EA046015B1 - AQUEOUS PHARMACEUTICAL COMPOSITION ANTI-IL17A ANTIBODIES AND ITS APPLICATION - Google Patents

Description

Technical field

The present invention relates to aqueous compositions for anti-IL17a antibodies and, in particular, to aqueous compositions for anti-IL17a antibodies containing a VHH variable domain and a VL variable domain, which can be used as a medicament for the treatment of IL-17A-mediated diseases .

State of the art

Antibodies, also referred to as immunoglobulins (Ig), are soluble glycoproteins in blood and tissue fluid that play a key role in the humoral immune system in vertebrates. Antibodies are synthesized by B lymphocytes in response to foreign biological and chemical substances (antigens) of various structures. Due to their high specificity and high affinity of binding to a specific antigen, as well as the ability to generate antibodies to an unlimited repertoire of antigens, antibodies and their derivatives are among the most important reagents for use in basic and applied medical research.

Canonical antibodies are large (~150 kDa - IgG) multimeric proteins containing two identical heavy H chains (one variable VH domain, three constant CH1, CH2, CH3 domains and a hinge region between the CH1 and CH2 domains ) and two identical light chains (consisting of a variable VL domain and a constant CL domain). The four-chain molecule is linked through non-covalent and covalent (disulfide) bonds between the chains. Using the protease papain, the antibody molecule can be split into two fragments: Fab (Fragment antigen binding, antigen binding fragment) and Fc (Fragment crystallizable, fragment capable of crystallization). Accordingly, one region of the antibody molecule (Fab) determines its antigen specificity, and the other (Fc) performs effector functions that are aimed at eliminating the antigen. The CH1 and CH2 domains of the H chain are separated by a hinge region, which determines the mobility of the Fab fragment and the interaction of the IgG molecule with IgG effector receptors located on cells. The CH2 domain contains binding sites for both FcY receptors that mediate cellular activation (ADCC and ADCP) and complement molecules (CDC). In addition, this domain contains a site that is the site of carbohydrate attachment for all immunoglobulin isotypes. The CH3 domain largely determines the stability of the IgG dimer and interacts with the FcRn receptor on the cell surface, determining the pharmacokinetic properties of antibodies and their metabolism and distribution within the body. The combination of the antigen-binding regions (CDR-Complementarity Determining Regions) of the variable heavy chain (VH) domain and the variable light chain ( _VL ) domain forms the antigen binding site, while the framework regions of the variable domains and constant domains are not directly involved in antigen recognition. The minimized Fab derivative for classical antibodies is a single-chain construct in which the variable domains of the heavy and light chains are connected by a linker sequence (scFv).

An important discovery was the discovery in the blood of representatives of the Camelidae family (camels, llamas, vicuñas) in a significant amount of specific non-canonical antibodies with a simplified structure. Such antibodies (heavy chain antibodies, HCAbs) consist of a dimer of only one truncated heavy chain (without the CH1 domain), and the light chain is completely absent. The antigen-binding region of HCAb is formed by only one heavy chain variable domain ( _VHH ), which is directly linked through the hinge region to the Fc domain. V _HH is often referred to as a single-domain antibody, nanobody, mini-antibody, or nanoantibody. As it turned out, such a single-domain structure in isolated form, in addition to its small size (12-15 kDa), has a number of advantages over classical IgG antibodies, namely aggregation, chemical and thermal stability. VHH antibodies can be efficiently cloned and expressed in bacterial and yeast cells. Possessing such properties, they have received technological development both in the therapeutic area developed by Ablynx, and in the field of laboratory and industrial chromatography (Capture Select affinity sorbents).

Heavy chain antibodies (HCAbs), consisting of a dimer of the immunoglobulin heavy chain only, were first discovered by electrophoretic analysis of immunoglobulins in the blood serum of various representatives of the camelid family. The relative proportion of HCAbs varies from about 15-25% (total IgG) in llamas and vicunas to about 60-80% in camels

Non-canonical antibodies (HCAbs), at least in the case of camelids, are thought to represent the result of relatively recent evolution of canonical antibody genes. The two heavy chain constant domains, CH2 and CH3, are highly conserved between HCAbs and canonical antibodies. In the composition of HCAb antibodies, the domain corresponding to the first constant CH1 domain of classical antibodies is absent. The genome of the dromedary camel (Dromedary species) contains a cluster of approximately fifty VH- and forty VHH-generative genes, followed by multiple D-segment genes, J-segments and constant region genes (ί'.'μ. Cy, Ce, Ca) . It is obvious that some of the Cγ genes are intended for the formation of HCAbs (mutation leads to loss of the CH1 domain), while the rest are intended for the formation of canonical antibodies (with the retained CH1 domain). Same

- 1 046015 genes of segments D and J can randomly connect with either one of the VH genes or one of the VHH genes. This indicates that the VH and VHH genes are located at the same locus.

The organization of the variable domains of non-canonical antibodies (VHH) and the variable domains (VH) of classical antibodies is very similar, because In humans, the VH domains of the IgG3 subclass have high homology with the VH and VHH of camelids. In both cases, the V domains consist of four conserved framework regions (FRs) that surround three hypervariable complementarity determining regions (CDRs). Also, in both cases, a spatial 3D structure typical of the immunoglobulin V domain is formed of two β-layers, one of which consists of four amino acid chains and the second of five. In this structure, all three hypervariable regions are clustered on one side of the V domain, where they are involved in antigen recognition and are located in loops connecting β-structures. However, there are also important differences associated with the functioning of VHH in a single domain format. Thus, CDR1 and CDR3 of VHH are markedly increased. Often, in hypervariable regions of VHH, cysteine residues are found in two regions at once (most often in CDR1 and CDR3, less often in CDR2 and CDR3). Studies of VHH crystal structures have shown that these cysteine residues form disulfide bonds, and this further stabilizes the loop structure of this antibody. The most obvious and reproducible distinctive feature of VHH is represented by four substitutions of hydrophobic amino acid residues with hydrophilic ones in the second framework region (Val37Phe, Gly44Glu, Leu45Arg, Trp47Gly, according to Kabat numbering). This framework region of the VH domain is highly conserved, enriched in hydrophobic amino acid residues and is especially important in forming a connection with the variable domain V _L of the light chain. In this aspect, the VHH domain is very different: these substitutions of hydrophobic amino acids for hydrophilic ones make the association of VHH and V _L impossible. These substitutions also explain the generally high solubility of VHH (nanoantibodies) when produced as a recombinant protein.

The repertoires of possible paratopes (antigen-binding portions of an antibody) of HCAbs and canonical antibodies appear to be markedly different. Since these two types of antibodies coexist in the same organism, it can be assumed that they do not compete, but complement each other. For example, it has been noted more than once that both types of antibodies can arise in parallel, mutually exclusive, or in different proportions, in relation to different epitopes of antigenic material during immunization of the same animal. Despite the perceived lower diversity of possible paratopes in single-domain antibodies compared to canonical double-domain antibodies, many publications have convincingly demonstrated that HCAbs can be generated against a wide variety of epitopes on a very wide range of antigens. Apparently, this is facilitated by enlarged CDR1 and CDR3 regions. It should also be noted that there is a surprisingly large (in comparison with the V domains of classical antibodies) number of somatic hypermutations in V _HH , which apparently accumulate during the affinity maturation of antibodies during immunization. X-ray diffraction analysis showed that the antigen-binding loop regions of VHH are capable of forming structures unusual for classical V domains. While in the case of the VH and VL domains of classical antibodies all six CDR regions make more or less equal contributions to antigen binding, in the case of VHH the CDR3 region is usually more important for paratope formation. It has been shown that the CDR3 region in VHH (but not in VH or VL) can form unusual long finger-like protrusions that can penetrate into the structure of the antigen, in particular recognizing the active sites of enzymes. The small size of the antigen-binding region V _HH and its ability to form unusual protruding paratopes explains the possibility of obtaining HCAbs capable of recognizing epitopes that are inaccessible to classical antibodies (for example, in the formation of antibodies that are effective enzyme inhibitors).

