 His + MAN + 1.0 PS80 −4.27% 16.30 71 His + MAN + 0.1 −0.32% 15.55 74 Poloxamer His + MAN + 1.0 −0.37% 16.87 72 Poloxamer Bold: positive, best result; italic: negative, worst result; no bold or italic: average result

[0894] It has been shown that polysorbate 80 has a negative effect on the aggregation stability of anti-IL17 antibody. SEC demonstrates increased gain of impurities during thermostress with an increase in the content of this surfactant in the formulation. The content of poloxamer 188 as part of anti-IL17 antibody does not significantly affect the antibody stability. The acid-alkaline profile of the test protein does not significantly depend on the content of surfactants.

[0895] Based on the results of the study, the following exemplary placebo formulation is acceptable for the dosage form:

[0896] L-Histidine 0.4 mg/mL

[0897] L-Histidine hydrochloride m/h 0.4 mg/mL

[0898] Mannitol 54.5 mg/mL

[0899] Poloxamer 188 0-1.0 mg/mL

[0900] pH 6.0±0.5

Example 3. Development of Anti IL17 Excipient Composition Based on Acetate Buffer Solution

[0901] Buffer solution pH/ionic strength optimization was then studied.

[0902] The following test formulations (per ml) were prepared:

TABLE-US-00028  5 mM Acet, pH 5.0 Netakimab 10 mg Sodium acetate trihydrate 0.44 mg Acetic acid glac. to pH 5.0 10 mM Acet, pH 5.0 Netakimab 10 mg Sodium acetate trihydrate 0.87 mg Acetic acid glac. to pH 5.0 20 mM Acet, pH 5.0 Netakimab 10 mg Sodium acetate trihydrate 1.74 mg Acetic acid glac. to pH 5.0 20 mM Acet, pH 4.0 Netakimab 10 mg Sodium acetate trihydrate 0.98 mg Acetic acid glac. to pH 4.5 20 mM Acet, pH 6.0 Netakimab 10 mg Sodium acetate trihydrate 2.31 mg Acetic acid glac. to pH 5.5

[0903] As demonstrated in Example 2, the solution pH/buffer capacity do not have a significant impact on the results of PEG aggregation, therefore the results of this experiment are not shown for the acetate buffer solution in Example 3.

[0904] Evaluation of Thermal Stability and Temperature of Protein Aggregation

[0905] The evaluation of thermal stability and the temperature of protein aggregation was then performed, the resulted presented in Table 8.

TABLE-US-00029 TABLE 8 Results summary for sample before and after stresses. Change Total change in purity, in acid-base Change Aggregation % profile, % in pH temperature, Thermostress 50° C., 48 h ° C. Test samples SEC IEC DLS  5 mM Acet, pH 5.0 −0.10 14.74 5.23 74 10 mM Acet, pH 5.0 −0.12 14.68 5.18 74 20 mM Acet, pH 5.0 −0.11 15.81 5.01 77 20 mM Acet, pH 4.0 −0.18 15.07 4.52 74 20 mM Acet, pH 6.0 −0.15 15.23 5.56 77 Bold: positive, best result; italic: negative, worst result; no bold or italic: average result

[0906] It has been experimentally confirmed that an increase in the buffer capacity stabilizes the pH of the acetate buffer solution, but does not have a significant effect on the thermal stability of anti-IL17 antibody. It has also been shown that the test protein is stable in the pH range of 4.0-6.0.

[0907] The following placebo formulation is acceptable for further development (per ml)

TABLE-US-00030 Sodium acetate trihydrate 1.74 mg Acetic acid glac. to pH 5.0 ± 1.0

[0908] Selecting an Osmotic Agent

[0909] In the present study, four typical osmolytics were selected. Restrictions on possible parenteral administration are taken into account when selecting osmolytic concentration.

[0910] The following test formulations (per ml) were prepared:

TABLE-US-00031 Name Composition 20 mM ACET + TRE Netakimab 10 mg Sodium acetate trihydrate 1.74 mg Trehalore dihydrate 100 mg Acetic acid glac. to pH 5.0 20 mM ACET + SUC Netakimab 10 mg Sodium acetate trihydrate 1.74 mg Sucrose 100 mg Acetic acid glac. to pH 5.0 20 mM ACET + MAN Netakimab 10 mg Sodium acetate trihydrate 1.74 mg Mannitol 54.5 mg Acetic acid glac. to pH 5.0 20 mM ACET + SORB Netakimab 10 mg Sodium acetate trihydrate 1.74 mg Sorbitol 54.5 mg Acetic acid glac. to pH 5.0 20 mM ACET + PROL Netakimab 10 mg Sodium acetate trihydrate 1.74 mg L-Proline 27 mg Acetic acid glac. to pH 5.0

TABLE-US-00032 TABLE 9 Results summary for sample before and after stresses. Total change in Change in acid-base profile, % purity, % (modulo) Protein, Formulation Thermostress 50° C., 96 h No. mg/ml name SEC IEC 1 10 Acet + Tre −0.0 22.90 2 10 Acet + Suc −1.46 24.77 3 10 Acet + Man −0.15 26.18 4 10 Acet + Sorb −0.29 25.52 5 10 Acet + Prol −0.44 33.50 Bold: positive, best result; italic: negative, worst result; no bold or italic: average result

[0911] According to the results of the present study, an acceptable exemplary placebo formulation (excluding excipients):

TABLE-US-00033 Sodium acetate trihydrate 1.74 mg/ml Trehalose dihydrate  100 mg/ml Acetic acid glac. to pH 5.0

[0912] This formulation showed good stabilizing properties during thermostress at 50° C., shake-test and freezing, as compared to the rest tests samples. It showed the smallest change in purity by SEC after stressing and acceptable changes in the acid-base profile of the samples.

[0913] Selecting Stabilizers

[0914] To obtain a stable dosage form comprising a maximum concentration of anti-IL17 antibody, stabilizers were screened for samples with a protein concentration of 60, 100 and 120 mg/ml. To ensure the physiologicity of the solution, taking into account the contribution of protein and other stabilizers to osmolality, the content of trehalose dihydrate was reduced to 80 or 50 mg/ml.

[0915] The histidine-containing formulations of Example 2 were used as a reference solution. However, a stable histidine solution was obtained at a concentration of not more than 70 mg/ml.

[0916] Due to increased aggregation of highly concentrated solutions of proteins under thermostress at this stage, the thermostress temperature was reduced, which was compensated by longer thermostating time.

[0917] The following test formulations (per ml) were prepared:

TABLE-US-00034 Name Composition  4.5 mM His + Netakimab 40, 60, 70 mg mannitol L-Histidine 0.4 mg Mannitol 54.5 mg  4.5 mM His + Netakimab 40, 60, 70 mg mannitol L-Histidine 0.4 mg Mannitol 54.5 mg Poloxamer 188 1.0 mg  20 mM acetate Netakimab 60, 100,120 mg  80 trehalose Sodium acetate 1.74 mg trihydrate Acetic acid glac. to pH 5.0  20 mM acetate Netakimab 60, 100,120 mg  80 trehalose Sodium acetate 1.74 mg  0.5 Poloxamer 188 trihydrate Trehalose dihydrate 80 mg Poloxamer 188 0.5 mg Acetic acid glac. to pH 5.0  20 mM acetate Netakimab 60, 100,120 mg  80 trehalose Sodium acetate 1.74 mg  1.0 Poloxamer 188 trihydrate Trehalose dihydrate 80 mg Poloxamer 188 1.0 mg Acetic acid glac. to pH 5.0  20 mM acetate Netakimab 60, 100,120 mg  80 trehalose Sodium acetate 1.74 mg  0.5 Polysorbate 20 trihydrate Trehalose dihydrate 80 mg Polysorbate 20 0.5 mg Acetic acid glac. to pH 5.0  20 mM acetate Netakimab 60, 100,120 mg  80 trehalose Sodium acetate 1.74 mg HPB 10 trihydrate Trehalose dihydrate 80 mg Cyclodextrin HPB 10 mg Acetic acid glac. to pH 5.0   20 mM acetate Netakimab 60, 100,120 mg   80 trehalose Sodium acetate 1.74 mg HPB 20 trihydrate Trehalose dihydrate 80 mg Cyclodextrin HPB 20 mg Acetic acid glac. to pH 5.0  20 mM acetate Netakimab 60, 100,120 mg  80 trehalose Sodium acetate 1.74 mg  5 mM Methionine trihydrate Trehalose dihydrate 80 mg L-Methionine 0.746 mg Acetic acid glac. to pH 5.0  20 mM acetate Netakimab 60, 100,120 mg  80 trehalose Sodium acetate 1.74 mg  10 mM Methionine trihydrate Trehalose dihydrate 80 mg L-Methionine 1.492 mg Acetic acid glac. to pH 5.0  20 mM acetate Netakimab 60, 100,120 mg  80 trehalose Sodium acetate 1.74 mg  20 mM Methionine trihydrate Trehalose dihydrate 80 mg L-Methionine 2.984 mg Acetic acid glac. to pH 5.0  20 mM acetate Netakimab 60, 100,120 mg  50 trehalose Sodium acetate 1.74 mg  3 NaCl trihydrate Trehalose dihydrate 50 mg Sodium chloride 3 mg Acetic acid glac. to pH 5.0   20 mM acetate Netakimab 60, 100,120 mg   50 trehalose Sodium acetate 1.74 mg  100 mM Glycine trihydrate Trehalose dihydrate 50 mg Glycine 7.507 mg Acetic acid glac. to pH 5.0  20 mM acetate Netakimab 60, 100,120 mg  50 trehalose Sodium acetate 1.74 mg 100 mM Glycine + trihydrate 10 mM Meth Trehalose dihydrate 50 mg Glycine 7.507 mg L-Methionine 1.492 mg Acetic acid glac. to pH 5.0  20 mM acetate Netakimab 60, 100,120 mg  50 trehalose Sodium acetate 1.74 mg 100 mM Lysine trihydrate Trehalose dihydrate 50 mg L-Lysine monohydrate 16.42 mg Acetic acid glac. to pH 5.0  20 mM acetate Netakimab 60, 100,120 mg  50 trehalose Sodium acetate 1.74 mg 100 mM Serine trihydrate Trehalose dihydrate 50 mg L-Serine 10.91 mg Acetic acid glac. to pH 5.0  20 mM acetate Netakimab 60, 100,120 mg  50 trehalose Sodium acetate 1.74 mg 100 mM Guanidine trihydrate hydrochloride Trehalose dihydrate 50 mg Guanidine hydrochloride 9.55 mg Acetic acid glac. to pH 5.0  20 mM acetate Netakimab 60, 100,120 mg  50 trehalose Sodium acetate 1.74 mg  25 mM Leucine trihydrate Trehalose dihydrate 50 mg L-Leucine 3.28 mg Acetic acid glac. to pH 5.0  20 mM acetate Netakimab 60, 100,120 mg  50 trehalose Sodium acetate 1.74 mg  5 mM Tryptophan trihydrate Trehalose dihydrate 50 mg L-Tryprophan 1.02 mg Acetic acid glac. to pH 5.0  20 mM acetate Netakimab 60, 100,120 mg  50 trehalose Sodium acetate 1.74 mg 100 mM Glutamate trihydrate Trehalose dihydrate 50 mg Monosodium glutamate 16.91 mg Acetic acid glac. to pH 5.0  20 mM acetate Netakimab 60, 100,120 mg  50 trehalose Sodium acetate 1.74 mg 100 mM Arginine trihydrate hydrochloride Trehalose dihydrate 50 mg L-Arginine 21.07 mg hydrochloride Acetic acid glac. to pH 5.0  20 mM acetate Netakimab 60, 100,120 mg  50 trehalose Sodium acetate 1.74 mg  50 mM Glutamate trihydrate  50 mM Arginine Trehalose dihydrate 50 mg Monosodium glutamate 8.46 mg L-Arginine 10.53 mg hydrochloride Acetic acid glac. to pH 5.0

TABLE-US-00035 TABLE 10 SEC results summary for samples before and after stresses. Variation of monomer content, SEC, % Thermo- Thermo- Thermo- Thermo- stress, stress, stress, stress, Protein, 42° C., 42° C., 37° C., 37° C., No. mg/ml Formulation name 96 h 10 days 1 week 2 weeks 4.5 mM Histidine buffer solution-based formulations  1 40 54.5 mg/mL mannitol −0.68 −1.26 −0.72 −0.30  2 60 −0.84 −2.96 −1.56 −1.71  3 70 −1.75 −3.67 −1.23 −2.07  4 40 54.5 mg/mL mannitol + −0.55 −1.22 −0.65 −0.29  5 60 1.0 mg/mL poloxamer −0.38 −1.03 −1.28 −1.54  6 70 −1.72 −3.38 −1.39 −1.98 20 mM Acetate buffer solution-based formulations  7 60   80 mg/mL trehalose d/h −0.11 −1.50 −0.18 −0.56  8   80 mg/mL trehalose d/h + −0.17 −1.29 −0.25 −0.27 0.5 mg/mL Poloxamer  9   80 mg/mL trehalose d/h + −0.05 −1.25 −0.31 −0.49 1 mg/mL Poloxamer 10   50 mg/mL trehalose d/h −0.43 −1.47 −0.13 −1.16 100 mM Gly 11   50 mg/mL trehalose d/h   0.15 −1.53 −0.09 −0.89 10 mM Meth 12   50 mg/mL trehalose d/h −0.29 −2.58 −0.24 −0.59 100 mM Glutamate 13   50 mg/mL trehalose d/h −0.15 −3.82 −0.79 −1.38 50 mM Glutamate 50 mM Arginine 14 100   80 mg/mL trehalose d/h −0.53 −2.96 −1.35 −0.81 15   80 mg/mL trehalose d/h −1.02 −3.54 −1.08 −1.47 0.5 mg/mL Poloxamer 188 16   80 mg/mL trehalose d/h + −0.97 −2.99 −0.99 −1.52 1 mg/mL Poloxamer 17   80 mg/mL trehalose d/h −1.43 −4.46 −1.94 −1.56 0.5 mg/mL Polysorbate 20 18   80 mg/mL trehalose d/h −1.11 −3.38 −1.67 −1.84 10 mg/mL HPB Cyclodextrine 19   80 mg/mL trehalose d/h −1.37 −3.22 −1.72 −1.16 20 mg/mL HPB Cyclodextrine 20   80 mg/mL trehalose d/h −1.08 −3.46 −1.88 −1.22 5 mM Methionine 21   80 mg/mL trehalose d/h −0.48 −2.99 −1.63 −1.05 10 nnM Methionine 22   80 mg/mL trehalose d/h −0.77 −3.70 −0.12 −1.32 20 mM Methionine 23   50 mg/mL trehalose d/h −2.79 −6.34 −2.60 −2.94 3 mg/mL NaCl 24   50 mg/mL trehalose d/h −1.76 −3.45 −2.50 −1.06 100 mM Glycine 25   50 mg/mL trehalose d/h −1.45 −3.56 −2.04 −1.25 100 mM Glycine + 10 mM Methionine 26   50 mg/m trehalose d/h −4.58 −8.00 −4.15 −4.70 100 mM Lysine 27   50 mg/mL trehalose d/h −1.27 −3.59 −2.20 −1.20 100 mM Serine 28   50 mg/mL trehalose d/h −5.84 −8.08 −4.74 −5.57 100 mM Guanidine hydrochloride 29   50 mg/mL trehalose d/h −1.12 −3.86 −2.30 −2.19 25 mM Leucine 30   50 mg/mL trehalose d/h −1.74 −3.38 −1.53 −1.89 5 mM Tryptophan 31 100   50 mg/mL trehalose d/h −1.92 −5.59 −2.42 −1.93 100 mM Glutamate 32   50 mg/mL trehalose d/h −5.35 −7.73 −4.26 −5.58 100 mM Arginine hydrochloride 33   50 mg/mL trehalose d/h −3.40 −6.94 −2.65 −3.84 50 nnM Glutamate 34 120   50 mM Arginine −0.28 −4.13 −1.86 −1.94 80 mg/mL trehalose d/h 35   80 mg/mL trehalose d/h + −0.32 −3.10 −1.06 −1.27 0.5 mg/mL Poloxamer 36   80 mg/mL trehalose d/h + −0.36 −3.01 −0.98 −1.10 1 mg/mL Poloxamer 37   50 mg/mL trehalose d/h −2.32 −3.27 −1.13 −2.29 100 mM Gly 38   50 mg/mL trehalose d/h −2.45 −4.50 −0.64 −2.39 10 mM Methionine 39   50 mg/mL trehalose d/h −3.02 −6.18 −1.88 −2.69 100 mM Glutamate 40   50 mg/mL trehalose d/h −3.13 −8.26 −1.18 −3.73 50 mM Glutamate 50 mM Arginine

[0918] As confirmed by SEC, formulation containing trehalose dihydrate and poloxamer 188 exhibit the excellent stabilizing properties in the range of anti-IL17 antibody of the disclosure concentrations of 60-120 mg/ml. Also, the stabilizing effect of L-methionine and glycine on the test protein under thermostress was observed. The histidine buffer solution-based formulation has a lower solubility; however, it shows sufficient thermal stability for further use.

[0919] Selecting Stabilizers

[0920] To confirm the stability of the anti-IL17 antibody of the disclosure in the recommended formulations, the samples were subjected to accelerated aging at +37° C. At this stage, the formulations were analyzed to determine such quality indicators as specific activity, low molecular weight impurities, acid-base profile, purity. The results are shown in table 11.

TABLE-US-00036 TABLE 11 Protein 2 4 concen- weeks weeks Change Quality tration, Incoming at at after 4 Sample indicator Norm mg/ml control 37° C. 37° C. weeks Placebo pH 6.0 ± 0.5 40 6.17 — 6.11 −0.05 composition: 60 6.17 — 6.15 −0.02 L-Histidine 70 6.18 — 6.14 −0.04 0.4 mg/ml Purity, Not less 40 97.02 96.72 95.60 −1.42 L-Histidine SEC than 95 % 60 97.22 95.46 94.28 −2.94 hydrochloride (aggregate 70 97.31 94.95 93.67 −3.64 monohydrate content− 0.4 mg/ml upper Mannitol value, 54.4 mg/ml monomer content- lower value) SDS-PAGE Not less 40 95.66 95.26 94.37 −1.29 than 95 % 60 95.64 95.10 93.71 −1.93 in reduced 70 95.70 94.58 94.25 −1.45 conditions Not less 40 95.90 94.15 92.32 −3.58 than 90 % 60 95.88 93.67 92.00 −3.88 in 70 95.12 93.68 92.09 −3.03 nonreduced Acid-basic — 40 12.64 17.02 22.30 23.54 profile, 75.99 70.39 64.22 IEX HPLC 11.37 12.59 13.48 60 12.90 19.20 23.01 24.18 75.20 69.28 63.11 11.9 11.52 13.88 70 12.88 20.02 23.40 25.18 75.46 66.32 62.87 11.66 13.66 13.73 Potency 80-125 % 40 111 — 102 −9 of 60 109 — 98 −11 reference 70 105 — 96 −9 standard Placebo pH 6.0 ± 0.5 40 6.15 — 6.13 −0.02 composition: 60 6.20 — 6.18 −0.02 L-Histidine 70 6.22 — 6.16 −0.06 0.4 mg/ml Purity, Not less 40 97.11 96.16 95.44 −1.67 L-Histidine SEC than 95 % 60 97.28 95.12 94.69 −2.59 hydrochloride (aggregate 70 97.52 94.29 93.89 −3.63 monohydrate content- 0.4 mg/ml upper Mannitol value, 54.5 mg/ml monomer Poloxamer 188 content- 1 mg/ml lower value) SDS-PAGE Not less 40 95.23 94.76 94.12 −1.11 than 95 % 60 95.39 95.02 93.48 −1.91 in reduced 70 95.42 94.67 94.12 −1.30 conditions Not less 40 95.64 94.87 92.75 −2.89 than 90 % 60 95.43 93.58 92.49 −2.94 in 70 95.29 93.45 92.19 −3.10 nonreduced Acid-basic — 40 12.32 17.02 21.69 21.98 profile, 75.68 70.39 64.69 IEX HPLC 12.00 12.59 13.62 60 12.09 19.20 23.44 24.42 75.31 69.28 63.10 12.60 11.52 13.46 70 12.40 20.02 24.09 27.18 75.76 66.32 62.17 11.84 13.66 13.74 Potency 80-125 % 40 100 — 96 −4 of 60 102 — 92 −10 reference 70 106 — 94 −12 standard Placebo pH 6.0 ± 0.5 60 5.21 — 5.24 0.03 composition: 100 5.34 — 5.40 0.06 Sodium 120 5.34 — 5.41 0.07 acetate Purity, Not less 60 95.98 95.41 96.22 0.25 trihydrate SEC than 95 % 100 95.96 95.16 94.15 −1.81 1.74 mg/ml (aggregate 120 95.48 94.04 93.97 −1.51 Acetic acid to content- pH 5.0 upper Trehalose value, dihydrate monomer 80 mg/ml content- lower value) SDS-PAGE Not less 60 95.57 95.13 94.60 −0.97 than 95 % 100 95.30 94.99 94.58 −0.72 in reduced 120 95.44 95.26 94.58 −0.86 conditions Not less 60 95.31 95.06 94.58 −0.73 than 90 % 100 95.42 94.77 94.48 −0.94 in nonreduced 120 95.67 94.23 94.21 −1.46 Acid-basic — 60 13.33 20.34 22.83 26.60 profile, 76.17 66.32 62.87 IEX HPLC 10.50 13.34 14.30 100 13.38 20.94 23.10 27.78 76.01 65.23 62.12 10.61 13.83 14.78 120 13.12 21.00 22.11 32.38 75.19 64.91 59.00 11.69 14.09 18.89 Potency 80-125 % 60 98 95 −3 of 100 99 92 −7 reference 120 104 97 −7 standard Placebo pH 6.0 ± 0.5 60 5.21 — 5.28 0.07 composition: 100 5.33 — 5.41 0.08 Sodium 120 5.32 — 5.42 0.10 acetate Purity, Not less 60 95.98 96.02 96.04 0.07 trihydrate SEC than 95 % 100 95.98 94.89 93.83 −2.15 1.74 mg/ml (aggregate 120 95.98 94.71 94.00 −1.97 Acetic acid to content- pH 5.0 upper Trehalose value, dihydrate monomer 80 mg/ml content- Poloxamer 188 1 mg/ml lower value) SDS-PAGE Not less 60 94.98 94.58 94.21 −0.77 than 95 % 100 94.89 94.60 94.37 −0.52 in reduced 120 95.35 95.10 94.37 −0.98 conditions Not less 60 95.01 93.54 92.91 −2.10 than 90 % 100 94.58 93.15 92.06 −2.52 in nonreduced 120 95.55 94.34 93.66 −1.89 Acid-basic — 60 13.56 20.34 22.99 28.02 profile, 76.02 65.03 62.01 IEX HPLC 10.42 14.63 15.00 100 13.49 19.98 23.87 30.90 76.45 65.24 61.00 10.06 14.78 15.13 120 13.52 22.10 23.78 35.16 75.69 64.19 58.11 10.79 13.71 18.11 Potency 80-125 % 60 108 — 101 −7 of 100 103 — 97 −6 reference 120 110 — 99 −11 standard

[0921] Accelerated aging of samples for 1 month at +37° C. has proved the maintenance of the homogeneity and specific activity of anti-IL17 antibody of the disclosure with the exemplary acceptable storage formulations:

TABLE-US-00037 Anti-IL17 antibody 10-70 mg/mL L-Histidine 0.4 mg/mL L-Histidine hydrochloride monohydrate 0.4 mg/mL Mannitol 54.5 mg/mL Poloxamer 188 0-1 mg/mL pH 6.0 ± 0.5 Anti-IL17 antibody 10-120 mg/mL Sodium acetate trihydrate 0.44-1.74 mg/mL Trehalose dihydrate 80-100 mg/mL Poloxamer 188 0-1 mg/mL Acetic acid glac. to pH 5.0 pH 5.0 ± 0.5

[0922] Although the invention has been described with reference to preferred embodiments, it is to be understood that modifications may be resorted to as will be apparent to those skilled in the art. Such modifications and variations are to be considered within the purview and scope of the present invention.

[0923] Representative, non-limiting examples of the present invention were described above in detail with reference to the attached drawing. This detailed description is merely intended to teach a person of skill in the art further details for practicing preferred aspects of the present teachings and is not intended to limit the scope of the invention. Furthermore, each of the additional features and teachings disclosed above and below may be utilized separately or in conjunction with other features and teachings.

[0924] Moreover, combinations of features and steps disclosed in the above detailed description, as well as in the experimental examples, may not be necessary to practice the invention in the broadest sense, and are instead taught merely to particularly describe representative examples of the invention. Furthermore, various features of the above-described representative examples, as well as the various independent and dependent claims below, may be combined in ways that are not specifically and explicitly enumerated in order to provide additional useful embodiments of the present teachings.

[0925] Additional Exemplary Studies

[0926] Additional exemplary studies were conducted using different pharmaceutical compositions including anti-IL17a antibody as described herein (e.g. Netakimab) for treating different IL17a mediated diseases. The exemplary pharmaceutical compositions used for these studies are described in Table 11.1:

TABLE-US-00038 TABLE 11.1 Clinical Therapeutic Composition per trial code Indication doses, mg Phase 1 mL of solution BCD-085-2 plaque  40, 80, 120 II anti-IL17 monoclonal psoriasis antibody 40.0 mg, BCD-085-2ext plaque  80, 120 histidine psoriasis hydrochloride BCD-085-3 ankylosing  40, 80, 120 monohydrate 0.4 mg, spondylitis L-histidine 0.4 mg, BCD-085-3ext ankylosing  80, 120 mannitol 54.5 mg, spondylitis water for injection ad 1.0 mL BCD-085-7, plaque 120 III anti-IL-17 BCD-085-4 psoriasis monoclonal antibody BCD-085-5 ankylosing 120 60.0 mg, spondylitis sodium acetate BCD-085-8 psoriatic 120 trihydrate 1.74 mg, arthritis trehalose dihydrate 80 mg, poloxamer (kollifor) 188 0.5 mg, glacial acetic acid ad pH 5.0, water for injection ad 1.0 mL

[0927] In some examples, 80 mg was administered as 2 syringes (1 mL each, 40 mg BCD-085), where in others, 120 mg was administered as 3 syringes (1 mL each, 40 mg BCD-085) or 120 mg was administered as 2 syringes (1 mL each, 60 mg BCD-085).

[0928] The different doses of the pharmaceutical compositions and/or Netakimab described in Table 11.1 were shown to be suitable for treatment of the respective IL17a mediated diseases as described in Table 11.1, and by following the dosage regimens as further detailed herein. As such, different doses/dosage regimens of Netakimab and its pharmaceutical compositions as described herein may be used for treatment in a subject.

[0929] The results of the exemplary studies are described herein.

Example 4. Use of Netakimab at Different Doses to Treat Plaque Psoriasis (PSO), Proof-of Concept Study (BCD-085-2)

[0930] Study Design

[0931] BCD-085-2 is a multicenter double-blind placebo-controlled randomized phase II clinical study in patients with moderate-to-severe plaque psoriasis. The primary objective was to find an effective and safe dose of BCD-085 for multiple injections in patients with moderate to severe plaque-type psoriasis. Pharmacokinetics and immunogenicity assessments were included in secondary objectives of the study.

[0932] The study population is presented by adult patients (18-65 years old inclusively) with moderate to severe plaque psoriasis established for at least 6 months before screening, with baseline BSA involved with psoriasis ≥10%, PASI score of 12 or greater, sPGA score of 3 or greater, who are candidates for systemic or phototherapy or have failed previous biologic therapy. Patients with previous use of monoclonal antibodies were allowed to participate (with exception of previous IL17/IL17R inhibitors use) after appropriate wash-out periods.

[0933] 120 patients were randomized (1:1:1:1) into the 4 treatment groups: 1) BCD-085 40 mg, 2) BCD-085 80 mg, 3) BCD-085 120 mg and 4) placebo. BCD-085-2 study used 40 mg/1 ml formulation of BCD-085 in pre-filled syringes. BCD-085/placebo was used on Day 1 at weeks 0, 1, 2, 4, 6, 8 and 10. For blinding purposes, patients from 40 mg and 80 mg arms received two or one SC injections of placebo (1 mL each), respectively. Patients in the control arm received 3 SC injections of placebo (each injection was 1.0 mL). Patients were followed up for safety up to week 14.

[0934] The hypothesis of the study was that BCD-085 has superior efficacy over placebo in patients with moderate-to-severe plaque psoriasis. The superiority margin (δ) was 0.1 (10%), type 1 error (α) of −5% (0.05), type 2 error (β) of 20% (0.2) and power of 80%. The primary endpoint in this study was the proportion of patients who achieved PASI75 at week 12. PASI 75 achievement was defined as at least 75% improvement of the overall PASI score at Week 12 versus baseline. Secondary endpoints include assessment of PASI 50 and PASI 90, sPGA 0-1, percent improvement in PASI, BSA and NAPSI scores, change in itching assessment by VAS (mm), assessment of QoL (SF-36 and DLQI). The efficacy endpoints were evaluated at weeks 0, 4, 8 and 12. Safety endpoints included rates of adverse events (AE), SAE, 3-4 grade AE according to CTCAE 4.03, rates of early study discontinuation due to AE. Pharmacokinetic endpoints included standard BK parameters (C.sub.min, AUC.sub.(0-168), AUC.sub.(0-672), T.sub.max, T½, Vd, K.sub.el, CL). Immunogenicity parameters included incidence of binding and neutralizing antibodies to BCD-085 after multiple drug injections.