Despite its high potential and unique specificity compared to classical IgG antibodies, the use of single-domain VHH for therapeutic use is limited in some cases due to the rapid elimination of this small molecule from the body. There are a number of solutions to improve the pharmacokinetics of VHH structures, which include the use of chemical conjugation with PEG and covalent coupling to a polypeptide that mediates reduced clearance (such as human serum albumin (HSA) and Fc-fusion proteins, which have a half-life of up to three weeks ). The successful use of small peptides attached to V _HH using recombinant technology methods and capable of high-affinity non-covalent interaction with the same components (HSA and IgG) in human blood has also been shown. However, the manufacturability and immunogenicity of these approaches remains unclear and is only at the stage of testing their applicability both in clinical trials and in earlier stages of research.

In addition, the greatest limitation in the use of antibodies as medicines is aggregation and chemical stability, affinity and immunogenicity. Since most monoclonal antibodies are currently derived from mice, regular use of such antibodies in patients leads to the development of an immune response to antibody therapy (for example, allergic reactions). These types of immune responses may result in eventual loss of effectiveness at the very least and, at worst, possible severe anaphylaxis.

- 2 046015 chemical reactions. On the other hand, therapeutic antibodies that are aggregatively or chemically unstable during drug storage impair its therapeutic properties and may enhance immunogenicity when administered to human patients.

In connection with the above, it is relevant to create antibodies based on VHH antibodies, which would have (compared to previously known antibodies) improved functional and therapeutic properties, in particular increased aggregation, chemical and thermal stability, and improved affinity, and at the same time differ would be easy and simple to obtain on an industrially significant scale.

Various antibody designs containing the VHH domain are known from the prior art.

Publication PCT/EP 2008/066368 describes antibodies that contain individual variable domains associated with an Fc fragment. Nanobodies can be used as variable domains, with the Fc fragment derived from an IgE-type antibody. Said domain and Fc fragment can be connected via a linker located in the hinge region.

Patent application US 2009/0202979 discloses antibodies comprising all or part of V _HH antibodies directly linked to human antibody constant portions.

Amino acid substitutions are also known to affect the physicochemical and biological properties of antibodies.

For example, application US 2011/0028348 describes heavy chain variable domains in which amino acid substitutions are introduced at positions 35, 45, 47, 93-100 and 100a to increase the hydrophilicity of the resulting antibody.

To date, methods have been developed to optimize the structure of isolated VHH and VH monodomains, reducing their immunogenicity and improving aggregation stability.

Thus, Vincke and co-workers found that the Glu-49^Gly and Arg-50^Leu substitutions in characteristic amino acids result in a separate domain that is more stable, but less soluble. Other substitutions in the FR-2 framework region Phe-42^-Val and Gly/Ala-52^Trp critically affect the affinity of the antibody to the antigen due to reorientation of the H3 loop, increasing its kinetic dissociation constant by 6-10 times (6.85-10 -31/s). When replacing Phe-42^-Val, a decrease in the stability of the resulting antibodies was observed. Replacement of Gly-49 and Leu-50 in the VH sequence led to a decrease in domain stability, while humanization of Glu-49 and Arg-50 in VHH made it possible to obtain stable variable domains.

It is also known from the literature that in the presence of short HCDR3 regions, leveling the shielding effect of the classical VHH conformation, and introducing the VH-characteristic substitution Trp-47 with Gly-47 and substitutions Tyr-37 with Val-37, Glu-44 with Gly-44 and Arg-45 to Leu-45, isolated VHH domains can restore the ability to bind to the VL domain.

The connection between an increase in the aggregation stability of therapeutic antibodies of the classical IgG structure and a decrease in their immunogenicity has been demonstrated in many studies and summarized in the review by Hermeling et al., 2004. However, no antibodies containing VHH domains but associated with light chain variable domains were found as part of full-length human IgG.

Thus, there is a need to create a new antibody format that would have increased stability and affinity, good expression, and low immunogenicity.

In addition, approaches to creating such molecules that are easy to prepare and have improved aggregation stability, increased affinity and high levels of expression in mammalian cell cultures, and an aqueous composition for such antibodies, have not previously been described.

The essence of the invention

The present invention discloses aqueous pharmaceutical compositions of antibodies containing VHH derivatives that are attached to the variable domains of the light chains of full-length human IgG, thereby forming a construct that (as a result, has low immunogenicity) has improved aggregation stability, increased affinity compared to traditional a human antibody with both a VH variable domain heavy chain (instead of a VHH variable domain) and a VL variable domain light chain, and the structure of a therapeutic monoclonal antibody. More specifically, the present invention relates to such antibodies that are specific for I17a.

The present invention discloses an aqueous pharmaceutical composition suitable for parenteral administration to a subject to inhibit the activity of the L17a protein, comprising a pharmaceutically effective amount of an anti-[L17a antibody comprising a VHH-derived domain and a VL variable domain.

As described in patent application No. PCT/RU2015/000163, incorporated herein by reference, it has been shown that an anti-IL17a antibody comprising both the VHH domain and the variable

- 3046015 VL domain (referred to herein as antibodies of the invention) has increased affinity and stability for IL17;i compared to recombinant human anti-IL17a antibodies with integrated human immunoglobulin cassettes, such as secukinumab. In this regard, it would be useful to administer an aqueous antibody composition of the invention to a patient with an IL-17a-mediated disease. Examples of the three complementarity determining regions (CDRs) of the VHH domain of an anti-IL17a antibody responsible for binding to IL-17a may be those corresponding to SEQ ID NO: 1,2,3.

However, due to the structural differences between human antibodies, such as secukinumab, and the antibodies of the invention, aqueous compositions suitable for secukinumab and related antibodies are not necessarily suitable for the antibodies of the invention. For example, the antibodies of the present invention comprise a VHH variable domain combined with a light chain VL variable domain, wherein human antibodies such as secukinumab have a heavy chain with a VH variable domain combined with three constant domains, with the heavy domain attached to the light chain. Thus, there are significant structural differences in size, weight and configuration between the antibodies of the invention and antibodies based on human antibodies, such as secukinumab. These differences may influence the proper selection of suitable aqueous pharmaceutical compositions for each antibody. An aqueous pharmaceutical composition suitable for secukinumab may not necessarily be suitable for an aqueous pharmaceutical composition for an antibody of the present invention, such as netakimab. Additional testing, as described in detail herein, was required to determine suitable aqueous pharmaceutical compositions for the antibodies of the invention.

In this regard, it will be useful to identify suitable aqueous pharmaceutical compositions for the antibodies of the invention that provide sufficient colloidal stability, thermal stability, reduce antibody aggregation and homogeneity of the antibodies in the composition.

Thus, the present invention relates to the identification of suitable aqueous pharmaceutical compositions for the antibodies of the invention.

An example of an antibody of the invention is netakimab (also referred to herein as BCD-085). Netakimab is a humanized monoclonal IgG antibody with a weight average molecular weight of approximately 149 kDa that is specific for human IL17a. The drug is also known under the brand name Aleira. Netakimab has a heavy chain with a mutant humanized variant of the VHH domain. The heavy chain has 455 amino acids (SEQ ID NO: 5). Netakimab has a human kappa light chain of 215 amino acids (SEQ ID NO: 6).

Another anti-IL17a antibody of the present invention that is suitable for the aqueous pharmaceutical compositions described herein includes a VHH domain with 3 CDR regions corresponding to SEQ ID NO: 1, 2, 3, respectively, and in some examples a VL variable domain corresponding to SEQ ID NO: 4.

A broad aspect of the present invention is an aqueous pharmaceutical composition suitable for parenteral administration to a subject to inhibit the activity of IL17a protein. The aqueous pharmaceutical composition may include a pharmaceutically effective amount of an anti-IL17a antibody comprising a VHH-derived domain and a VL variable domain; histidine-based buffering agent; and an effective amount of sugar alcohol as an osmotic agent.

In some embodiments, an anti-IL17a antibody may comprise a VHH-derived domain and a VL variable domain, wherein the VHH-derived domain may be directly linked to the VL variable domain.

In some embodiments, the VHH domain of an anti-IL17a antibody may comprise 3 hypervariable regions HCDR1, HCDR2, and HCDR3, wherein

HCDR1 may comprise the amino acid sequence SEQ ID NO: 1;

HCDR2 may comprise the amino acid sequence SEQ ID NO: 2;

HCDR3 may comprise the amino acid sequence SEQ ID NO: 3; and wherein the VL variable domain of the anti-IL17a antibody may comprise the amino acid sequence of SEQ ID NO: 4.