[0935] Study Results

[0936] Demographics and baseline characteristics were comparable between groups (Table 12).

TABLE-US-00039 TABLE 12 Baseline characteristics of patients (BCD-085-2 study) BCD-085 40 mg BCD-085 80 mg BCD-085 120 mg Placebo Parameter (n = 30) (n = 30) (n = 28) (n = 26) Age (years), 41.50 [32.00-50.00] 35.00 [29.00-45.00] 45.00 [35.00-54.00] 41.50 [32.00-48.00] Median [IQR] BMI (kg/m.sup.2), 25.81 [23.7-28.09] 26.85 [23.62-29.59] 29.72 [24.15-31.94] 24.95 [22.95-30.12] median [IQR] Male sex,   23 (76.67%)   19 (63.33%)   22 (78.57%)   15 (57.69%) no. (%) Duration of   178 [76.00-224.00]   137 [73.00-187.00]   137 [46.00-191.00   112 [69.00-211.00] the disease (months), median [IQR] PASI score,  25.7 [17.4-30.7]  21.9 [17.4-28.2] 23.55 [16.4-30.6]  26.4 [17.8-31.1] median [IQR] BSA %,   31 [18-39] 23.05 [17.5-36] 31.8 [21.9-40]   31 [16-38] median [IQR] sPGA score,    4 [3-4]    4 [3-4]    4 [3-4]    4 [3-4] median [IQR] Prior use of    6 (20%)    4 (14.33%)    4 (14.29%)    3 (11.54%) systemic glucocorticoids, no. (%) Prior use of   21 (70%)   19 (63%)   19 (67.86%)   20 (76.92%) phototherapy, no. (%) Prior biologic    1 (3.33%)    1 (3.33%)    1 (3.57%)    0 (0.00%) treatment, no. (%) Note: IQR—interquartile range

[0937] The efficacy population comprised 114 patients. Six of 120 randomized subjects were not included in the efficacy assessment due to the following reasons: IC recalled before the first dosing (1 patient in the 80 mg BCD-085 arm and 2 patients in the 120 mg BCD-085 arm), violated inclusion/exclusion criteria (1 patient in the 40 mg BCD-085 arm), and violation of the dosing regimen (2 patients in the placebo arm). The analysis has shown that BCD-085 in all tested doses is superior to placebo in patients with moderate to severe plaque-type psoriasis. Over 90% of patients in the highest-dose arm (120 mg) responded to the treatment. The main efficacy results are presented on Table 13, FIG. 5, FIG. 6, FIG. 7.

TABLE-US-00040 TABLE 13 Comparative assessment of the frequency of PASI75 responses at Week 12 (BCD-085-2 Study) Proportion of PASI 75 Arm Drug achievers, n (%) p-value 1 (n = 30) BCD-085 (40 mg) 24 (80.0%) p.sub.1 < 0.0001 2 (n = 30) BCD-085 (80 mg) 25 (83.33%) p.sub.2 < 0.0001 3 (n = 28) BCD-085 (120 mg) 26 (92.86%) 4 (n = 26) Placebo  6 (23.08%) Note: .sup.1—two-tailed Fisher's exact test; .sup.2 —Yates-corrected χ.sup.2 test.

[0938] To prove the protocol-stated hypothesis of BCD-085 being superior to placebo, the 95% CIs were calculated for the difference in proportions of PASI 75 achievement (individual pairwise comparisons were performed for placebo versus each BCD-085 arm). The hypothesis was accepted if the lower bound of the estimated 95% CI for the difference in proportions of PASI 75 achievement was above the pre-specified margin of clinically non-meaningful differences (δ) of 10% (0.10). The results are provided in Table 14.

TABLE-US-00041 TABLE 14 Comparative assessment of the frequency of PASI75 responses at Week 12 (BCD-085-2 Study) Difference in PASI 75 achievement 95% CI p-value.sup.1 Arms 1 and 4 56.92% [31.72%; 82.13%] <0.0001 Arms 2 and 4 60.25% [35.69%; 84.83%] <0.0001 Arms 3 and 4 69.78% [47.28%; 92.28%] <0.0001 Note: .sup.1—two-tailed Yates-corrected χ.sup.2 test

[0939] This table shows that the lower bounds of the 95% CIs for all pairwise comparisons (placebo versus BCD-085) fall outside the pre-specified superiority margin. Thus, the hypothesis of BCD-085 being superior to placebo in patients with moderate to severe plaque psoriasis was accepted and the primary study objective was met. Of note, the superiority of BCD-085 to placebo was proved for all tested doses (40 mg, 80 mg, and 120 mg). The dynamic assessment of PASI 75 and PASI percent improvement from baseline have shown pronounced results from week 4 (FIG. 6, FIG. 7).

[0940] PASI90 was reported in 66.7%, 60.0%, 78.6% of BCD-085 patients respectively vs 19.2% for placebo at week 12 (p<0.0001 for groups 1, 2, 3 vs placebo). Also, 83.3%, 90.0%, 89.3% of BCD-085 patients achieved clear or almost clear skin (sPGA 0/1) in groups 1, 2, 3 respectively vs 30.8% for placebo (p<0.0001 for groups 1, 2, 3 compared with placebo) at week 12. The mean percentage decrease in the percent affected BSA at week 12 was 92.2% in group 1 (range 70.2% to 100%), 94.8% in group 2 (range 62.9% to 100%), 97.8% in group 3 (range 67.7% to 100%) vs 27.1% for placebo (range 0 to 69.7%), p<0.0001 for groups 1, 2, 3 vs placebo.

[0941] BCD-085 also showed significant efficacy in nail psoriasis (FIG. 8). Population for assessing nail psoriasis was 66 patients (other patients didn't have signs of nail psoriasis during the study period). The mean percentage change in NAPSI score at week 12: 25% in group 1 (range 0 to 44.8%), 43.4% in group 2 (range 18.6% to 78.6%), 73.1% in group 3 (range 50% to 81.7%) vs 0 for placebo (range −9.3% to 0%), p=0.0002 for group 1, 2, 3 respectively vs placebo.

[0942] The QoL assessment demonstrated that the DLQI score decreased significantly with time indicating an improvement in the QoL in the BCD-085 arms and did not change in the placebo arm. BCD-085 has been proven superior to placebo, and the primary study objective was met. Although there were no differences among three BCD-085 doses for most endpoints, the best overall reduction of the signs/symptoms of psoriasis was detected in the 120 mg BCD-085 arm.

[0943] Pharmacokinetics

[0944] After a single injection of 40 mg, 80 mg, and 120 mg BCD-085, Netakimab was detectable in the serum for 0.5 to 4 h post-dose. Its concentration changed with time similarly for all doses. Changes in Netakimab concentration were proportional to the dose administered. There was a slow absorption with a gradual linear increase in the serum concentration of BCD-085 with a maximum seen at the end of Week 1. Higher doses (80 mg and 120 mg) were characterized with higher C.sub.max and AUC.sub.(0-168) as compared with 40 mg dose. (FIG. 9)

[0945] A long-term absorption resulted in the C.sub.max of BCD-085 at 144 [78-168] h post-dose, which is near the time of the second injection. No terminal half-life for BCD-085 after a single dosing in this trial suggested it unfeasible to calculate such PK parameters as AUC.sub.(0-∞), T.sub.1/2, and K.sub.e, thus the data for these endpoints are not presented.

[0946] Upon repeated injections of 40 mg, 80 mg, and 120 mg of BCD-085, the minimal serum concentration was rather high (>60% C.sub.max) and was reached before the second injection of BCD-085. With re-administrations, BCD-085 accumulated in the serum, and its concentration increased 1.8-3.6-fold. Higher doses (80 mg and 120 mg) show higher induction potential as compared with 40 mg because fewer injections were needed to achieve concentrations around C.sub.max-mult (FIG. 10).

[0947] Safety

[0948] The safety analysis included all patients who received at least one dose of BCD-085 (n=117, Table 15). At least one AE/SAE was reported in 45.16% of patients (group 1), 36.67% of patients (group 2), 25.00% of patients (group 3), and 39.29% of patients (group 4) (p=0.443). Treatment-related AEs were judged in 19.35% patients in group 1, in 10.00% patients in group 2, in 7.14% patients in group 3, and in 10.71% patients in group 4 (p=0.534). No grade 4 AEs and no SAEs were reported. No patients had to discontinue the study treatment due to AEs/SAEs. Grade 3 AEs were reported in 3.23% of patients in Arm 1, 3.33% of patients in Arm 2, 3.57% patients in Arm 3, and 7.14% patients in Arm 4 (p=0.872, two-two-tailed Fisher's exact test). The most common AEs were neutropenia, acute respiratory tract infections, increased blood pressure, and elevated liver transaminases. Most of the AEs were mild. Only one local reaction (grade 1) was detected in group 1 (BCD-085, 40 mg).

TABLE-US-00042 TABLE 15 Summary of safety data (BCD-085-2 Study) BCD-085, BCD-085, BCD-085, 40 mg 80 mg 120 mg Placebo Parameter (n = 31) (n = 30) (n = 28) (n = 28) p-value Any adverse 14 (45.16%) 11 (36.67%) 7 (25.00%) 11 (39.29%) 0.443 events Any serious NONE adverse events Therapy-related  6 (19.35%)  3 (10.00%) 2 (7.14%)  3 (10.71%) 0.534 adverse events: Adverse events  1 (3.23%)  1 (3.33%) 1 (3.47%)  2 (7.14%) 0.872 with grade 3 of toxicity Adverse events NONE with grade 4 of toxicity Administration  1 (3.23%)  0 0  0 1.000 site reactions Therapy NONE discontinuation due to AEs/SAEs Common adverse events Neutroponia  4 (12.90%)  2 (6.67%) 1 (3.57%)  1 (3.57%) 0.539 Upper respiratory  3 (9.68%)  1 (3.33%) 1 (3.57%)  1 (3.57%) 0.721 tract infection Elevated serum  0  3 (10.00%) 1 (3.57%)  2 (7.14%) 0.291 gamma-glutamyl transferase (GGT)

[0949] Immunogenicity

[0950] The population for immunogenicity assessment included 117 patients (those who received at least one injection of the study product and provided at least two blood samples for testing, one of which was taken before the first dosing on Day 1, Week 0). Blood samples were drawn at week 0 before injection and at week 14. Immunogenicity assessment did not detect any binding anti-BCD-085 antibodies in any patient.

Conclusion

[0951] The analysis has shown that BCD-085 in all tested doses is superior to placebo. The highest efficacy was shown for the dose of 120 mg: 92.860 of patients achieved PASI75 at week 12 (compared with 23.08% in the placebo arm, two-sided 95% CI is [47.28%; 92.28%], p<0.0001, chi-square test with Yates correction). Toxicity of BCD-085 was mild: rate of AE did not differ between groups (inc. placebo), grade 1-2 laboratory abnormalities and elevation of blood pessure were the most frequent types of AE. The were no cases of SAE, early withdrawal due to safety reasons, ADA formation.

Example 5. Long-Term Use of Netakimab in Patients with Moderate to Severe Plaque Psoriasis (BCD-085-2Ext Study)

[0952] Study Design

[0953] BCD-085-2ext was a multicentre open-label Phase II extension study of the efficacy and safety of BCD-085 80 mg and 120 mg in patients with moderate-to-severe plaque psoriasis who completed the BCD-085-2 study according to the Protocol. The primary objective was to assess the efficacy and safety of the maintenance therapy (up to 1 year) of BCD-085.

[0954] If summarizing the duration of the follow-up in the main study BCD-085-2 (14 weeks) and its extension phase BCD-085-2ext (42 weeks), the total follow-up for 1 subject in both studies was 56 weeks (about 1 year).

[0955] Patient Population and Study Design

[0956] The study included 103 patients, who completed the BCD-085-2 study according to the Protocol. Patients who achieved PASI 50 and less (unresponders) after BCD-085-2 study received BCD-085 SC 120 mg in Q2W regimen (BCD-085 given once every 2 weeks), patients who achieved PASI 50 and more received BCD-085 SC 80 mg in Q2W regimen. After 6 months of treatment patients who achieved PASI 100 were switched from BCD-085 Q2W to BCD-085 Q4W (BCD-085 given once every four weeks) in the same doses. Patients who did not achieve PASI 100 were considered to be poor responders, they continued to receive the same dose of BCD-085 in Q2W regimen until the end of the study (FIG. 11).

[0957] During 12 weeks of BCD-085-2ext study patients were treated in Q2W regimen in two arms:

[0958] Arm 1: BCD-085 80 mg;

[0959] Arm 2: BCD-085 80 120 mg.

[0960] Because a Q4W regimen was introduced after 6 month of treatment (12 weeks of BCD-085-2ext study), patients were distributed into 4 arms:

[0961] Arm 1: BCD-085 120 mg (Q2W/Q4W);

[0962] Arm 2: BCD-085 80 mg (Q2W/Q4W);

[0963] Arm 3: BCD-085 120 mg (Q2W);

[0964] Arm 4: BCD-085 80 mg (Q2W).

[0965] Baseline characteristics are provided in BCD-085-2 study.

[0966] The primary endpoint was the proportion of patients who achieved PASI 75 by Week 38 of the present study (or Week 52 if considering the participation in the main study BCD-085-2). Secondary endpoints include assessment of PASI 90, PASI 100 and sPGA 0-1. The efficacy endpoints were evaluated at weeks 12 and 38 of BCD-085-2ext study (weeks 24 and 52 of treatment). Immunogenicity parameters included incidence of binding and neutralizing antibodies to BCD-085 after one year of treatment (week 56).

[0967] The study involved 86 patients enrolled in the Russian Federation and 17 patients in the Republic of Belarus.

[0968] Results

[0969] Efficacy

[0970] The primary efficacy endpoint of this study was the proportion of patients who achieved PASI 75 by Week 38 of the present study (or Week 52 if considering the participation in the main study BCD-085-2). The achievement of PASI 75 was defined as at least 75% improvement of the PASI score at Week 38 in comparison with the baseline value before the beginning of the therapy with BCD-085 (at screening for BCD-085-2 study). Efficacy was assessed in ITT (intent-to-treat, total population, n=103).

[0971] The analysis showed that the proportion of patients who achieved PASI 75 after 1 year of treatment with BCD-085 was 98.06% (including non-responders—patients who did not achieve PASI 50 at the moment of inclusion in the extension phase).

[0972] Data on efficacy after 6 months of the study treatment (i.e. 12 weeks of BCD-085-2ext study) are presented in two arms of patients who were receiving BCD-085 80 mg and 120 mg.

[0973] Data on efficacy after 1 year of the treatment (i.e. after 38 weeks of BCD-085-2ext study) are presented in 4 arms:

[0974] Arm 1: BCD-085 120 mg (Q2W/Q4W),

[0975] Arm 2: BCD-085 80 mg (Q2W/Q4W),

[0976] Arm 3: BCD-085 120 mg (Q2W),

[0977] Arm 4: BCD-085 80 mg (Q2W).

[0978] In this study, the two subpopulations were identified: a subpopulation highly sensitive to the study treatment (Arms 1 and 2, where patients were receiving BCD-085 in Q2W regimen and then, after Week 12, in Q4W regimen, n=45) and a subpopulation of patients who responded slower (Arms 3 and 4, where patients were receiving BCD-085 in Q2W regimen throughout the entire study; n=58).

[0979] Results of PASI 75 assessment in the ITT population are presented in Table 16 and FIG. 12.

TABLE-US-00043 TABLE 16 Proportion of patients who achieved PASI 75 after one year of treatment (week 38 of BCD-085-2ext study) (BCD-085-2ext Study) Proportion of patients who achieved PASI 75 at Week 38.sup.1 (one year of treatment) Therapy arm number % P-value.sup.1 All patients, 101 98.06 — n = 103 Arm 1, n = 6 6 100 1.000 Arm 2, n = 39 38 97.44 Arm 3, n = 21 20 95.24 0.3621 Arm 4, n = 37 37 100 .sup.1two-tailed Fisher's exact test. .sup.1The timepoint-38 weeks-in BCD-085-2ext study is equal to 52 weeks if summarized with the duration of previous BCD-085-2 study (here and onwards)

[0980] A comparison in the subpopulation of patients more sensitive to the therapy (Arms 1 and 2) showed the absence of significant differences (p=1.000, two-sided exact Fisher's test) between BCD-085 80 mg and 120 mg. However, the efficacy was the highest with BCD-085 120 mg (Arm 1): 100% of patients achieved PASI 75.

[0981] A comparison in the subpopulation of patients less sensitive to the therapy (Arms 3 and 4) also showed the absence of significant differences. Arm 3 showed a lower response because it included most severe patients, who did not have the minimal response (PASI 50) at inclusion in the extension phase and did not achieve PASI 100 after 12 weeks of the extension study. However, 95.24% of patients in this arm achieved PASI 75, which confirms the high efficacy of the therapy even in slow responders.

[0982] Assessment of the Loss of Response after One Year of Treatment

[0983] Biological therapy of psoriasis with TNF-alpha inhibitors is known to be associated with a loss of response over time. Monoclonal antibodies to interleukin-17 have been shown to have a high level of efficacy over a long time. To confirm this fact, a loss of response in patients receiving BCD-085 for one year was evaluated. A proportion of patients with a loss of PASI 75/90/100 after 1 year of therapy was compared with ASI 75/90/100 at Week 12 of the BCD-085-2 study among patients who were receiving BCD-085 in both studies (n=77). This population did not include patients who were receiving placebo during the BCD-085-2 study.

TABLE-US-00044 TABLE 17 Proportion of patients with a loss of response PASI 75/90/100 after one year of treatment (BCD-085-2ext Study) Proportion of patients with a loss of response at Week 38 (52 weeks of treatment) Arms Absolute number % PASI 75 n = 77 2 2.60 Arm 2, n = 33 1 3.03 Arm 3, n = 13 1 7.69 Arm 4, n = 31 0 0 PASI 90 n = 77 3 3.90 Arm 2, n = 33 1 3.03 Arm 3, n = 13 0 0 Arm 4, n = 31 4 12.90 PASI 100 n = 77 7 9.09 Arm 2, n = 33 6 18.18 Arm 3, n = 13 0 0 Arm 4, n = 31 1 3.23 In Arm 1, all patients were receiving placebo during the main period.

[0984] As seen from the Table 17 above, a loss of response was detected in few patients. Failures to achieve PASI 90 were seen mostly in Arm 4 (in 12.9% of patients), where subjects were receiving BCD-085 80 mg in Q2W regimen. A loss of PASI 100 was shown mainly in Arm 2 (18.18%), where patients received BCD-085 80 mg in Q2W/Q4W regimen.

[0985] A loss of PASI 75 was recorded only in 2 patients (2.6%) of the total population (n=77, without patients who were receiving placebo in the main study). This shows that the majority of patients maintained a sustained response with long-term treatment with BCD-085. Cases of loss of PASI 90/100 in the arms receiving BCD-085 80 mg might show that this dose was not effective enough.

[0986] An effect of the switch from a more frequent dosing regimen (Q2W) to a less frequent one (Q4W) on the maintenance of the clinical response was studied. This was assessed using the proportion of patients in Arms 1 and 2 (n=45) who maintained PASI 100 by the end of the follow-up (Table 18).

TABLE-US-00045 TABLE 18 Proportion of patients who maintained/lost PASI 100 after swithching the regimen (Q2W/Q4W) (BCD-085-2ext Study) Proportion of Proportion of patients who patients with a maintained loss of PASI 100 PASI 100 Abs. Abs. Arm number % number % P-value.sup.1 n = 45 38 84.44 7 15.56 — (patients of Arms 1 and 2) Arm 1, n = 6 6 100 0 0 0.5686 Arm 2, n = 39 32 82.05 7 17.95 .sup.1two-tailed Fisher's exact test

[0987] There were no patients in Arm 1 (patients receiving BCD-085 120 mg in Q2W/Q4W regimen), who lost PASI 100 response by the end of the extension study and 17.95 of patients lost the PASI 100 response in Arm 2 (patients receiving BCD-085 80 mg in Q2W/q4 regimen). Thus, the use of BCD-085 120 mg in Q4W regimen allowed maintaining high treatment response in more patients than the use of BCD-085 80 mg with the same dosing frequency.

[0988] Assessment of BCD-085 Efficacy after 6 Months of Treatment (12 Weeks of BCD-085-2Ext Study)

[0989] The Table 19 presents data on efficacy at Week 12 of the BCD-085-2ext study (i.e. after 6 months of inclusion into the previous BCD-085-2 study and start of study treatment) in ITT population (n=103). A comparison was performed in two arms, depending on the dose of BCD-085 received during the first 12 weeks of the BCD-085-2ext study (80 mg or 120 mg).

TABLE-US-00046 TABLE 19 Proportion of patients who achieved PASI 75 after 6 months of treatment (BCD-085-2ext Study) Therapy arm Abs. number % P-value.sup.1 Proportion of patients who achieved PASI 75 at Week 12 (after 6 months of treatment) All patients, n = 103 92 89.32 —  80 mg arm, n = 76 75 98.68 <0.0001 120 mg arm, n = 27 17 62.96 Proportion of patients who achieved PASI 90 at Week 12 (after 6 months of treatment) All patients, n = 103 63 61.17 —  80 mg arm, n = 76 56 73.68 <0.0001 120 mg arm, n = 27 7 25.93 Proportion of patients who achieved PASI 100 at Week 12 (after 6 months of treatment) All patients, n = 103 45 43.69  80 mg arm, n = 76 39 51.32 0.0167 120 mg arm, n = 27 6 22.22 .sup.1two-tailed Fisher's exact test.

[0990] The sPGA score 0-1 (clean or almost clean skin) was achieved by 87.38% after 6 months of therapy (Table 20).

TABLE-US-00047 TABLE 20 Proportion of patients who achieved sPGA score 0-1 after 6 months of treatment (BCD-085-2ext Study) Therapy arm number % P-value.sup.1 Proportion of patients who achieved sPGA score 0-1 at Week 12 (after 6 months of treatment) All patients, n = 103 90 87.38 —  80 mg arm, n = 76 73 96.05 <0.0001 120 mg arm, n = 27 17 62.96

[0991] The data show that the proportion of patients with PASI 75/90/100 and sPGA score 0-1 after 12 weeks in the BCD-085-2ext study was significantly lower with BCD-085 120 mg. These differences are explained by the absence of the lowest response (PASI 50) in patients of the BCD-085 120 mg arm at inclusion in the BCD-085-2ext study, i.e. they had more severe state at baseline and developed treatment response slower.

[0992] Assessment of BCD-085 Efficacy after One Year of Treatment

[0993] By the end of the extension study, PASI 90/100 was achieved by 92.23/59.22 of patients in the ITT population (n=103), respectively (Table 21, FIG. 13, FIG. 14)

TABLE-US-00048 TABLE 21 Proportion of patients who achieved PASI 90 and PASI 100 after one year of treatment (38 weeks of BCD-085-2ext study) Therapy arm number % P-value.sup.1 Proportion of patients who achieved PASI 90 at Week 38 (one year of treatment) All patients, n = 103 95 92.23 — Arm 1, n = 6 6 100 1.000.sup.1 Arm 2, n = 39 38 97.44 Arm 3, n = 21 17 80.95 0.241.sup.1 Arm 4, n = 37 34 91.89 Proportion of patients who achieved PASI 100 at Week 38 (one year of treatment) All patients, n = 103 61 59.22 Arm 1, n = 6 6 100 0.5686.sup.1 Arm 2, n = 39 32 82.05 Arm 3, n = 21 7 33.33 0.6439.sup.2 Arm 4, n = 37 16 43.24 .sup.1—two-tailed Fisher's exact test; .sup.2Yates-correctedχ.sup.2 test

[0994] The highest response was shown in Arm 1, where all the subjects achieved PASI 90/100. No significant differences were found between the arms (Arms 1 and 2, Arms 3 and 4) in any parameter.

[0995] After one year of treatment sPGA score 0-1 was achieved by 95.150 of patients and sPGA score 0 (clean skin) was achieved by 59.220 of patients (Table 22, FIG. 15, FIG. 16).

TABLE-US-00049 TABLE 22 Proportion of patients who achieved sPGA score 0-1 and sPGA score 0 (clean skin) after 52 weeks of treatment (38 weeks of BCD-085-2ext study) Abs. Therapy arm number % P-value.sup.1 Proportion of patients who achieved sPGA score 0-1 at Week 38 (52 weeks of treatment) All patients, n = 103 98 95.15 — Arm 1, n = 6 6 100 1.000 Arm 2, n = 39 38 97.44 Arm 3, n = 21 20 95.24 1.000 Arm 4, n = 37 34 91.89 Proportion of patients who achieved sPGA score 0 at Week 38 (52 weeks of treatment) All patients, n = 103 61 59.22 — Arm 1, n = 6 6 100.00 0.5719 Arm 2, n = 39 31 79.49 Arm 3, n = 21 7 33.33 0.4135 Arm 4, n = 37 17 45.95 .sup.1two-tailed Fisher's exact test

[0996] The best results for sPGA assessment were seen in patients receiving BCD-085 120 mg in Q2W/Q4W regimen.

[0997] Safety

[0998] Safety analysis included the data from all patients who received at least one dose of BCD-085 (n=103, Table 23).

[0999] Regardless of the dose and dosing regimen, BCD-085 showed a favorable safety profile, which did not differ between the groups.

[1000] During the period studied, at least one AE/SAE was recorded in 36.890 of patients (38 out of 103): 33.330 of patients in Arm 1 (2 out of 6), 35.90 of patients in Arm 2 (14 out of 39), 38.100 of patients in Arm 3 (8 out of 21), and 37.840 of patients in Arm 4 (14 out of 37) (p=1.0000, exact Fisher's test).

TABLE-US-00050 TABLE 23 Summary of safety data (BCD-085-2ext Study) All Arm patients 1 (n = 6) 2 (n = 39) 3 (n = 21) 4 (n = 37) n % n % n % n % n % Any AEs/SAEs 38 36.89 2 33.33 14 35.90 8 38.10 14 37.84 P-value.sup.1 1.0000 Therapy-related 6 5.83 0 0 4 10.26 1 4.76 1 2.70 AEs/SAEs P-value.sup.1 0.6542 Any SAEs 1 0.97 0 0 1 2.56 0 0 0 0 P-value.sup.1 1.0000 Therapy-related None SAEs AEs, Grade 3/4 5 4.85 1 16.67 2 5.13 0 0 2 5.41 P-value.sup.1 0.3528 Therapy-related 5 4.85 1 16.67 2 5.13 0 0 2 5.41 AEs, Grade 3/4 P-value.sup.1 1.0000 Local reactions None Therapy discontinuation due to AE/SAE Note: .sup.1two-tailed exact Fisher's test.

[1001] AEs/SAEs related to the study therapy were recorded in 5.83 of patients (6/103): four patients in Arm 2 (10.260), one patient in Arm 3 (4.763), and one patient in Arm 4 (2.70 (p=0.6542, two-sided exact Fisher's test).

[1002] During the study, two SAEs not related to the study therapy were recorded in one patient of Arm 2 (2.56): left-sided obstructive pyelonephritis (kidney stone disease) and acute pancreatitis. In both cases, hospitalization was a seriousness criterion.

[1003] Grade 3/4 AEs not related to the study therapy were recorded in 4.850 of patients (5/103): one patient in Arm 1, two patients in Arms 2 and 4, and no patients in Arm 3.

[1004] Most common AEs were lymphocytosis, liver function tests increased, indirect bilirubin increased, and blood pressure increased (Table 24)

[1005] The AEs were mostly mild or moderate (Grade 1/2, CTCAE 4.03).

TABLE-US-00051 TABLE 24 The most frequent AEs (more that 1 case per arm) (BCD-085-2ext Study) Arm 1 Arm 2 Arm 3 Arm 4 (n = 6) (n = 39) (n = 21) (n = 37) P- Deviation n % n % n % N % value.sup.1 Blood and lymphatic system disorders Lymphocytosis 0 0.00 2 5.13 0 0.00 1 2.70 0.8287 (Grade 2) Hepatobiliary disorders ALT increased 0 0.00 0 0.00 0 0.00 5 13.51 0.0434 (total) Grade 1 0 0.00 0 0.00 0 0.00 4 10.81 0.1018 Grade 2 0 0.00 0 0.00 0 0.00 1 2.70 0.6214 AST increased 0 0.00 0 0.00 2 9.52 1 2.70 0.2127 (Grade 1) GGT increased 0 0.00 4 10.26 1 4.76 2 5.41 0.7992 (total) Grade 1 0 0.00 1 2.56 0 0.00 1 2.70 1.0000 Grade 2 0 0.00 2 5.13 1 4.76 1 2.70 1.0000 Grade 3 0 0.00 1 2.56 0 0.00 0 0.00 1.0000 Indirect 0 0.00 2 5.13 0 0.00 0 0.00 0.4215 bilirubin increased (Grade 2) Cardiac and vascular disorders BP increased 0 0.00 0 0.00 2 9.52 3 8.11 0.1613 (total) Grade 2 0 0.00 0 0.00 2 9.52 1 2.70 0.2127 Grade 3 0 0.00 0 0.00 0 0.00 2 5.41 0.2804 Note: .sup.1exact Fisher's test.