In some embodiments, the anti-IL17a antibody may be netakimab.

In some embodiments, netakimab may be in an amount of 5 to 150 mg/ml.

In some embodiments, netakimab may be in an amount of 10 to 100 mg/ml.

In some embodiments, netakimab may be in an amount of 10 to 70 mg/ml.

In some embodiments, netakimab may be in an amount of 40 mg/ml.

In some embodiments, netakimab may be in an amount of 60 mg/ml.

In some embodiments, netakimab may be in an amount of 70 mg/ml.

In some embodiments, the sugar alcohol may be mannitol.

In some embodiments, the mannitol may be in an amount of 25-60 mg/ml.

In some embodiments, the mannitol may be in an amount of 50-60 mg/ml.

In some embodiments, the mannitol may be in an amount of 54.5 mg/ml.

- 4 046015

In some embodiments, a suitable amount of histidine buffering agent may be added to adjust the pH to about 5.5 to 6.5.

In some embodiments, the buffering agent may consist of L-histidine in an amount of 0.4 to 1.6 mg/ml; and L-histidine hydrochloride monohydrate in an amount of 0.4 to 1.6 mg/ml.

In some embodiments, the aqueous pharmaceutical composition may further include a suitable solubilizer.

In some embodiments, the solubilizer may be poloxamer 188.

In some embodiments, poloxamer 188 may be in an amount that is greater than 0 mg/ml but equal to or less than 1 mg/ml.

In accordance with another broad aspect of the present invention, there is provided an aqueous pharmaceutical composition suitable for parenteral administration to a subject to inhibit the activity of IL17a protein. The aqueous pharmaceutical composition may include

Anti-PL7a antibody containing derivative domain and Vp variable domain L-histidine

L-Γhistidine hydrochloride monohydrate Mannitol

Pol oxamer 188 pH 6.0 ±0.5

10-70 mg/ml

0.4 mg/ml

0.4 mg/ml

54.5 mg/ml

0-1 mg/ml

In some embodiments, said VHH domain of said anti-IL17a antibody may comprise the 3 hypervariable regions HCDR1, HCDR2, and HCDR3, wherein

HCDR1 may comprise the amino acid sequence SEQ ID NO: 1;

HCDR2 may comprise the amino acid sequence SEQ ID NO: 2;

HCDR3 may comprise the amino acid sequence SEQ ID NO: 3; and wherein the VL variable domain of said anti-IL17a antibody may comprise the amino acid sequence of SEQ ID NO: 4.

In some embodiments, the anti-IL17a antibody may be netakimab.

In some embodiments, netakimab may be in an amount of 40 mg/ml.

In some embodiments, netakimab may be in an amount of 60 mg/ml.

In some embodiments, netakimab may be in an amount of 70 mg/ml.

In accordance with another broad aspect, there is provided an aqueous pharmaceutical composition suitable for parenteral administration to a subject for inhibiting the activity of IL17a protein, wherein said aqueous pharmaceutical composition may include

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

In accordance with another broad aspect of the present invention, there is provided an aqueous pharmaceutical composition suitable for parenteral administration to a subject to inhibit the activity of IL17a protein. The aqueous pharmaceutical composition may include a pharmaceutically effective amount of an anti-IL17a antibody comprising a VHH-derived domain and a VL variable domain; acetate-based buffering agent; and a disaccharide as an osmotic agent.

In some embodiments, said VHH domain of said anti-IL17a antibody may comprise 3 hypervariable regions HCDR1, HCDR2 and HCDR3, wherein

HCDR1 may comprise the amino acid sequence SEQ ID NO: 1;

HCDR2 may comprise the amino acid sequence SEQ ID NO: 2;

HCDR3 may comprise the amino acid sequence SEQ ID NO: 3; and wherein the VL variable domain of said anti-IL17a antibody may comprise the amino acid sequence of SEQ ID NO: 4.

In some embodiments, the anti-IL17a antibody may be netakimab.

In some embodiments, netakimab may be in an amount of 5 to 150 mg/ml.

In some embodiments, netakimab may be in an amount of 10 to 120 mg/ml.

In some embodiments, netakimab may be in an amount of 60 mg/ml.

In some embodiments, netakimab may be in an amount of 100 mg/ml.

In some embodiments, netakimab may be in an amount of 120 mg/ml.

In some embodiments, the disaccharide may be trehalose.

In some embodiments, trehalose may be added to the composition in the form of trehalose dihydrate in an amount of 50 to 120 mg/ml.

In some embodiments, trehalose may be added to the composition as trehalose dihydrate in an amount of 50 mg/ml.

In some embodiments, trehalose may be added to the composition as di

- 5 046015 trehalose hydrate in an amount of 80 mg/ml.

In some embodiments, the acetate-based buffering agent may contain from 0.4 to 1.8 mg/ml sodium acetate trihydrate; and a suitable amount of acetic acid to adjust the pH of the composition to 4.0 to 6.0, inclusive.

In some embodiments, the aqueous composition may further include a suitable solubilizer.

In some embodiments, the solubilizer may be poloxamer 188.

In some embodiments, poloxamer 188 may be in an amount that is greater than 0 mg/ml and equal to or less than 1.0 mg/ml.

In accordance with another broad aspect of the present invention, there is provided an aqueous pharmaceutical composition suitable for parenteral administration to a subject to inhibit the activity of IL17a protein. The aqueous pharmaceutical composition may include

Anti-PL7a antibody containing a derivative domain and a variable domain

Sodium acetate trihydrate

Trehalose dihydrate

Poloxamer 188

Acetic acid, ice.

pH 5.0 ±0.5

НН10 - 120 mg/ml 0.44-1.74 mg/ml 80-100 mg/ml 0-1 mg/ml up to pH 5.0

In some embodiments, said VHH domain of said anti-IL17a antibody may comprise 3 hypervariable regions HCDR1, HCDR2 and HCDR3:

HCDR1 may comprise the amino acid sequence SEQ ID NO: 1;

HCDR2 may comprise the amino acid sequence SEQ ID NO: 2;

HCDR3 may comprise the amino acid sequence SEQ ID NO: 3; and wherein the VL variable domain of said anti-IL17a antibody may comprise the amino acid sequence of SEQ ID NO: 4.

In some embodiments, the anti-IL17a antibody may be netakimab.

In some embodiments, netakimab may be in an amount of 60 mg/ml.

In some embodiments, netakimab may be in an amount of 100 mg/ml.

In some embodiments, netakimab may be in an amount of 120 mg/ml.

In another broad aspect, there is provided an aqueous pharmaceutical composition suitable for parenteral administration to a subject to inhibit the activity of IL17a protein, wherein said aqueous composition may comprise Netakimab 60 mg/ml

Sodium acetate trihydrate 1.74 mg/ml

Trehalose d/g 80 mg/ml

Acetic acid, ice. up to pH 5.0 pH 5.0 ±0.5

In another broad aspect, there is provided an aqueous pharmaceutical composition suitable for parenteral administration to a subject to inhibit the activity of the IL17a protein, wherein said aqueous composition may comprise Netakimab

Sodium acetate trihydrate

Trehalose d/g

Poloxamer 188

Acetic acid, ice.

pH 5.0 ±0.5 mg/ml 1.74 mg/ml 80 mg/ml 0.5 mg/ml to pH 5.0

In accordance with another broad aspect, there is provided an aqueous pharmaceutical composition suitable for parenteral administration to a subject for inhibiting the activity of IL17a protein, wherein said aqueous composition may include

Netakimab

Sodium acetate trihydrate Trehalose d/g

Poloxamer 188 Acetic acid, ice. pH 5.0 ±0.5 mg/ml

1.74 mg/ml mg/ml mg/ml up to pH 5.0

In accordance with another broad aspect, there is provided an aqueous pharmaceutical composition suitable for parenteral administration to a subject for inhibiting the activity of the IL17a protein, wherein said aqueous composition may include

- 6 046015

Netakimab

Sodium acetate trihydrate

Trehalose d/g

Paul oxamer 188

Acetic acid, ice.