[1006] Grade 3 adverse events, except for 2 cases of increased blood pressure (Arm 4: 5.410), were recorded as single events: increased diastolic B in 1 patient from Arm 2 (2.56), increased GGT in 1 patient in Arm 2 (2.56); deforming osteoarthritis of the right knee and two-sided gonarthrosis (psoriatic arthropathy, pain syndrome) in 1 patient from Arm 1 (16.67%).

[1007] No cases of therapy discontinuation due to AEs or SAEs were recorded.

[1008] No local reactions related to the administration of the study drug were recorded.

[1009] During the study period, there were no cases of inflammatory bowel disease or candidiasis with long-term use of BCD-085. To assess the risk of increasing AE rate during long-term use of BCD-085, exposure-adjusted AEs incidence rate (FAIR) was assessed during BCD-085-2ext study (42 weeks) and compared with that during the BCD-085-2 study (14 weeks). Data of patients who were receiving BCD-085 80 mg and 120 mg were considered (Table 25).

TABLE-US-00052 TABLE 25 exposure-adjusted AEs incidence rate in BCD-085-2ext vs BCD-085-2 study (BCD-085-2ext Study) Dose, mg BCD-085-2 BCD-085-2ext 80 120 80 120 Number Number Number Number of of of of cases cases cases cases during during during during the the the the period period period period studied, studied, studied, studied, Parameter n EAIR n EAIR n EAIR n EAIR AE/SAE 11 1.2571 7 0.8571 28 0.4211 10 0.4233 Related 3 0.3429 2 0.2449 4 0.0602 1 0.0423 AE/SAE Grade 3-4 1 0.1143 1 0.1224 2 0.0301 2 0.0847 AE Grade 3-4 1 0.1143 0 0.0000 0 0.0000 0 0 AE related to the study therapy

[1010] The exposition-adjusted AE/SAE rate was 1.2571 and 0.8571 AE per 1 patient-year for BCD-085 80 mg and 120 mg, respectively, during the BCD-085-2 study and 0.4211 and 0.4233 AE per 1 patient-year for BCD-085 80 mg and 120 mg, respectively, during the BCD-085-2ext study. Thus, the occurrence rate of AE/SAE did not increase during the extension study. The results justify a possibility of long-term use of BCD-085 80 mg and 120 mg without risks of increasing the rate of adverse effects.

[1011] Immunogenicity

[1012] The immunogenicity analysis included data from 101 patients, who received at least one dose of BCD-085 starting from Week 0 of the present study and did not have missed/lost/spoiled serum samples taken on any day of Week 42 of BCD-085-2ext study.

[1013] The immunogenicity analysis did not reveal binding antibodies after 42 weeks of the BCD-085-2ext study (i.e. 56 weeks from the beginning of the BCD-085-2 study).

Conclusion

[1014] A high efficacy of BCD-085 during long-term use was shown: 98.06% of patients achieved meaningful clinical improvement in psoriasis course regardless of the dose and dosing regimen of BCD-085.

[1015] The highest efficacy was recorded in patients who were receiving BCD-085 120 mg in Q2W/Q4W regimen: by the end of the BCD-085-2ext study, 100% of these patients achieved PASI 100 and sPGA score 0-1.

[1016] In the population of patients who were receiving BCD-085 for 1 year (during the previous study BCD-085-2 and the current study BCD-085-2ext), PASI 75 was lost only in 2.6% of subjects. Cases of loss of PASI 90/100 were seen more often in the arms receiving BCD-085 80 mg, thus showing that this dose was not effective enough.

[1017] Among patients who were switched from Q2W to Q4W use of BCD-085 (Q2W/Q4W regimen) the best result was shown for BCD-085 120 mg, neither subject lost PASI 100 response.

[1018] Thus, the overall analysis demonstrated high efficacy of long-term use of BCD-085 in patients with moderate to severe plaque psoriasis who failed to respond to previous standard therapy. It was demonstrated that BCD-085 can be used less often (once a month) after 6 months of treatment if administered at the dose of 120 mg.

Example 6. Use of Netakimab in Standard and Low Frequent Regimens in Patients with Moderate to Severe Plaque Psoriasis (BCD-085-7 Study)

[1019] Study Design

[1020] BCD-085-7 is an ongoing multicenter double-blind placebo-controlled Phase III study in patients with moderate-to-severe plaque psoriasis. Study objective is to evaluate the efficacy and safety of BCD-085 given once every four weeks (Q4W regimen) in comparison with BCD-085 given once every 2 weeks (Q2W regimen).

[1021] Study BCD-085-7 uses the 60 mg/1 ml formulation for BCD-085 in pre-filled syringes. The route of administration is SC injections with 2 pre-filled syringes (2 SC injections, given within 15 min). The study is ongoing and has results of the first 12 weeks.

[1022] Patient Population and Study Design

[1023] The includes 213 patients with moderate-to-severe plaque psoriasis (PASI≥10, BSA≥10 and sPGA≥3) aged 18 and older, who met other eligibility criteria. The study doesn't include patients previously treated with monoclonal antibodies targeting IL17 (or IL17 receptor) and patients previously treated with 2 or more medicines containing monoclonal antibodies or their fragments. After screening examination patients were randomized in 2:2:1 ratio into 3 arms: 1) BCD-085 Q2W arm, 2) BCD-085 Q4W arm and 3) placebo arm. Patients received BCD-085/placebo in the blinded manner for 12 weeks. Arm 1 received BCD-085 120 mg at weeks 0, 1, 2, then at weeks 4, 6, 8, 10. Arm 2 received BCD-085 120 mg at weeks 0, 1, 2, then at weeks 6, 10 (for blinding purpose patients received placebo at weeks 4 and 8). Patients from Arm 3 received placebo at weeks 0, 1, 2, 4, 6, 8, 10. On Week 12, the primary endpoint was assessed with a PASI 75, and the therapies was unblinded.

[1024] From week 14 all patients from Arm 1 and 2 will receive BCD-085 in Q4W regimen up to week 50. All patients from Arm 3 (placebo) will receive BCD-085 at weeks 12, 13, 14 and then every 4 weeks starting from week 14 to week 50. From week 54 only responders (who achieved PASI75 and more at week 52) will continue the extension study period in Q4W regimen starting from week 54. Patients from Arms 1 and 2 will receive BCD-085 up to week 154 and patients from Arm 3 will receive BCD-085 up to week 166. The follow-up period for all patients is 4 weeks (FIG. 17).

[1025] The primary endpoint is the proportion of patients in each study arm who achieved PASI 75 at Week 12 of the study. Secondary endpoints include assessment of sPGA 0-1, PASI 90 and PASI 100, percent improvement in PASI and NAPSI scores, change in itching assessment by VAS (mm), assessment of dermatologic QoL (DLQI). The BCD-085-7 study includes the assessment of psoriatic arthritis (PsA) by evaluation of ACR20/50/70 response (among patients with active PsA at baseline). The efficacy endpoints are evaluated at weeks 0, 8, 12, 24, 42 and 52 of the study in the main period and at weeks 62, 74, 86, 98, 110, 122, 134, 146 and 154 of treatment with BCD-085 in the OLE period. Safety endpoints include rates of adverse events (AE), SAE, 3-4 grade AE according to CTCAE 4.03, rates of early study discontinuation due to AE. Immunogenicity parameters include incidence of binding and neutralizing antibodies to BCD-085 at weeks 0, 12, 24 and 54 of the study in the main period and at weeks 86, 98, 110, 134, 154 of treatment with BCD-085 in the OLE period.

[1026] The BCD-085-7 study was based on sequential hypotheses testing:

[1027] BCD-085 in either regimen has superior efficacy over the placebo; margin (δ) 0 (0%), type-I-error 0.025, type-II-error 80%;

[1028] BCD-085 in Q4W regimen has non-inferior efficacy when compared with Q2W regimen; margin (δ) −0.2038 (−20,38%), type-I-error 0.05 (two-sided significance level), type-II-error 80%.

[1029] Verification of the Superiority Hypothesis

[1030] The statistical hypothesis stating the superior efficacy of BCD-085 over placebo was sequentially checked by comparing the lower bound of the 95% confidence interval for the difference in the proportion of patients with PASI 75 by Week 12 in BCD-085 Q2W and placebo arm, then—in BCD-085 Q4W arm and placebo arm, with the pre-specified superiority margin (5, 0%).

[1031] Results

[1032] The efficacy was evaluated in 2 populations of patients: ITT using NRI method (n=213) and PP population (n=210). Two patients have discontinued the study early due to IC recall and one patient was lost to follow up before week 12.

[1033] Demographics and baseline characteristics did not differ between groups (Table 26, Table 27).

TABLE-US-00053 TABLE 26 Demographic and baseline characteristics of patients (BCD-085-7 Study) BCD-085 Q2W BCD-085 Q4W Placebo Parameter (n = 85) (n = 84) (n = 44) P value Age (years),   42 [35-49] 41.5 [32-53]   39 [33-53] 0.9344.sup.1 median [IQR] Body mass (kg), 87.3 [75-96.1] 89.5 [78-98]  83.5 [70-95] 0.3078.sup.1 median [IQR] Height (sm),  178 [170-184]  176 [168-182] 175.5 [168-180] 0.6110.sup.2 median [IQR] BMI (kg/m.sup.2), 27.9 [24.5-31.5] 28.5 [25.5-32.5]  27.1 [24.2-30.0] 0.3958.sup.1 median [IQR] Females (%)   22 (22.58)   26 (30.95)    9 (20.45) 0.4319.sup.3 Males (%)   63 (74.12)   58 (69.05)   35 (79.55) childbearing   13 (59.09)   18 (69.23)    4 (44.44) 0.4114.sup.4 potential in women (%) Duration of the  120 [36-204]  111 [36-183]   100 [34-193] 0.8727.sup.1 disease (months), median [IQR] BSA, %   20 [13-42]   22 [14.5-43]  22.5 [13-44] 0.9136.sup.1 PASI score 18.4 [14.2-27] 17.9 [15.1-28.6]  19.7 [16.3-29.4] 0.3469.sup.1 NAPSI score   7 [0-29]   14 [2-28]   14 [0-37] 0.5001.sup.1 sPGA score   3 [3-4]   4 [3-4]    4 [3-4] 0.1210.sup.1 Itch assessment   47 [27-67]   48 [27-71]  45.5 [23-70] 0.961.sup.1 by VAS, mm Beck's Depression   6 [2-9]   6 [2-11]  6.5 [2-10] 0.7388.sup.1 Inventory, score DLQI score   13 [10-20]   13 [9-18]   15 [9-20] 0.7450.sup.2 Psoriatic   6 (7.06)   10 (11.9)    2 (4.55) 0.3478.sup.4 arthritis in anamnesis, n (%) Psoriatic arthritis at screening visit, n (%)   6 (7.06)   7 (8.33)    2 (4.55) 0.7883.sup.4 .sup.1—Kruskal-Wallis test, .sup.2—analysis of variance, .sup.3—Yates-corrected Pierson's χ.sup.2 test, .sup.4—exact Fisher's test

TABLE-US-00054 TABLE 27 Previous treatment of psoriasis (BCD-085-7 Study) BCD-085 Q2W BCD-085 Q4W Placebo Type of previous (n = 85) (n = 84) (n = 44) treatment N % n % n % P value Monoclonal antibodies 5 5.88 6 7.14 1 2.27 0.6389.sup.2 and janus kinase inhibitors Adalimumab 3 3.53 2 2.38 1 2.27 1.0000.sup.2 Infliximab 0 0.00 1 1.19 0 0.00 0.6009.sup.2 Ustekinumab 0 0.00 2 2.38 0 0.00 0.1963.sup.2 Guselkumab 1 1.18 0 0.00 0 0.00 1.0000.sup.2 Tofacitinib 1 1.18 1 1.19 0 0.00 1.0000.sup.2 GCS 23 27.06 32 38.10 16 36.36 0.2802.sup.1 Systemic use 10 11.76 8 9.52 5 11.36 0.8820.sup.2 Topical use 15 17.65 22 26.19 12 27.27 0.3149.sup.1 Other systemic 22 25.88 29 34.52 21 47.73 0.0447.sup.1 therapies Methotrexate 17 20.00 24 28.57 19 43.18 0.0212.sup.1 Cyclosporin A 4 4.71 3 3.57 1 2.27 0.9032.sup.2 Apremilast 1 1.18 0 0.00 0 0.00 1.0000.sup.2 Acitretin 1 1.18 3 3.57 0 0.00 0.4366.sup.2 Phototherapy 47 55.29 50 59.52 30 68.18 0.3677.sup.1 Note: .sup.1Yates-corrected Pierson's χ.sup.2 test; .sup.2two-sided exact Fisher's test.

[1034] Efficacy Results (the First 12 Weeks)

[1035] The difference in PASI 75 response rates at Week 12 was 77.65% (BCD-085 Q2W and placebo) with 95% CI [67.07%; 88.23%](P<0.0001, Fisher's exact test) and 83.33% (BCD-085 Q4W and placebo) with 95% CI [73.63%; 93.03%] (P<0.0001, Fisher's exact test). The results show that lower bounds of 95% CI for BCD-085 Q4W and BCD-085 Q2W arms (73.63% and 67.07%, respectively) exceed the superiority margin (0%). Thus, both BCD-085 regimens in patients with moderate to severe plaque psoriasis were superior in efficacy over placebo.

[1036] According to statistical methods used to assess efficacy, the study hypothesis of non-inferior efficacy of BCD-085 once every 4 weeks vs. BCD-085 once every 2 weeks was tested comparing the lower bound of the 95% confidence interval for the difference in proportions of patients with PASI 75 at Week 12 between the BCD-085 Q4W and BCD-085 Q2W with the pre-specified non-inferiority margin (δ) equal to −20.38%.

[1037] Difference in the proportion of patients with PASI 75 at Week 12 between BCD-085 Q4W and BCD-085 Q2W arms was 5.68% with 95% CI [−7.41%; 18.78%] (P=0.4603, Yates-corrected Pierson's χ.sup.2 test). The lower bound of the 95% CI (−7.41%) is within the pre-specified margin of −20.38%. This shows that the efficacy of BCD-085 every 4 weeks was non-inferior to that of BCD-085 every 2 weeks (Table 28).

TABLE-US-00055 TABLE 2 Assessment of the primary endpoint (PASI75 at week 12) with 95% CI (ITT population, n = 213) (BCD-085-7 study) PASI75 at week 12, n = 213 group N % P value 95% CI (%) BCD-085 66 77.65 0.46031  −7.41; 18.78].sup.1 Q2W (85) BCD-085 70 83.33 Q4W (84) Placebo (44) 0 0 <0.00012  7.07; 88.23].sup.2 <0.00013  73.63; 93.03].sup.3  Q4W (Pearson's chi-square test with Yates correction), .sup.2BCD-085 Q2W vs Placebo (exact Fisher test), .sup.3BCD-085 Q4W vs Placebo (exact Fisher test) indicates data missing or illegible when filed

[1038] The comparison of secondary efficacy endpoints (proportion of patients who achieved PASI 75, PASI 90, PASI 100, sPGA 0-1, relative change in PASI score, change in itch severity according to VAS, change in NAPSI score, change in quality of life according to DLQI, ACR 20/50/70 in patients with psoriatic arthritis) confirmed the results obtained after the assessment of the primary endpoint (Table 29, FIG. 18, FIG. 19, FIG. 20, FIG. 21, FIG. 22, FIG. 23).