pH 5.0 ±0.5

120 mg/ml 1.74 mg/ml 80 mg/ml 0-1 mg/ml up to pH 5.0

In accordance with another broad aspect, there is provided an aqueous pharmaceutical composition suitable for parenteral administration to a subject for inhibiting the activity of the IL17a protein, wherein said aqueous composition may include

Netakimab 120 mg/ml

Sodium acetate trihydrate 1.74 mg/ml

Trehalose d/g 80 mg/ml

Acetic acid, ice. up to pH 5.0 pH 5.0 ±0.5

In another broad aspect, there is provided an aqueous pharmaceutical composition suitable for parenteral administration to a subject to inhibit the activity of IL17a protein, wherein said aqueous composition may comprise Netakimab 120 mg/ml

Sodium acetate trihydrate 1.74 mg/ml

Trehalose d/g 80 mg/ml

Pol oxamer 188 0.5 mg/ml

Acetic acid, ice. up to pH 5.0 pH 5.0 ±0.5

In accordance with another broad aspect, there is provided an aqueous pharmaceutical composition suitable for parenteral administration to a subject for inhibiting the activity of the IL17a protein, wherein said aqueous composition may include

Netakimab 120 mg/ml

Sodium acetate trihydrate 1.74 mg/ml

Trehalose d/g 80 mg/ml

Pol oxamer 188 1 mg/ml

Acetic acid, ice. up to pH 5.0 pH 5.0 ±0.5

In accordance with another broad aspect, the use of a composition as defined herein is provided for the treatment of an IL17a-mediated disease.

In some embodiments, the IL17a-mediated disease may be one of, wherein the IL17a-mediated disease or disorder may be 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-associated arthritis; enthesitis; spondyloarthropathy, axial spondyloarthritis; Behçet's disease; inflammatory bowel disease, Crohn's disease, ulcerative colitis; asthma, allergic disorders, atopic allergies; ichthyosis; red hairy pityriasis; papulopustular rosacea; gangrenous pyoderma; hidradenitis suppurativa; psoriasis, psoriatic arthropathy, type I psoriasis, type II psoriasis, plaque psoriasis; dermatitis, atopic dermatitis, autoimmune dermatitis, dermatological conditions; systemic sclerosis; transplantation, graft-versus-host disease, graft rejection, acute or chronic immune disease associated with organ transplantation, acute immune disease related to transplantation, chronic immune disease associated with transplantation, small bowel transplant rejection, pancreas transplant rejection, transplant rejection of any organ or tissue graft rejection, cardiac graft rejection, cartilage graft rejection, kidney graft rejection, liver graft rejection, allograft rejection, skin allograft rejection, heterograft rejection of any organ or tissue, bone graft rejection, bone marrow graft (BMT) rejection, parathyroid graft rejection ; bone erosion; sarcoidosis, atherosclerosis, Wegener's disease, microscopic polyangiitis with kidney damage, uveitis, phacogenic uveitis, non-infectious uveitis, cachexia, acute transverse myelitis, primary biliary cirrhosis, autoimmune polyglandular syndrome type I and II, Schmidt's syndrome, acute respiratory distress syndrome; arthropathy, seronegative arthropathy, arthropathy associated with ulcerative colitis, Reiter's syndrome, enteropathic synovitis, atheromatosis/coronary sclerosis, autoimmune bullous disease, pemphigus, pemphigus foliaceus, linear IgA-dependent bullous dermatosis, autoimmune hemolytic anemia, giant cell arteritis, primary th sclerosing hepatitis , cryptogenic autoimmune hepatitis, cryptogenic fibrosing alveolitis, systemic scleroderma associated with interstitial lung disease, rheumatoid arthritis associated with interstitial lung disease,

- 7 046015 systemic lupus erythematosus associated with pulmonary disease, dermatomyositis/polymyositis associated with pulmonary disease, Sjögren's syndrome associated with pulmonary disease, ankylosing spondylitis associated with pulmonary disease, vasculitis, diffuse pulmonary vasculitis, primary vasculitis, fibrosis, pulmonary disease with infiltration of lymphocytes, autoimmune hepatitis, autoimmune hepatitis type I (classical autoimmune or lupoid hepatitis), autoimmune hepatitis type II (associated with antibody to LKM), autoimmune hypoglycemia, osteoarthritis, primary sclerosing cholangitis, erythematosis; systemic lupus erythematosus, discoid lupus erythematosus, lupus nephritis; multiple sclerosis (all types), sympathetic ophthalmia, pulmonary hypertension secondary to connective tissue disease, Goodpasture's syndrome, pulmonary manifestations of polyarteritis nodosa, acute rheumatic attack, rheumatoid spondylitis, Still's disease, systemic scleroderma, scleroderma disease, scleroderma, Takayasu's disease/arteritis; autoimmune thrombocytopenia, idiopathic thrombocytopenia; autoimmune thyroiditis, hyperthyroidism, autoimmune hypothyroidism (Hashimoto's disease), autoimmune atrophic hypothyroidism; vitiligo, acute liver diseases, chronic liver diseases, cholestasis, diseases mediated by Th2 type and Th1 type, malignant tumors such as lung cancer, breast cancer, stomach cancer, bladder cancer, colorectal cancer, pancreatic cancer, pancreatic carcinoma , ovarian cancer, prostate cancer and malignancies of the hematopoietic system (leukemia and lymphomas), acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, adenocarcinoma, B-cell lymphoma, Burkitt's lymphoma, inflammatory responses to cardiopulmonary bypass, chronic myelocytic leukemia (CML) ), chronic inflammatory pathologies, chronic lymphocytic leukemia (CLL), rectocolytic carcinoma (colorectal carcinoma), cystic fibrosis, malignant lymphoma, malignant histiocytosis, malignant melanoma, multiple myeloma, non-Hodgkin's lymphoma, nasopharyngeal cancer, solid tumors, hairy cell leukemia, Hodgkin's disease, sarcoma, myelodysplastic syndrome, cytokine therapy-related disorders, demyelinating diseases, inflammatory demyelinating disease, pulmonary fibrosis, idiopathic pulmonary fibrosis, usual interstitial pneumonia, iridocyclitis/uveitis/optic neuritis, lymphedema, mixed connective tissue disease, monoclonal gammopathy, chronic neonatal lung diseases, nephritis, nephrotic, neurodegenerative disorders, osteoporosis, paraneoplastic syndrome/hypercalcemia associated with malignancy, phenomenon and Raynaud's disease, skin changes, systemic inflammatory response syndrome, thrombocytopenia, toxic effects, urticaria, acute coronary syndrome , Still's disease developed in adults, aplastic anemia, coronary sclerosis, atopic eczema; autoimmune disorder associated with streptococcal 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 risk of multiple sclerosis, erythema multiforme, severe erythema multiforme, pemphigoid, bullous pemphigoid, cicatricial pemphigoid, mucosal pemphigoid, gestational pemphigoid, iritis, keratitis, motor neuron disease, non-A hepatitis, none B, optic neuritis, oligoarticular JIA, polyarteritis nodosa, polychondritis, poliosis, polymyositis, recurrent neuromyelitis optica, rheumatic heart disease, SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, osteitis), secondary amyloidosis, ankylosing spondylitis, systemic inflammatory response syndrome , cranial arteritis and arthropathy associated with Yersinia or Salmonella.

In accordance with another broad aspect, there is provided a method of treating an IL17a-mediated disease, comprising administering a pharmaceutically effective amount of an aqueous pharmaceutical composition as defined herein.

In accordance with another broad aspect of the present invention, there is provided a method for preparing an aqueous pharmaceutical composition suitable for parenteral administration to a subject for inhibiting the activity of IL17a protein. The method includes combining a pharmaceutically effective amount of an anti-[L17a antibody containing a VHH-derived domain and a VL variable domain with a histidine-based buffering agent; and an effective amount of mannitol as an osmotic agent.

In some embodiments, the anti-IL17a antibody may be netakimab.

According to another broad aspect, there is provided a method of preparing an aqueous pharmaceutical composition suitable for parenteral administration to a subject to inhibit the activity of the IL17a protein, comprising combining a pharmaceutically effective amount of an anti-IL17a antibody comprising a VHH-derived domain and a VL variable domain with an acetate-based buffering agent; and an effective amount of trehalose as an osmotic agent.

In some embodiments, the anti-IL17a antibody may be netakimab.

In some embodiments, poloxamer 188 may be added as a solubilizer.

- 8 046015

In another broad aspect, a method of treating psoriasis is provided, comprising administering to a patient in need of such treatment a dose of 40 mg of netakimab once weekly for weeks 0, 1, 2, 4, 6, 8, 10.

In some embodiments, the method may include, after dosing netakimab at week 10, subsequently dosing 40 mg of netakimab once every four weeks.

In some embodiments, the method may include, after dosing netakimab at week 10, subsequently dosing 40 mg of netakimab once every two weeks.

In another broad aspect, a method of treating psoriasis is provided, comprising administering to a patient in need of such treatment a dose of 80 mg of netakimab once weekly for weeks 0, 1, 2, 4, 6, 8, 10.

In another broad aspect, a method of treating psoriasis is provided, comprising administering to a patient in need of such treatment a dose of 80 mg of netakimab once weekly for weeks 0, 1, 2, 6, 10.

In some examples, the method may include, after dosing netakimab at week 10, subsequently dosing 80 mg of netakimab once every four weeks.

In some examples, the method may include, after dosing netakimab at week 10, subsequently dosing 80 mg of netakimab once every two weeks.

In another broad aspect, a method of treating psoriasis is provided, comprising administering to a patient in need of such treatment a dose of 80 mg of netakimab once weekly for weeks 0, 1, 2, 4, 6, 8, 10, 12.

In some embodiments, the method may include, after administering a dose of 80 mg of netakimab at week 12, subsequently administering a dose of 80 mg of netakimab once every four weeks.

In some embodiments, the method may include, after administering a dose of 80 mg of netakimab at week 12, subsequently administering a dose of 80 mg of netakimab once every two weeks.

In some embodiments, the method may include, after administering a dose of 80 mg of netakimab at week 12, subsequently administering a dose of 80 mg of netakimab once every four weeks for the next 12 weeks.

In some embodiments, the method may include, after administering a dose of 80 mg of netakimab at week 12, subsequently administering a dose of 80 mg of netakimab once every two weeks for the next 12 weeks.

In some embodiments, the method may include administering netakimab according to the following dosage regimen:

1) administration of a dose of 80 mg netakimab once a week during weeks 0, 1, 2, 4, 6, 8, 10, 12;

2) administering a dose of 80 mg netakimab once every two weeks for the next 12 weeks thereafter;

3) administering a dose of 80 mg netakimab once every four weeks thereafter.

In some embodiments, the method may include administering netakimab according to the following dosage regimen:

1) administration of a dose of 80 mg netakimab once a week during weeks 0, 1, 2, 4, 6, 8, 10, 12;

2) administering a dose of 80 mg netakimab once every two weeks for the next 12 weeks thereafter;

3) administering a dose of 80 mg netakimab once every two weeks thereafter.

In some embodiments, the method may include administering netakimab according to the following dosage regimen:

1) administration of a dose of 80 mg netakimab once a week during weeks 0, 1, 2, 4, 6, 8, 10, 12;

2) administering a dose of 80 mg netakimab once every four weeks for the next 12 weeks thereafter;

3) administering a dose of 80 mg netakimab once every four weeks thereafter.

In some embodiments, the method may include administering netakimab according to the following dosage regimen:

1) administration of a dose of 80 mg netakimab once a week during weeks 0, 1, 2, 4, 6, 8, 10, 12;

2) administering a dose of 80 mg netakimab once every four weeks for the next 12 weeks thereafter;

3) administering a dose of 80 mg netakimab once every two weeks thereafter.

In some embodiments, a dose of 80 mg of netakimab may be administered in two injections containing 40 mg of netakimab.

In another broad aspect, a method of treating psoriasis is provided, comprising administering to a patient in need of such treatment a dose of 120 mg of netakimab once weekly for weeks 0, 1, 2, 4, 6, 8, 10.

In another broad aspect, a method of treating psoriasis is provided, comprising administering to a patient in need of such treatment a dose of 120 mg of netakimab once weekly for weeks 0, 1, 2, 6, 10.

- 9 046015

In some embodiments, the method may include, after dosing netakimab at week 10, subsequently dosing 120 mg of netakimab once every four weeks.

In some embodiments, the method may include, after dosing netakimab at week 10, subsequently dosing 120 mg of netakimab once every two weeks.

In another broad aspect, a method of treating psoriasis is provided, comprising administering to a patient in need of such treatment a dose of 120 mg of netakimab once weekly for weeks 0, 1, 2, 4, 6, 8, 10, 12.

In some embodiments, the method may include, after dosing netakimab at week 12, subsequently dosing 120 mg of netakimab once every four weeks.

In some embodiments, the method may include, after dosing netakimab at week 12, subsequently dosing 120 mg of netakimab once every two weeks.

In some embodiments, the method may include, after administering a 120 mg dose of netakimab at week 12, subsequently administering a 120 mg dose of netakimab once every four weeks for the next 12 weeks.

In some embodiments, the method may include, following administration of a 120 mg dose of netakimab at week 12, subsequent administration of a 120 mg dose of netakimab once every two weeks for the next 12 weeks.

In some embodiments, the method may include administering netakimab according to the following dosage regimen:

1) administration of a dose of 120 mg of netakimab once a week during weeks 0, 1, 2, 4, 6, 8, 10, 12;

2) administering a 120 mg dose of netakimab once every two weeks for the next 12 weeks thereafter;

3) administering a 120 mg dose of netakimab once every four weeks thereafter.

In some embodiments, the method may include administering netakimab according to the following dosage regimen:

1) administration of a dose of 120 mg of netakimab once a week during weeks 0, 1, 2, 4, 6, 8, 10, 12;

2) administering a 120 mg dose of netakimab once every two weeks for the next 12 weeks thereafter;

3) administering a 120 mg dose of netakimab once every two weeks thereafter.

In some embodiments, the method may include administering netakimab according to the following dosage regimen:

1) administration of a dose of 120 mg of netakimab once a week during weeks 0, 1, 2, 4, 6, 8, 10, 12;

2) administering a 120 mg dose of netakimab once every four weeks for the next 12 weeks thereafter;

3) administering a 120 mg dose of netakimab once every four weeks thereafter.

In some embodiments, the method may include administering netakimab according to the following dosage regimen:

1) administration of a dose of 120 mg of netakimab once a week during weeks 0, 1, 2, 4, 6, 8, 10, 12;

2) administering a 120 mg dose of netakimab once every four weeks for the next 12 weeks thereafter;

3) administering a 120 mg dose of netakimab once every two weeks thereafter.

In some embodiments, a 120 mg dose of netakimab may be administered in three injections containing 40 mg of netakimab.

In some embodiments, a dose of 120 mg of netakimab may be administered in two injections containing 60 mg of netakimab.

In some embodiments, netakimab may be administered by subcutaneous injection.

In some embodiments, netakimab may be administered by intravenous injection.

In some embodiments, the psoriasis may be plaque psoriasis.

In another broad aspect, a method of treating psoriatic arthritis is provided, comprising administering to a patient in need of such treatment a dose of 120 mg of netakimab once weekly for weeks 0, 1, 2, 4, 6, 8, 10.

In another broad aspect, a method of treating psoriatic arthritis is provided, comprising administering to a patient in need of such treatment a dose of 120 mg of netakimab once weekly for weeks 0, 1, 2, 6, 10.

In some embodiments, the method may include, after dosing netakimab at week 10, subsequently dosing 120 mg of netakimab once every four weeks.

In some embodiments, the method may include, after dosing netakimab at week 10, subsequently dosing 120 mg of netakimab once every two weeks.

In another broad aspect, a method of treating psoriatic arthritis is provided, comprising administering to a patient in need of such treatment a dose of 120 mg of netakimab once weekly for weeks 0, 1, 2, 4, 6, 8, 10, 12.

- 10 046015

In some embodiments, the method may include, after dosing netakimab at week 12, subsequently dosing 120 mg of netakimab once every four weeks.