TABLE-US-00056 TABLE 29 Efficacy of BCD-085 in BCD-085-7 study at weeks 8 and 12 (ITT population, n = 213) Endpoint Group Week 8 Week 12 PASI75 BCD-085 Q2W (85) 50 58.82 66 77.65 BCD-085 Q4W (84) 50 59.52 70 83.33 Placebo (44) 0 0 0 0 p value 1.0000.sup.1 0.4603.sup.1 <0.0001.sup.2 <0.0001.sup.2 <0.0001.sup.3 <0.0001.sup.3 PASI90 BCD-085 Q2W (85) 31 36.47 47 55.29 BCD-085 Q4W (84) 33 39.29 47 55.95 Placebo (44) 0 0 0 0 p value 0.8269.sup.1 1.0000.sup.1 <0.0001.sup.2 <0.0001.sup.2 <0.0001.sup.3 <0.0001.sup.3 PASI100 BCD-085 Q2W (85) 16 18.82 25 29.41 BCD-085 Q4W (84) 16 19.05 28 33.33 Placebo (44) 0 0 0 0 p value 1.0000.sup.1 0.7013.sup.1 0.0012.sup.2 <0.0001.sup.2 0.0012.sup.3 <0.0001.sup.3 SPGA 0-1 BCD-085 Q2W (85) 48 56.47 69 81.18 BCD-085 Q4W (84) 51 60.71 67 79.76 Placebo (44) 1 2.27 1 2.27 p value 0.6864.sup.1 0.9698.sup.1 <0.0001.sup.2 <0.0001.sup.2 <0.0001.sup.3 <0.0001.sup.3 .sup.1BCD-085 Q2W vs BCD-085 Q4W (Pearson's chi-square test with Yates correction), .sup.2BCD-085 Q2W vs Placebo (exact Fisher test), .sup.3BCD-085 Q4W vs Placebo (exact Fisher test)

[1039] Safety Results (the First 12 Weeks)

[1040] The use of BCD-085 during 12 weeks of the study was characterized by good tolerability and demonstrated a favorable safety profile (Table 30). During the study, there were no cases of early withdrawal due to the safety reasons. Local reaction was detected in one patient (2.270) in the Placebo group (redness at the site of injection). There were no cases of unexpected toxicity.

[1041] One therapy-related SAE (pneumonia) with grade 3 according to CTCAE 4.03 was registered in BCD-085 Q4W group. Neutropenia grade 3 was observed in 1 patient from group BCD-085 Q2W and elevated creatinine level was observed in 1 patient in placebo group. Other AEs were mild or moderate. There were no statistically significant differences between groups in the frequency of registration of AEs (Table 31).

TABLE-US-00057 TABLE 3 Assessment of safety outcomes after 12 weeks of treatment (BCD-085-7 study) BCD-085 BCD-085 Q2W Q4W Placebo (n = 85) (n = 84) (n = 44) Parameter n % n % n % p-value The proportion 15 17.65 14 16.67 8 18.18 0.9735.sup.1 of patients who develop AEs The proportion 0 0.00 1 1.19 0 0.00 0.60092.sup.2 of patients who develop SAEs The proportion 1 1.18 1 1.19 1 2.27 1.0000.sup.2 of patients who develop grade 3-4 AEs The proportion 0 0.00 0 0.00 1 2.27 0.2066.sup.2 of patients who develop injection site reactions The proportion 0 0.00 0 0.00 0 0.00 1.0000.sup.2 of patients who discontinued the study due to AEs/ SAEs .sup.1—X.sup.2 Pearson with Yates correction, .sup.2—Fisher exact test

TABLE-US-00058 TABLE 31 Safety profile after 12 weeks of treatment (BCD-085-7 study) BCD-085 BCD-085 Q2W Q4W Placebo (n = 85) (n = 84) (n = 44) P- Adverse event % % N % N % value Cardiovascular diseases Increased blood 0 0.00% 1 1.19% 0 0.00% 0.60.sup.1 pressure (2 gr) Increased systolic 1 1.18% 0 0.00% 0 0.00% 1.00.sup.1 blood pressure (2 gr) Increased diastolic 0 0.00% 1 1.19% 0 0.00% 0.60.sup.1 blood pressure (2 gr) Signs of focal 1 1.18% 0 0.00% 0 0.00% 1.00.sup.1 myocardial ischemia on an ECG (lgr) Infectious diseases Upper espiratory 0 0.00% 0 0.00% 1 2.27% 0.21.sup.1 tract infection (2 gr) Upper respiratory 0 0.00% 0 0.00% 1 2.27% 0.21.sup.1 tract infection (2 gr) Follicular tonsillitis 1 1.18% 0 0.00% 0 0.00% 1.00.sup.1 (2 gr) Pneumonia (3 gr) 0 0.00% 1 1.19% 0 0.00% 0.60.sup.1 Urinary tract 1 1.18% 0 0.00% 0 0.00% 1.00.sup.1 infection (2 gr) Diseases of the skin and subcutaneous tissue Erythema (1 gr) 0 0.00% 0 0.00% 1 2.27% 0.21.sup.1 Eczema (2 gr) 1 1.18% 0 0.00% 0 0.00% 1.00.sup.1 General reactions and reactions to the injection Injection-related 1 1.18% 1 1.19% 0 0.00% 1.00.sup.1 reaction: dizziness (1 gr) Abdominal pain 0 0.00% 1 1.19% 0 0.00% 0.60.sup.1 (2 gr) Laboratory deviations Hyperhemoglobin- 1 1.18% 0 0.00% 0 0.00% 1.00.sup.1 emia (2 gr) Thrombocytopenia 0 0.00% 1 1.19% 0 0.00% 0.60.sup.1 (1 gr) Leukopenia (total) 1 1.18% 2 2.38% 0 0.00% 0.61.sup.1 1 gr 0 0.00% 1 1.19% 0 0.00% 0.60.sup.1 2 gr 1 1.18% 1 1.19% 0 0.00% 1.00.sup.1 Neutropenia (total) 3 3.53% 1 1.19% 0 0.00% 0.54.sup.1 2 gr 2 2.35% 1 1.19% 0 0.00% 0.80.sup.1 3 gr 1 1.18% 0 0.00% 0 0.00% 1.00.sup.1 Lymphocytosis 1 1.18% 0 0.00% 1 2.27% 0.68.sup.1 (2 gr) Hyperbilirubinemia 4 4.71% 2 2.38% 1 2.27% 0.70.sup.1 (2 gr) Increased AST 1 1.18% 1 1.19% 0 0.00% 1.00.sup.1 activity (2 gr) Increased ALT 1 1.18% 0 0.00% 0 0.00% 1.00.sup.1 activity (2 gr) Hypercholesterol- 1 1.18% 1 1.19% 0 0.00% 1.00.sup.1 emia (2 gr) Hyperglycemia 0 0.00% 3 3.57% 0 0.00% 0.17.sup.1 (2 gr) Increase in serum 0 0.00% 0 0.00% 1 2.27% 0.21.sup.1 creatinine (3 gr) Proteinuria (total) 1 1.18% 0 0.00% 2 4.55% 0.11.sup.1 1 gr 1 1.18% 0 0.00% 1 2.27% 0.68.sup.1 2 gr 0 0.00% 0 0.00% 1 2.27% 0.21.sup.1 Injuries Thermal burn (1 gr) 0 0.00% 0 0.00% 1 2.27% 0.21.sup.1 .sup.1—Fisher exact test

[1042] Immunogenicity Results (the First 12 Weeks)

[1043] The immunogenicity analysis included data from 209 patients who received at least one dose of the study drug and provided at least two blood samples for testing, one of which was taken before the first dosing on Day 1, Week 0 (85 patients in the BCD-085 Q2W group, 81 patients in the BCD-085 Q4W group and 43 patients in the Placebo group, n=209). Blood samples were drawn at week 0 before injection and at week 12.

TABLE-US-00059 TABLE 32 Assessment of immunogenicity after 12 weeks of treatment (BCD-085-7 study) BCD-085 Q2W BCD-085 Q4W Placebo (n = 85) (n = 81) (n = 43) P- n % n % n % value.sup.1 Proportion 1 1.18 0 0 0 0 1.000 of patients with BAbs Proportion not identified of patients with NAbs .sup.1Fisher exact test

[1044] Immunogenicity assessment showed the presence of binding antibodies in one patient from BCD-085 Q2W group after 12 weeks of treatment. No neutralizing activity was detected (Table 32).

Conclusion

[1045] 83.3% and 77.7% patients from BCD-085-Q4W, BCD-085-Q2W arms achieved PASI75 at week 12 (p=0.46 for BCD-085-Q4W vs BCD-085-Q2W) compared to 0% in placebo arm (p<0.0001), sPGA (0-1) was reached by 79.8%, 81.2% and 2.27% patients in BCD-085-Q4W, BCD-085-Q2W, placebo arms, respectively. Adverse events (AEs) were registered in: 17.7%, 16.7% and 18.2% patients in BCD-085-Q4W, BCD-085-Q2W, placebo arms (p=1.0), respectively. One grade 3 (CTCAE 4.03) therapy-related SAE (pneumonia) was registered in BCD-085-Q4W arm. Grade 3 neutropenia was observed in 1 patient from BCD-085-Q2W, increase of creatinine was observed in 1 patient in placebo arm. Other AEs were mild or moderate (laboratory abnormalities were the most frequent), there were no local reactions in BCD-085 groups. Binding anti-drug antibodies were found in one patient (1.18%, BCD-085-Q2W arm). Neutralizing antibodies were not detected.

Example 7. Efficacy of Netakimab in Standard and Low Frequent Regimens in Treatment of Psoriatic Arthritis (PsA), Proof-of-Concept Sub-Study (BCD-085-7)

[1046] Study Design

[1047] In BCD-085-7 study described in Example 6 the efficacy of Netakimab versus placebo was evaluated on the limited population of patients who had baseline psoriatic arthritis. The endpoint for the assessment of psoriatic arthritis during this period was the proportion of patients (with patients with psoriatic arthritis) who achieved ACR 20/50/70 by Week 12. The parameter was assessed by estimating the 66/68 swollen/tender joint count, functional activity (HAQ-DI, assessed by the patient), disease activity (assessed by the physician and by the patient), patient's assessment of pain (VAS), and markers of inflammation (CRP and ESR).

[1048] Results

[1049] The population for the assessment of psoriatic arthritis included 15 patients (6 in BCD-085 Q2W arm, 7 in BCD-085 Q4W arm and 2 in placebo arm). One patient (BCD-085 Q4W arm) included in this population (rand. ID 10-131) was withdrawn at Visit 7 (Week 10), i.e. before the assessment at Visit 8 (Week 12). This patient was considered to be a non-responder.

TABLE-US-00060 TABLE 33 Proportion of patients who achieved ACR 20 (among patients with psoriatic arthritis, n = 15) Proportion of patients who achieved ACR 20 at Visit 8 (Week 12), n = 15 Treatment arm Abs. number % P value BCD-085 Q2W arm, n = 6 5 83.33 1.000.sup.1 BCD-085 Q4W arm, n = 7 6 85.71 Placebo arm, n = 2 0 0 0.1071.sup.2 0.0833.sup.3 .sup.1Comparison of BCD-085 Q2W vs BCD-085 Q4W (Fisher's exact test), .sup.2Comparison of BCD-085 Q2W vs placebo (Fisher's exact test), .sup.3Comparison of BCD-085 Q4W vs placebo (Fisher's exact test)

TABLE-US-00061 TABLE 34 Proportion of patients who achieved ACR 50 (among patients with psoriatic arthritis, n = 15) Proportion of patients who achieved ACR 50 at Visit 8 (Week 12), n = 15 Treatment arm Abs. number % P value BCD-085 Q2W arm, n = 6 3 50 0.5921.sup.1 BCD-085 Q4W arm, n = 7 2 28.57 0.4643.sup.2 Placebo arm, n = 2 0 0 1.000.sup.3 .sup.1Comparison of BCD-085 Q2W vs BCD-085 Q4W (Fisher's exact test), .sup.2Comparison of BCD-085 Q2W vs placebo (Fisher's exact test), .sup.3Comparison of BCD-085 Q4W vs placebo (Fisher's exact test)

TABLE-US-00062 TABLE 35 Proportion of patients who achieved ACR 70 (among patients with psoriatic arthritis, n = 15) Proportion of patients who achieved ACR 70 at Visit 8 (Week 12), n = 15 Treatment arm Abs. number % P value BCD-085 Q2W arm, n = 6 1 16.67 1.000.sup.1 BCD-085 Q4W arm, n = 7 1 14.29 1.000.sup.2 Placebo arm, n = 2 0 0 1.000.sup.3 .sup.1Comparison of BCD-085 Q2W vs BCD-085 Q4W (Fisher's exact test), .sup.2Comparison of BCD-085 Q2W vs placebo (Fisher's exact test), .sup.3Comparison of BCD-085 Q4W vs placebo (Fisher's exact test)

Conclusion

[1050] The analysis in patients with psoriatic arthritis (n=15) showed that ACR 20 at Week 12 was achieved by 83.33%, 85.71% and 00 of patients in the BCD-085 Q2W arm, BCD-085 Q4W arm and placebo arm, respectively (Table 33, FIG. 23). ACR 50 was achieved by 50%, 28.57% and 0% in the BCD-085 Q2W arm, BCD-085 Q4W arm and placebo arm, respectively (Table 34, FIG. 23). ACR 70 was achieved by 16.67%, 14.29% and 0% of patients in the BCD-085 Q2W arm, BCD-085 Q4W arm and placebo arm, respectively (Table 35, FIG. 23). The assessment at Week 12 did not show significant differences between the arms in any parameter. This may be caused by a low number of patients or too early assessment. However, the ACR 20 response in almost all patients with psoriatic arthritis who received BCD-085 shows pronounced positive dynamics.

Example 8. Use of Netakimab at Different Doses to Treat Ankylosing Spondylitis (AS), Proof-of Concept Study (BCD-085-3)

[1051] Study Design

[1052] BCD-085-3 (NCT02763111) was a multicentre double-blind randomized Phase II study in patients with active ankylosing spondylitis. The primary objective was to establish the therapeutically effective and safe dose of BCD-085 to be given as multiple injections in patients with active ankylosing spondylitis.