In some embodiments, the method may include, after dosing netakimab at week 12, subsequently dosing 120 mg of netakimab once every two weeks.

In some embodiments, a 120 mg dose of netakimab may be administered in three injections containing 40 mg of netakimab.

In some embodiments, a dose of 120 mg of netakimab may be administered in two injections containing 60 mg of netakimab.

In some embodiments, netakimab may be administered by subcutaneous injection.

In some embodiments, netakimab may be administered by intravenous injection.

In another broad aspect, there is provided a method of treating ankylosing spondylitis comprising administering to a patient in need of such treatment a dose of 40 mg of netakimab once weekly for weeks 0, 1, 2.

In some embodiments, the method may include, after dosing netakimab in week 2, subsequently dosing 40 mg of netakimab once every two weeks.

In another broad aspect, there is provided a method of treating ankylosing spondylitis comprising administering to a patient in need of such treatment a dose of 40 mg of netakimab once weekly for weeks 0, 1, 2, 4, 6, 8, 10, 12.

In some embodiments, the method may include, after dosing netakimab at week 12, subsequently dosing 40 mg of netakimab once every two weeks.

In another broad aspect, there is provided a method of treating ankylosing spondylitis comprising administering to a patient in need of such treatment an 80 mg dose of netakimab once weekly for weeks 0, 1, 2.

In some embodiments, the method may include, after dosing netakimab in week 2, subsequently dosing 80 mg of netakimab once every two weeks.

In another broad aspect, there is provided a method of treating ankylosing spondylitis comprising administering to a patient in need of such treatment a dose of 80 mg of netakimab once weekly for weeks 0, 1, 2, 4, 6, 8, 10, 12.

In some embodiments, the method may include, after administering a dose of 80 mg of netakimab at week 12, subsequently administering a dose of 80 mg of netakimab once every two weeks.

In some embodiments, the method may include, after administering a dose of 80 mg of netakimab at week 12, administering a dose of 80 mg of netakimab once every two weeks beginning in week 16.

In some embodiments, the method may include, after administering a dose of 80 mg of netakimab at week 12, subsequently administering a dose of 120 mg of netakimab once every two weeks beginning in week 16.

In some embodiments, a dose of 80 mg of netakimab may be administered in two injections containing 40 mg of netakimab.

In another broad aspect, there is provided a method of treating ankylosing spondylitis comprising administering to a patient in need of such treatment a dose of 120 mg of netakimab once weekly for weeks 0, 1, 2.

In some embodiments, the method may include, after dosing netakimab in week 2, subsequently dosing 120 mg of netakimab once every two weeks.

In another broad aspect, there is provided a method of treating ankylosing spondylitis comprising administering to a patient in need of such treatment a dose of 120 mg of netakimab once weekly for weeks 0, 1, 2, 4, 6, 8, 10, 12.

In some embodiments, the method may include, after dosing netakimab at week 12, subsequently dosing 120 mg of netakimab once every two weeks.

In some embodiments, the method may include, after administering a dose of 120 mg of netakimab at week 12, subsequently administering a dose of 80 mg of netakimab once every two weeks beginning in week 16.

In some embodiments, the method may include, following administration of a 120 mg dose of netakimab at week 12, subsequent administration of a 120 mg dose of netakimab once every two weeks beginning in week 16.

In some embodiments, a 120 mg dose of netakimab may be administered in three injections containing 40 mg of netakimab.

In some embodiments, a dose of 120 mg of netakimab may be administered in two injections containing 60 mg of netakimab.

In some embodiments, netakimab may be administered by subcutaneous injection.

In some embodiments, netakimab may be administered by intravenous injection.

According to another broad aspect, there is provided a pharmaceutical composition suitable for administration to a subject to inhibit the activity of the IL17a protein, wherein the pharmaceutical composition

- 11 046015 item contains for each 1 ml of pharmaceutical composition:

Netakimab 40 mg/ml

Histidine hydrochloride monohydrate 0.4 mg/ml

L-histidine 0.4 mg/ml mannitol 54.5 mg/ml water for injection up to 1.0 ml

In accordance with another broad aspect, there is provided a method of treating psoriasis, comprising administering to a patient a pharmacologically effective amount of a pharmaceutical composition as described herein.

In some embodiments, 1 ml of the pharmaceutical composition may be administered.

In some embodiments, 1 ml of the pharmaceutical composition may be administered once per week during weeks 0, 1, 2, 4, 6, 8, 10.

In some embodiments, the method may include, after dosing netakimab at week 10, subsequently administering 1 mL doses of netakimab once every four weeks.

In some embodiments, the method may include, after dosing netakimab at week 10, subsequently administering 1 mL doses of netakimab once every two weeks.

In some embodiments, 2 ml of the pharmaceutical composition may be administered.

In some embodiments, 2 ml of the pharmaceutical composition may be administered once per week during weeks 0, 1, 2, 4, 6, 8, 10.

In some embodiments, 2 ml of the pharmaceutical composition may be administered once per week during weeks 0, 1, 2, 6, 10.

In some embodiments, the method may include, after dosing netakimab at week 10, subsequently administering 2 mL doses of netakimab once every four weeks.

In some embodiments, the method may include, after dosing netakimab at week 10, subsequently administering 2 mL doses of netakimab once every two weeks.

In some embodiments, 2 ml of the pharmaceutical composition may be administered once per week during weeks 0, 1, 2, 4, 6, 8, 10, 12.

In some embodiments, the method may include, after dosing netakimab at week 12, subsequently administering 2 mL doses of netakimab once every four weeks.

In some embodiments, the method may include, after dosing netakimab at week 12, subsequently administering 2 mL doses of netakimab once every two weeks.

In some embodiments, the method may include, after administering 2 mL doses of netakimab at week 12, subsequently administering 2 mL doses of netakimab once every four weeks for the next 12 weeks.

In some embodiments, the method may include, after administering 2 mL doses of netakimab at week 12, subsequently administering 2 mL doses of netakimab once every two weeks for the next 12 weeks.

In some embodiments, the method may include administering a pharmaceutical composition according to the following dosage schedule:

1) administration of 2 ml of the pharmaceutical composition once a week during weeks 0, 1, 2, 4, 6, 8, 10, 12;

2) administering 2 ml of the pharmaceutical composition once every two weeks for the next 12 weeks thereafter;

3) administration of 2 ml of the pharmaceutical composition once every four weeks thereafter.

In some embodiments, the method may include administering a pharmaceutical composition according to the following dosage regimen:

1) administration of 2 ml of the pharmaceutical composition once a week during weeks 0, 1, 2, 4, 6, 8, 10, 12;

2) administering 2 ml of the pharmaceutical composition once every two weeks for the next 12 weeks thereafter;

3) administration of 2 ml of the pharmaceutical composition once every two weeks thereafter.

In some embodiments, the method may include administering a pharmaceutical composition according to the following dosage schedule:

1) administration of 2 ml of the pharmaceutical composition once a week during weeks 0, 1, 2, 4, 6, 8, 10, 12;

2) administering 2 ml of the pharmaceutical composition once every four weeks for the next 12 weeks thereafter;

3) administration of 2 ml of the pharmaceutical composition once every four weeks thereafter.

In some embodiments, the method may include administering a pharmaceutical composition according to the following dosage schedule:

1) administration of 2 ml of the pharmaceutical composition once a week during weeks 0, 1, 2, 4, 6, 8, 10, 12;

- 12 046015

2) administering 2 ml of the pharmaceutical composition once every four weeks for the next 12 weeks thereafter;

3) administration of 2 ml of the pharmaceutical composition once every two weeks thereafter.

In some embodiments, 2 ml may be delivered via syringe in two separate 1 ml doses.

In some embodiments, the syringe may be a pre-filled syringe.

In some embodiments, 3 ml of the pharmaceutical composition may be administered.

In some embodiments, 3 ml of the pharmaceutical composition may be administered once per week during weeks 0, 1, 2, 4, 6, 8, 10.

In some embodiments, 3 ml of the pharmaceutical composition may be administered once per week during weeks 0, 1, 2, 6, 10.

In some embodiments, the method may include, after dosing netakimab at week 10, administering 3 mL doses of netakimab once every four weeks.

In some embodiments, the method may include, after dosing netakimab at week 10, subsequently administering 3 mL doses of netakimab once every two weeks.

In some embodiments, 3 mL of the pharmaceutical composition may be administered once per week during weeks 0, 1, 2, 4, 6, 8, 10, 12.

In some embodiments, the method may include, after dosing netakimab at week 12, subsequently administering 3 mL doses of netakimab once every four weeks.

In some embodiments, the method may include, after dosing netakimab at week 12, subsequently administering 3 mL doses of netakimab once every two weeks.

In some embodiments, the method may include, after administering 3 mL doses of netakimab at week 12, subsequently administering 3 mL doses of netakimab once every four weeks for the next 12 weeks.

In some embodiments, the method may include, after administering 3 mL doses of netakimab at week 12, subsequently administering 3 mL doses of netakimab once every two weeks for the next 12 weeks.

In some embodiments, the method may include administering a pharmaceutical composition according to the following dosage regimen:

1) administration of 3 ml of the pharmaceutical composition once a week during weeks 0, 1, 2, 4, 6, 8, 10, 12;

2) administering 3 ml of the pharmaceutical composition once every two weeks for the next 12 weeks thereafter;

3) administration of 3 ml of the pharmaceutical composition once every four weeks thereafter.

In some embodiments, the method may include administering a pharmaceutical composition according to the following dosage schedule:

1) administration of 3 ml of the pharmaceutical composition once a week during weeks 0, 1, 2, 4, 6, 8, 10, 12;

2) administering 3 ml of the pharmaceutical composition once every two weeks for the next 12 weeks thereafter;

3) administration of 3 ml of the pharmaceutical composition once every two weeks thereafter.

In some embodiments, the method may include administering a pharmaceutical composition according to the following dosage regimen:

1) administration of 3 ml of the pharmaceutical composition once a week during weeks 0, 1, 2, 4, 6, 8, 10, 12;

2) administering 3 ml of the pharmaceutical composition once every four weeks for the next 12 weeks thereafter;

3) administration of 3 ml of the pharmaceutical composition once every four weeks thereafter.

In some embodiments, the method may include administering a pharmaceutical composition according to the following dosage schedule:

1) administration of 3 ml of the pharmaceutical composition once a week during weeks 0, 1, 2, 4, 6, 8, 10, 12;

2) administering 3 ml of the pharmaceutical composition once every four weeks for the next 12 weeks thereafter;

3) administration of 3 ml of the pharmaceutical composition once every two weeks thereafter.

In some embodiments, the 3 ml may be delivered by syringe in three separate 1 ml doses.

In some embodiments, the syringe may be a pre-filled syringe.

In some embodiments, the pharmaceutical composition may be administered intramuscularly.

- 13 046015

In some embodiments, the pharmaceutical composition may be administered subcutaneously.

In some embodiments, the pharmaceutical composition may be administered intravenously.

In some embodiments, the psoriasis may be plaque psoriasis.

In accordance with another broad aspect, there is provided a method of treating psoriatic arthritis, comprising administering to a patient a pharmacologically effective amount of a pharmaceutical composition as described herein.

In some embodiments, 1 ml of the pharmaceutical composition may be administered.

In some embodiments, 3 ml of the pharmaceutical composition may be administered.

In some embodiments, 3 ml of the pharmaceutical composition may be administered once per week during weeks 0, 1, 2, 4, 6, 8, 10.

In some embodiments, 3 ml of the pharmaceutical composition may be administered once per week during weeks 0, 1, 2, 6, 10.

In some embodiments, the method may include, after dosing netakimab at week 10, subsequently administering 3 mL doses of netakimab once every four weeks.

In some embodiments, the method may include, after dosing netakimab at week 10, subsequently administering 3 mL doses of netakimab once every two weeks.

In some embodiments, 3 mL of the pharmaceutical composition may be administered once per week during weeks 0, 1, 2, 4, 6, 8, 10, 12.

In some embodiments, the method may include, after dosing netakimab at week 12, subsequently administering 3 mL doses of netakimab once every four weeks.

In some embodiments, the method may include, after dosing netakimab at week 12, subsequently administering 3 mL doses of netakimab once every two weeks.

In some embodiments, the 3 ml may be delivered by syringe in three separate 1 ml doses.

In some embodiments, the syringe may be a pre-filled syringe.

In some embodiments, the pharmaceutical composition may be administered intramuscularly.

In some embodiments, the pharmaceutical composition may be administered subcutaneously.

In some embodiments, the pharmaceutical composition may be administered intravenously.

In accordance with another broad aspect, there is provided a method of treating ankylosing spondylitis, comprising administering to a patient a pharmacologically effective amount of a pharmaceutical composition as described herein.

In some embodiments, 1 ml of the pharmaceutical composition may be administered.

In some embodiments, 1 ml of the pharmaceutical composition may be administered once per week during weeks 0, 1, 2.

In some embodiments, the method may include, after dosing netakimab at week 2, subsequently administering 1 mL doses of netakimab once every two weeks.

In some embodiments, 1 ml of the pharmaceutical composition may be administered once per week during weeks 0, 1, 2, 4, 6, 8, 10, 12.

In some embodiments, the method may include, after dosing netakimab at week 12, subsequently administering 1 mL doses of netakimab once every two weeks.

In some embodiments, 2 ml of the pharmaceutical composition may be administered.

In some embodiments, 2 ml of the pharmaceutical composition may be administered once per week during weeks 0, 1, 2.

In some embodiments, the method may include, after dosing netakimab in week 2, subsequently administering 2-milliliter doses of netakimab once every two weeks.

In some embodiments, 2 ml of the pharmaceutical composition may be administered once per week during weeks 0, 1, 2, 4, 6, 8, 10, 12.

In some embodiments, the method may include, after dosing netakimab at week 12, subsequently administering 2 mL doses of netakimab once every two weeks.

In some embodiments, the method may include, after administering a 2 mL dose of netakimab at week 12, subsequently administering 2 mL doses of netakimab once every two weeks beginning at week 16.

In some embodiments, the method may include, after administering a 2 mL dose of netakimab at week 12, subsequently administering 3 mL doses of netakimab once every two weeks beginning at week 16.

In some embodiments, 2 ml may be delivered using a syringe in two

- 14 046015 individual doses of 1 ml.

In some embodiments, the syringe may be a pre-filled syringe.

In some embodiments, 3 ml of the pharmaceutical composition may be administered.

In some embodiments, 3 ml of the pharmaceutical composition may be administered once per week during weeks 0, 1, 2.

In some embodiments, the method may include, after dosing netakimab in week 2, subsequently administering 3 mL doses of netakimab once every two weeks.

In some embodiments, 3 mL of the pharmaceutical composition may be administered once per week during weeks 0, 1, 2, 4, 6, 8, 10, 12.

In some embodiments, the method may include, after dosing netakimab at week 12, subsequently administering 3 mL doses of netakimab once every two weeks.

In some embodiments, the method may include, after administering a 3 mL dose of netakimab at week 12, subsequently administering 2 mL doses of netakimab once every two weeks beginning at week 16.

In some embodiments, the method may include, after administering a 3 mL dose of netakimab at week 12, subsequently administering 3 mL doses of netakimab once every two weeks beginning at week 16.

In some embodiments, the 3 ml may be delivered by syringe in three separate 1 ml doses.

In some embodiments, the syringe may be a pre-filled syringe.

In some embodiments, the pharmaceutical composition may be administered intramuscularly.

In some embodiments, the pharmaceutical composition may be administered subcutaneously.

In some embodiments, the pharmaceutical composition may be administered intravenously.

According to another broad aspect, there is provided a pharmaceutical composition suitable for administration to a subject to inhibit the activity of the IL17a protein, wherein the pharmaceutical composition contains, for every 1 ml of the pharmaceutical composition:

Netakimab 60.0 mg sodium acetate trihydrate 1.74 mg trehalose dihydrate 80 mg Poloxamer (Kolliphor) 188 0.5 mg glacial acetic acid up to pH 5.0 water for injections up to 1.0 ml

In accordance with another broad aspect, there is provided a method of treating psoriasis, comprising administering to a patient a pharmacologically effective amount of a pharmaceutical composition as described herein.