[1053] Patient Population and Study Design

[1054] The study included 88 patients with active ankylosing spondylitis aged 18 to 65 years inclusively, who had established AS (modified New York criteria, 1984), BASDAI score of 4 or greater, with inadequate response to NSAIDs used for at least 3 months before screening, who met other eligibility criteria. The study did not include patients previously treated with MAbs targeting IL17 (or IL17 receptor) and patients previously treated with 2 or more therapeutic monoclonal antibodies. After the screening patients were randomized in ratio 1:1:1:1 into 4 arms: 1) BCD-085 40 mg, 2) BCD-085 80 mg, 3) BCD-085 120 mg and 4) placebo. BCD-085/placebo was used on Day 1 at weeks 0, 1, 2, 4, 6, 8, 10 and 12. For blinding purposes, patients from 40 mg and 80 mg arms received two or one SC injections of placebo (1 mL each), respectively. Patients in the control arm received 3 SC injections of placebo (each injection was 1.0 mL). Placebo used in all three arms had a similar composition that includes the excipients from the BCD-085 dosage form. Patients were observed up to week 16.

[1055] The hypothesis of the study was that BCD-085 is superior to placebo in patients with active ankylosing spondylitis. The superiority margin (δ) was 0.1 (10%), type 1 error (α) of −5% (0.05), type 2 error (β) of 20% (0.2) and power of 80%.

[1056] The primary endpoint was the proportion of patients in each study arm who achieved ASAS20 at Week 16 of the study. Secondary endpoints include assessment of ASAS40 and ASAS5/6, the mean change from baseline in the BASDAI, BASMI, MASES, BASFI, ASDAS-CRP and the chest expansion, change in the 24-h pain score and the mean CRP concentration, also assessment of QoL was provided. The efficacy endpoints were evaluated at weeks 0, 4, 8, 12 and 16. Safety endpoints included rates of adverse events (AE), SAE, 3-4 grade AE according to CTCAE 4.03, rates of early study discontinuation due to AE. Pharmacokinetic endpoints included standard PK parameters (C.sub.min, AUC.sub.(0-168), AUC.sub.(0-672), T.sub.max, T½, Vd, K.sub.el, CL). Immunogenicity parameters included incidence of binding and neutralizing antibodies to BCD-085 after multiple drug injections.

[1057] Results

[1058] Demographics and baseline characteristics did not differ between groups (Table 36).

TABLE-US-00063 TABLE 36 Baseline characteristics of patients (BCD-085-3 Study) BCD-085 40 mg BCD-085 80 mg BCD-085 120 mg Placebo Parameter n = 22 n = 22 n = 22 n = 22 Age, years, 40.0 [33.0-44.0] 34.0 [31.0-36.0] 38.0 [35.0-44.0] 41.0 [32.0-47.0] median [IQR] Man, n (%)   17 [77.27]   19 [86.36]   22 [100.00]   15 [68.18] Weight, kg, 75.5 [61.0-93.0] 79.0 [63.0-86.1] 79.1 [71.5-85.0] 81.3 [75.0-90.0] median [IQR] AS duration, 26.5 [11-75] 37.5 [20-56] 46.5 [13-96] 26.5 [10-48] months, median [IQR] Spinal pain,  7.5 [6-8]   7 [6-8]   7 [6-8]   7 [6-7] total score (0-10 scale), median [IQR] BASDAI, total 6.45 [5.4-7.4]  6.7 [5.8-7.1] 6.45 [4.7-7.3] 5.95 [5.1-7] score, median [IQR] BASFI, total  5.9 [4.3-7.2] 5.95 [4.5-6.9] 5.55 [3.9-6.8]   6 [4-6.7] score, median [IQR] BASMI, total 4.65 [3.2-5.2]  4.5 [2.8-5.1] 4.15 [3.5-5.4] 4.55 [3.3-5.1] score, median [IQR] Chest  3.5 [3-4]  3.5 [2-4]   3 [3-4]   3 [3-5] expansion, cm, median [IQR] Previous use   4 [18.18]   2 [9.09]   3 [13.64]   4 [18.18] of anti-TNFα, n (%) Note: IQR—interquartile range

[1059] The ASAS20 response rate at Week 16 was set as the primary efficacy endpoint. In all the BCD-085 arms, the proportion of ASAS20 responders at Week 16 was above 70%, while in the placebo arm, only about 40% of patients responded to the treatment.

[1060] The analysis has shown that BCD-085 in doses 80 and 120 mg is superior to placebo in patients with active ankylosing spondylitis. Results for ASAS20 achievement are shown below. To prove the protocol-stated hypothesis of BCD-085 being superior to placebo, the 95% CIs were calculated for the difference in proportions of ASAS20 achievement (individual pairwise comparisons were performed for placebo versus each BCD-085 arm). The hypothesis was accepted if the lower bound of the estimated 95% CI for the difference in proportions of ASAS 20 was above the pre-specified margin of clinically non-meaningful differences (5) of 10% (0.10) The results are provided in Table 37.

TABLE-US-00064 TABLE 37 The difference in proportions of ASAS20 (BCD-085-3 Study) Difference in ASA20 achievement 95% CI p-value.sup.1 Arms 1 and 4 29.87%  [1.69%; 58.05%] 0.0472 Arms 2 and 4 38.96% [12.36%; 65.56%] 0.0082 Arms 3 and 4 48.05% [23.71%; 72.39%] 0.0008 Note: .sup.1—two-tailed χ.sup.2 test

[1061] Table 37 shows that the lower bounds of the 95% CIs for pairwise comparisons (placebo versus BCD-085) between arms 2, 4 and arms 3, 4 fall outside the pre-specified superiority margin. Thus, the hypothesis of BCD-085 being superior to placebo in patients with active ankylosing spondylitis was accepted and the primary study objective was met. Of note, the superiority of BCD-085 to placebo was proved for tested doses 80 mg and 120 mg.

[1062] ASAS20 at week 12 was reported in 72,73% of patients in group 1, 81.82% in group 2 and 90.91% in group 3 vs 23.1% who received placebo (p=0.0043 for groups 1, 2, 3 vs. placebo, FIG. 24).

TABLE-US-00065 TABLE 38 Proportion of patients with ASAS20, ASAS40, and ASAS5/6 response during the study (BCD-085-3 Study) ASAS20 ASAS40 ASAS5/6 Arm* n (%) n (%) n (%) P value.sup.1 Week 4 1 (n = 22) 16 (72.73%)  9 (40.91%) 10 (45.45%) P.sub.2 = 0.0039 2 (n = 22) 17 (77.27%) 14 (63.64%) 12 (54.55%) P.sub.3 = 0.0246 3 (n = 22) 18 (81.82%) 11 (50.00%) 13 (59.09%) P.sub.4 = 0.0024 4 (n = 21)  7 (33.33%)  4 (19.05%)  2 (9.52%) Week 8 1 (n = 22) 14 (63.64%)  9 (40.91%) 11 (50.0%) P.sub.2 = 0.0140 2 (n = 22) 16 (72.73%) 13 (59.09%) 12 (54.55%) P.sub.3 = 0.0593 3 (n = 22) 17 (77.27%) 10 (45.45%) 11 (50.0%) P.sub.4 = 0.0007 4 (n = 21)  7 (33.33%)  4 (19.05%)  1 (4.76%) Week 12 1 (n = 22) 16 (72.73%) 12 (54.55%) 12 (54.55%) P.sub.2 = 0.0214 2 (n = 22) 16 (72.73%) 13 (59.09%) 12 (54.55%) P.sub.3 = 0.0069 3 (n = 22) 19 (86.36%) 15 (68.18%) 13 (59.09%) P.sub.4 = 0.0809 4 (n = 21)  9 (42.86%)  4 (19.05%)  5 (23.81%) Week 16 1 (n = 22) 16 (72.73%)  9 (40.91%) 11 (50.0%) P.sub.2 = 0.0043 2 (n = 22) 18 (81.82%) 14 (63.64%) 12 (54.55%) P.sub.3 = 0.0004 3 (n = 22) 20 (90.91%) 16 (72.73%) 15 (68.18%) P.sub.4 = 0.0027 4 (n = 21)  9 (42.86%)  3 (14.29%)  3 (14.29%) Note: .sup.1—two-tailed Fisher's exact test/two-tailed χ.sup.2 test; P.sub.2—ASAS20 assessment; P.sub.3—ASAS40 assessment; P.sub.4—ASAS 5/6 assessment *Arm 1: BCD-085 40 mg; Arm 2—BCD-085 80 mg; Arm 3—BCD-085 120 mg; Arm 4—placebo

[1063] The results of ASAS20, ASAS40, ASAS 5/6 are shown in the Table 38 (FIG. 25).

[1064] The percentage of patients achieved ASAS20, ASAS40, ASAS 5/6 was higher in BCD-085 arms, especially in 120 mg arm. Other secondary endpoints showed the similar dynamics: all BCD-085 arms demonstrated the better response in comparison with placebo arm. All secondary endpoints showed significant improvement by the time of second evaluation in comparison with screening. Achieved response was maintained throughout all study period.

[1065] Pharmacokinetics

[1066] After a single injection of 40 mg, 80 mg, and 120 mg BCD-085, the drug was detectable in the serum for 0.5 to 4 h post-dose. Its concentration changed with time similarly for all doses (FIG. 26). The changes in BCD-085 concentration were proportional to the dose administered. C.sub.max and AUC.sub.(0-168) had strong dose-dependent relationships.

[1067] A subsequent use of BCD-085 resulted in gradual increase of its concentrations without evident signs of cumulation (FIG. 27).

[1068] Safety

[1069] The safety analysis included all patients who received at least one dose of BCD-085 (n=88, Table 39). At least one AE/SAE was reported in 45.45% of patients (arm 1), 27.27% of patients (arm 2), 18.18% of patients (arm 3), and 31.82% of patients (arm 4) (p=0.298). ARs were judged therapy-related in 22.73% of patients in group 1, in 18.18% of patients in group 2, in 4.55% of patients in group 3, and in 22.73% of patients in group 4 (p=0.354). Grade 3-4 AEs were reported for 4.55% in arms 1 and 4, for 9.09% in arm 2. The most common AEs were neutropenia, diastolic blood pressure increased. Most of the AEs were mild. No local reactions were reported.

[1070] One patient withdrew prematurely due to an AE, this occurred in the BCD-085 80 mg arm. No serious adverse events, local reactions and lethal outcomes were recorded.

TABLE-US-00066 TABLE 39 Summary of safety data (Study BCD-085-3) BCD-085 BCD-085 BCD-085 40 mg 80 mg 120 mg Placebo P- Variables n = 22 n = 22 n = 22 n = 22 value* At least 1 AE 11 (50.00) 6 (27.27) 4 (18.18) 7 (31.82) 0.183 At least 1 TAE  5 (22.73) 4 (18.18) 1 (4.55) 5 (22.73) 0.354 Sever AE  1 (4.55) 2 (9.09) 0 1 (4.55) 0.900 Severe TAE  0 1 (4.55) 0 1 (4.55) 1.00 Withdrawal due  0 1 (4.55) 0 0 1.00 to AE Summary of severe Aes Anaemia  0 0 0 1 (4.55) 1.00 (Grade 3) Neutropenia  0 1 (4.55) 0 0 1.00 (Grade 4) Erosive  0 1 (4.55) 0 0 1.00 colitis (Grade 3) Episcleritis  1 (4.55) 0 0 0 1.00 (Grade 3)

[1071] Immunogenicity

[1072] The population for immunogenicity assessment included 85 patients (those who received at least one injection of the study product and provided at least two blood samples for testing, one of which was taken before the first dosing on Day 1, Week 0). Blood samples were drawn at week 0 before injection, at week 8 and at week 16. Immunogenicity assessment did not detect any binding anti-BCD-085 antibodies in any patient.

Conclusion

[1073] Treatment with BCD-085 leads to significant improvement in all AS symptoms in comparison with placebo. The dose of 120 mg of BCD-085 had the most pronounced effect. The drug was well tolerated in all doses with no differences with placebo in safety profiles.

Example 9. Long-Term Use of Netakimab in Patients with Ankylosing Spondylitis (BCD-085-3Ext Study)

[1074] Study Design

[1075] Study BCD-085-3ext was a multicentre open-label Phase II extension study of the efficacy and safety of BCD-085 80 mg and 120 mg in patients with active ankylosing spondylitis who completed the BCD-085-3 study according to the Protocol. The primary objective was to assess the efficacy and safety of the maintenance therapy (up to 1 year) of BCD-085. The study is completed, the results are analyzed.

[1076] If summarizing the duration of the follow-up in the main study BCD-085-2 (16 weeks) and its extension phase BCD-085-2ext (40 weeks), the total follow-up for 1 subject in both studies was 56 weeks (about 1 year) (FIG. 28).

[1077] Patient Population and Study Design

[1078] The study included 81 patients, who completed the BCD-085-3 study according to the Protocol. Patients who didn't reached ASAS20 (unresponders) after BCD-085-3 study received BCD-085 120 mg in Q2W regimen up to 1 year, patients who reached ASAS20 after BCD-085-3 study received BCD-085 80 mg in Q2W regimen up to 1 year.

[1079] During BCD-085-2ext study patients were treated in two arms:

[1080] Arm 1: BCD-085 80 mg;

[1081] Arm 2: BCD-085 80 120 mg.

[1082] The primary endpoint was the proportion of patients in each study arm who achieved ASAS20 at Week 36 of the BCD-085-ext study. Secondary endpoints include assessment of ASAS40 and ASAS5/6, the mean change from baseline in the BASDAI, BASMI, MASES, BASFI, ASDAS-CRP and the chest expansion, change in the 24-h pain score and also assessment of QoL. The efficacy endpoints were evaluated at weeks 12, 24 and 36 of BCD-085-2ext study (weeks 28, 40 and 52 of treatment). Safety endpoints included rates of adverse events (AE), SAE, 3-4 grade AE according to CTCAE 4.03, rates of early study discontinuation due to AE. Immunogenicity parameters included incidence of binding and neutralizing antibodies to BCD-085 after one year of treatment (week 40 of BCD-085-3ext study).

[1083] Results

[1084] In general, according to the results of the efficacy evaluation, it was established:

[1085] Long-term (over a year) therapy with BCD-085 results in a high efficacy persistant within the time;

[1086] Long-term use of BCD-085 was not associated with high rates efficacy loss;

[1087] Use of the study drug at a dose of 120 mg allows to achieve a response to therapy by more patients, including patients in whom the use of BCD-085 for 16 weeks did not lead to the onset of a clinical response.

[1088] Evaluation of response by ASAS criteria (ASAS20/40, ASAS5/6) found that more than 70% of patients at each time point of OLE study achieved the appropriate response to therapy regardless of the dose used. In addition, the proportion of patients who have reached ASAS20 at 52 weeks of the OLE stage was 79.01% (86.42% with the use of the last-observation-carried-forward method). The proportion of patients who achieved ASAS40 one year of therapy was 71.60% (77.78% with the last-observation-carried-forward method).

[1089] Evaluation of other endpoints in the general patient population (n=81) demonstrated the existence of a similar trend for all parameters: against the background of the use of BCD-085, there was a pronounced, statistically significant improvement in all signs of AS, which formed to the first assessment point during the extended phase (week 28) and remained unchanged until the end of the study (Table 40).

TABLE-US-00067 TABLE 40 Main efficacy data obtained from BCD-085-3ext study (irrespectively to the regimen) BCD-085-3 BCD-085-3ext Base- Week Week Week Week p.sup.1 Parameter line 16 28 40 52 value BASDAI 6.3 2.9 2.1 2.2 2.25 <0.0001 score BASMI 4.5 3.6 3.4 3.2 3 <0.0001 score MASES 3 0 0 0 0 <0.0001 score Chest 3 4 4 4 4 <0.0001 excursion BASFI 5.9 3.2 2.2 2.3 1.9 <0.0001 score ASDAS- 3.92 2.25 1.83 1.825 1.845 <0.0001 CRP score SF-36 (physical 31.2 39.5 41.6 NA 43.9 <0.0001 component) SF-36 (mental 40.5 49.4 53.4 NA 54.1 <0.0001 component) Pain assessment, 7 3 2 2 2 <0.0001 NRS Nocturnal 7 2 2 2 1 <0.0001 pain assessment, NRS Note: .sup.1—Friedman's test

[1090] Thus, it can be concluded that the treatment with BCD-085 results in a significant improvement in majority of AS symptoms, which is formed mainly within the first month after the start of therapy and persisting throughout the year of treatment.

[1091] Evaluation of the Loss of the Achieved Effect with an Increase in the Duration of Therapy

[1092] The analysis of the ASAS20/40 responses dynamics did not reveal a tendency to lose response during the OLE study. In general, the loss of response was noted in 4.760 of patients.

[1093] Long-Term Efficacy Data on BCD-085 Use at Doses of 80 mg and 120 mg

[1094] The long-term use of the BCD-085 in the maximum dose of 120 mg leads is highly effective in patients who did not have sufficient effect of treatment within the first 16 weeks. At the end of OLE ASAS20/40, ASAS5/6 responses were reached by 63.16%, 52.66% and 52.66% of patients, respectively.

[1095] For other secondary endpoints, the presence of a similar dynamics over time was shown (Table 41).

TABLE-US-00068 TABLE 41 Main efficacy parameters for efficacy of BCD-085 at a doses of 80 and 120 mg within phase 2 studies (BCD-085-3 and BCD-085-3ext) BCD-085-3 BCD-085-3ext p.sup.1 Parameter Week 16 Week 28 Week 40 Week 52 value BASDAI BCD-085 80 mg 2.45 1.9 2 1.9 <0.0001 score BCD-085 120 mg 5.8 3.3 3 3.2 <0.0001 BASMI score BCD-085 80 mg 3.25 3.1 3 2.8 <0.0001 BCD-085 120 mg 5.2 4 4 4 0.0002 MASES score BCD-085 80 mg 0 0 0 0 0.0003 BCD-085 120 mg 1 0 0 0 0.0007 Chest BCD-085 80 mg 4 4.5 4 4 0.1759 excursion BCD-085 120 mg 4 4 4 4 0.3012 BASFI score BCD-085 80 mg 2.3 1.95 1.8 1.5 <0.0001 BCD-085 120 mg 5.8 4 4 3.2 <0.0001 ASDAS-CRP BCD-085 80 mg 2.135 1.695 1.65 1.61 <0.0001 score BCD-085 120 mg 3.77 2.48 2.45 2.5 <0.0001 SF-36 BCD-085 80 mg 40.1 42.95 NA 44.6 0.0018 (physical BCD-085 120 mg 34.2 36.9 NA 38.3 0.1504 component) SF-36 BCD-085 80 mg 50.80 53.35 NA 54.6 0.0477 (mental BCD-085 120 mg 43.5 54 NA 50.3 0.0032 component) Pain BCD-085 80 mg 3 2 2 2 <0.0001 assessment, BCD-085 120 mg 7 3 3 3 <0.0001 NRS Pain BCD-085 80 mg 2 1.5 1 1 <0.0001 assessment, BCD-085 120 mg 5 3 3 3 0.0001 NRS Note: .sup.1—Friedman's test; dispersive analysis for repeatable observations

[1096] The data show that patients from group 1 (80 mg), when included in BCD-085-3ext study, had low values of all major activity indices of ankylosing spondylitis (week 16 of the BCD-085-3 study). The continued use of the drug in them led to the stabilization of the effect (the average values of most indices went to the “plateau”).

[1097] Patients from group 2 (120 mg) had initially higher values of all major indices when they were included (1.5-2 times higher than those in the 80 mg group), which is due to the lack of ASAS20 to the previous 16 weeks of treatment in the main study. The use of BCD-085 at a dose of 120 mg during OLE study leads to a pronounced and statistically significant decrease in the BASDAI, BASFI, BASMI indices and the assessment of pain. Thus, the BASDAI index, which reflects the activity of ankylosing spondylitis, was ≈3.2 in this group, which corresponds to an inactive disease. According to ASAS-EULAR2016 recommendations changes in the ASDAS score ≥1.1 and BASDAI score ≥2 are considered clinically significant. The data presented in the table above indicate the presence of these changes in the BCD-085 120 mg group, which confirms the significance of the effects.

[1098] Safety

[1099] The safety analysis included all patients who received at least one dose of BCD-085 within BCD-085-3ext study (n=81).

[1100] In general, at least one AE was registered in 40.74% (33) of participants, while treatment-related AEs were presented in 28.40% (23) patients. There were no cases of SAEs, grade 4 AEs or deaths within the whole study period (Table 42).

[1101] During BCD-085-3ext study two cases of early withdrawal related AE were reported (microbial eczema, positive blood test for tuberculosis).

TABLE-US-00069 TABLE 42 Safety data obtained from BCD-085-3ext study Proportion of Type of deviation patients (n = 81) Any AE 33 (40.74%) Any SAE  0 (0.00%) Treatment-related AEs 23 (28.40%) Grade 3 AEs  4 (4.94%) Treatment-related AEs of grade 3  2 (2.47%) Local reactions  1 (1.23%) Study withdrawal due to AEs  2 (2.47%)

[1102] The majority of AEs were presented by single episodes throughout the study. Predominantly registered AEs belonged to infections, blood and lymphatic system disorders, and liver and biliary tract abnormalities. Cardiovascular disorders were less common.

[1103] Mainly registered AEs, including treatment-related, were mild and moderate (1-2 gr. by CTCAE v. 4.03), which allow to conclude that the safety profile of BCD-085 was favorable. There were four patients with grade AEs, represented by neutropenia, increased GGT activity, URTI, and increased blood pressure. Two episodes of increase in blood pressure (gr.3), recorded in one patient, required medical therapy and resolved without consequences.

[1104] The expectancy of AE was based of known safety profiles of other IL-17 inhibitors, and data from previous clinical studies of BCD-085 (BCD-=85-1, BCD-085-2, BCD-085-2ext, and BCD-085-3. There was the only unexpected AE in BCD-085-3ext study-facial paresthesia. However, disorders of the nervous system accompanied by sensitivity abnormalities (facial nerve paralysis, sciatica) were previously described for secukinumab and ixekizumab, which may indicate some probability of such AE in patients treated with IL-17-inhibitors.

[1105] There was a series of AE episodes, which is of interest as part of the safety assessment of therapeutic monoclonal antibodies in general and interleukin-17 blockers in particular.

[1106] Two cases of positive blood tuberculosis test were registered with a normal chest radiograph and without any other signs of active tuberculosis.

[1107] One case of gr.2 mycosis (esophageal candidiasis) was identified (1.23%). This AE resolved without consequences within the standard therapy.

[1108] According to the protocol, manifestations of ankylosing spondylitis were not registered as AE. In this regard, it is necessary to note the episode of iridocyclitis, interpreted by the investigators as a manifestation of ankylosing spondylitis and not registered as AE. Iridocyclitis resolved without consequences within the standard therapy.

[1109] Given the route of administration of BCD-085 (subcutaneous injections), the development of local reactions was expected. The proportion of patients with local reactions was 1.23% (2 local reactions were recorded in one patient, represented by hyperemia, edema, pruritus, pain and the formation of local infiltrate), which indicates a low frequency of this adverse event.

[1110] There were no cases of antidrug-antibodies formation within the whole study period.

[1111] Thus, the use of BCD-085 throughout the year in patients with AS shows a favorable safety profile and good tolerability. The drug is characterized by a low probability of local reactions, SAEs, the frequency of AEs did not increase within the time of therapy. A comparison with the available data on the safety of other monoclonal antibodies against interleukin-17 (secukinumab, ixekizumab) indicates the comparability of safety profiles.

Conclusion

[1112] It was shown that long-term use of BCD-085 at 120 mg allowed to reach response even in late responding patients (who did not reach ASAS20 at week 16), e.g. after 1 year of treatment ASAS20/40 and ASAS5/6 were obtained by 63.16%, 52.66% and 52.66% of patients, respectively. Safety analysis showed that long-term use of BCD-085 was well tolerated by patients, immunogenicity analysis didn't reveal any cases of ADA formation.

Example 10. Efficacy of Netakimab in Patients with Ankylosing Spondylitis (BCD-085-5 Study)

[1113] Study Design

[1114] BCD-085-5 is an ongoing multicentre double-blind placebo-controlled Phase III study in patients with active ankylosing spondylitis. The primary objective is to evaluate the efficacy and safety of BCD-085 versus placebo in patients with active ankylosing spondylitis.

[1115] Study BCD-085-5 used the 60 mg/1 ml formulation for BCD-085 in pre-filled syringes. The route of administration was SC injections with 2 pre-filled syringes (2 SC injections, given for 15 min) at weeks 0, 1, 2 and then every other week within 3 years of treatment.

[1116] Patient Population and Study Design

[1117] The study includes 228 patients with active ankylosing spondylitis aged 18 to 65 years inclusively, who met the eligibility criteria. Patients should have ankylosing spondylitis according to the modified New York criteria (1984), diagnosed at least 3 months before signing the ICF. The study doesn't include patients previously treated with MAbs targeting IL17 (or IL17 receptor) and patients previously treated with 2 or more anti-TNF-alfa drugs. After the screening patients were randomized in ratio 1:1 into 2 arms: 1) BCD-085 120 mg and 2) placebo. Patients received BCD-085/placebo in the blinded manner on Day 1 at weeks 0, 1, 2, 4, 6, 8, 10, 12 and 14. From week 16 the therapy is open-label, patients from both groups start to receive BCD-085 120 mg in Q2W regimen (except responders from placebo arm: patients who achieved ASAS20 at week 14 in this group are excluded from the study). When procedures of visit at week 154 (week 170 for patients initially randomized to placebo arm) are completed, patients will undergo an 4-week safety follow up.

[1118] Results

[1119] Data from the first 16 weeks are presented.

[1120] Baseline characteristics were similar between treatment arms. The mean age at baseline was 39.14±9.99 years, 75.88% of patients (pts) were male and the mean symptoms duration was 4.3±4.48 years. All patients had active AS (mean BASDAI: 6.21±1.55), 76.8% of patients were naïve to any biological treatment. At week 16, ASAS40 response rate was higher in BCD-085 arm, compared to placebo arm: 40.35% versus (vs.) 2.63% pts respectively (95% CI for the difference in the ASAS40 response rate was [27.37%; 48.07%] (p<0.0001, FIG. 29). Higher efficacy of BCD-085 was also proved by comparison of all other secondary efficacy endpoints (FIG. 30); improvement in BASDAI, MASES and BASFI became significant from Wk 4 and remained low during the study.

[1121] Both arms were comparable in the Berlin spine score (4.18±4.58 in BCD-085 arm vs. 4.19±4.32 in placebo arm) and the SPARCC score (5.67±8.33 in BCD-085 arm vs. 5.23±7.86 in placebo arm) at baseline (p 0.05). Data analysis at week 16 revealed that BCD-085 arm achieved significant decline in bone marrow edema in direct comparison with placebo arm: by week 16 the mean change from baseline in the Berlin spine score was −2.16±2.87 in BCD-085 arm vs. −0.30±1.55 in placebo arm (p<0.0001) and the mean change from baseline in the SPARCC score was −3.80±6.68 in BCD-085 arm vs. −1.82±4.12 in placebo arm (p<0.01, FIG. 31).

[1122] At week 1 the difference in total back pain score between study arms became statistically significant (FIG. 32). At week 16 use of BCD-085 was associated with statistically significant improvements from baseline in BASDAI (−2.8 vs 0.2, p<0.0001), BASFI (−0.9 vs 0.9, p<0.0001) and physical component of SF36 (6.3 vs. −2.6, p<0.0001) (FIG. 33). WPAI response in BCD-085 arm was significantly better at week 16, as compared with placebo (Table 43).

TABLE-US-00070 TABLE 43 Change in WPAI at week 16 (medians; upper and lower quartiles) BCD-085 (n = 114) Placebo (n = 114) Change from Change from baseline to baseline to Parameter Baseline Wk16 Baseline Wk16 % work time missed   0 [0; 18.4]     0 [−11.1; 0]  0 [0; 15.8]   0 [0; 29.9] due to health % impairment while   50 [30; 70]   −80 [−40; 0] 50 [40; 70]  10 [−10; 20] working due to health % overall work 55.1 [40; 84] −15.6 [−40; 0] 60 [50; 75] 1.2 [−10.3;20] impairment due to health % activity   60 [40; 80]   −20 [−40; −10] 60 [50; 70]   0 [−10; 20] impairment due to health

[1123] Safety

[1124] Most reported adverse events (AE) and treatment-related adverse events (TRAE) were mild/moderate (Table 44). The most frequent AEs were anaemia, neutropenia and ALT increase. One serious adverse event (SAE) not related to the treatment (bone fracture, which required surgery), was reported in NTK arm.

TABLE-US-00071 TABLE 44 Summarized safety data Arm Percentage of BCD-085 Placebo patients with (n = 114) (n = 114) p-value Any AE/SAE 33.33% (38) 25.44% (29) 0.245 TRAE 17.54% (20) 14.04% (16) 0.586 Any SAE  0.88% (1)  0 1.00 Grade 3-4 AEs  2.63% (3)  3.51% (4) 1.00 TRAE of grade 3-4  1.75% (2)  1.75% (2) 1.00 Local reactions  1.75% (2)  0.88% (1) 1.00

[1125] Netakimab up to a dose of 120 mg (e.g. doses suggested herein) is a well-tolerated drug with a favorable safety profile that leads to decline in AS activity, to improvement of function, axial mobility, MRI signs of inflammation and quality of life.