In some embodiments, 1 ml of the pharmaceutical composition may be administered.

In some embodiments, 1 ml of the pharmaceutical composition may be administered once per week during weeks 0, 1, 2, 4, 6, 8, 10.

In some embodiments, the method may include, after dosing netakimab at week 10, subsequently administering 1 mL doses of netakimab once every four weeks.

In some embodiments, the method may include, after dosing netakimab at week 10, subsequently administering 1 mL doses of netakimab once every two weeks.

In some embodiments, 2 ml of the pharmaceutical composition may be administered.

In some embodiments, 2 ml of the pharmaceutical composition may be administered once per week during weeks 0, 1, 2, 4, 6, 8, 10.

In some embodiments, 2 ml of the pharmaceutical composition may be administered once per week during weeks 0, 1, 2, 6, 10.

In some embodiments, the method may include, after dosing netakimab at week 10, subsequently administering 2 mL doses of netakimab once every four weeks.

In some embodiments, the method may include, after dosing netakimab at week 10, subsequently administering 2 mL doses of netakimab once every two weeks.

In some embodiments, 2 ml of the pharmaceutical composition may be administered once per week during weeks 0, 1, 2, 4, 6, 8, 10, 12.

In some embodiments, the method may include, after dosing netakimab at week 12, subsequently administering 2 mL doses of netakimab once every four weeks.

In some embodiments, the method may include, after dosing netakimab at week 12, subsequently administering 2 mL doses of netakimab once every two weeks.

- 15 046015

In some embodiments, the method may include administering a dose of netakimab at week 12, then administering 2-milliliter doses of netakimab once every four weeks for the next 12 weeks.

In some embodiments, the method may include, after dosing netakimab at week 12, subsequently administering 2 mL doses of netakimab once every two weeks for the next 12 weeks.

In some embodiments, the method may include administering a pharmaceutical composition according to the following dosage schedule:

1) administration of 3-ml doses of netakimab once a week during weeks 0, 1, 2, 4, 6, 8, 10, 12;

2) administering 2-mL doses of netakimab once every two weeks for the next 12 weeks thereafter;

3) administering 2-mL doses of netakimab once every four weeks thereafter.

In some embodiments, the method may include administering a pharmaceutical composition according to the following dosage regimen:

1) administration of 2-ml doses of netakimab once a week during weeks 0, 1, 2, 4, 6, 8, 10, 12;

2) administering 2-mL doses of netakimab once every two weeks for the next 12 weeks thereafter;

3) administering 2-mL doses of netakimab once every two weeks thereafter.

In some embodiments, the method may include administering a pharmaceutical composition according to the following dosage schedule:

1) administration of 2-ml doses of netakimab once a week during weeks 0, 1, 2, 4, 6, 8, 10, 12;

2) administering 2-mL doses of netakimab once every four weeks for the next 12 weeks thereafter;

3) administering 2-mL doses of netakimab once every four weeks thereafter.

In some embodiments, the method may include administering a pharmaceutical composition according to the following dosage regimen:

1) administration of 2-ml doses of netakimab once a week during weeks 0, 1, 2, 4, 6, 8, 10, 12;

2) administering 2-mL doses of netakimab once every four weeks for the next 12 weeks thereafter;

3) administering 2-mL doses of netakimab once every two weeks thereafter.

In some embodiments, 2 ml may be delivered via syringe in two separate 1 ml doses.

In some embodiments, the syringe may be a pre-filled syringe.

In some embodiments, the pharmaceutical composition may be administered intramuscularly.

In some embodiments, the pharmaceutical composition may be administered subcutaneously.

In some embodiments, the pharmaceutical composition may be administered intravenously.

In accordance with another broad aspect, there is provided a method of treating psoriatic arthritis, comprising administering to a patient a pharmacologically effective amount of a pharmaceutical composition as described herein.

In some embodiments, 1 ml of the pharmaceutical composition may be administered.

In some embodiments, 2 ml of the pharmaceutical composition may be administered.

In some embodiments, 2 ml of the pharmaceutical composition may be administered once per week during weeks 0, 1, 2, 4, 6, 8, 10.

In some embodiments, 2 ml of the pharmaceutical composition may be administered once per week during weeks 0, 1, 2, 6, 10.

In some embodiments, the method may include, after dosing netakimab at week 10, subsequently administering 2 mL doses of netakimab once every four weeks.

In some embodiments, the method may include, after dosing netakimab at week 10, subsequently administering 2 mL doses of netakimab once every two weeks.

In some embodiments, 2 ml of the pharmaceutical composition may be administered once per week during weeks 0, 1, 2, 4, 6, 8, 10, 12.

In some embodiments, the method may include, after dosing netakimab at week 12, subsequently administering 2 mL doses of netakimab once every four weeks.

In some embodiments, the method may include, after dosing netakimab at week 12, subsequently administering 2 mL doses of netakimab once every two weeks.

In some embodiments, 2 ml may be delivered via syringe in two separate 1 ml doses.

In some embodiments, the syringe may be a pre-filled

- 16 046015 syringe.

In some embodiments, the pharmaceutical composition may be administered intramuscularly.

In some embodiments, the pharmaceutical composition may be administered subcutaneously.

In some embodiments, the pharmaceutical composition may be administered intravenously.

In accordance with another broad aspect, there is provided a method of treating ankylosing spondylitis, comprising administering to a patient a pharmacologically effective amount of a pharmaceutical composition as described herein.

In some embodiments, 1 ml of the pharmaceutical composition may be administered.

In some embodiments, 1 ml of the pharmaceutical composition may be administered once per week during weeks 0, 1, 2.

In some embodiments, the method may include, after dosing netakimab at week 2, subsequently administering 1 mL doses of netakimab once every two weeks.

In some embodiments, 1 ml of the pharmaceutical composition may be administered once per week during weeks 0, 1, 2, 4, 6, 8, 10, 12.

In some embodiments, the method may include, after dosing netakimab at week 12, subsequently administering 1 mL doses of netakimab once every two weeks.

In some embodiments, 2 ml of the pharmaceutical composition may be administered.

In some embodiments, 2 ml of the pharmaceutical composition may be administered once per week during weeks 0, 1, 2.

In some embodiments, the method may include, after dosing netakimab in week 2, subsequently administering 2-milliliter doses of netakimab once every two weeks.

In some embodiments, 2 ml of the pharmaceutical composition may be administered once per week during weeks 0, 1, 2, 4, 6, 8, 10, 12.

In some embodiments, the method may include, after dosing netakimab at week 12, subsequently administering 2 mL doses of netakimab once every two weeks.

In some embodiments, the method may include, after administering a 2 mL dose of netakimab at week 12, subsequently administering 2 mL doses of netakimab once every two weeks beginning at week 16.

In some embodiments, 2 ml may be delivered via syringe in two separate 1 ml doses.

In some embodiments, the syringe may be a pre-filled syringe.

In some embodiments, the pharmaceutical composition may be administered intramuscularly.

In some embodiments, the pharmaceutical composition may be administered subcutaneously.

In some embodiments, the pharmaceutical composition may be administered intravenously.

In another broad aspect, netakimab is provided for the treatment of psoriasis at doses of 40 mg of netakimab administered once weekly during weeks 0, 1, 2, 4, 6, 8, and 10.

In another broad aspect, netakimab is provided for the treatment of psoriasis at doses of 40 mg of netakimab administered once weekly for weeks 0, 1, 2, 4, 6, 8, 10 and once every four weeks thereafter.

In another broad aspect, netakimab is provided for the treatment of psoriasis at doses of 40 mg of netakimab administered once weekly for weeks 0, 1, 2, 4, 6, 8, 10 and once every two weeks thereafter.

In another broad aspect, netakimab is provided for the treatment of psoriasis at doses of 80 mg of netakimab administered once weekly during weeks 0, 1, 2, 4, 6, 8, and 10.

In another broad aspect, netakimab is provided for the treatment of psoriasis at doses of 80 mg of netakimab administered once weekly for weeks 0, 1, 2, 4, 6, 8, 10 and once every four weeks thereafter.

In another broad aspect, netakimab is provided for the treatment of psoriasis at doses of 80 mg of netakimab administered once weekly for weeks 0, 1, 2, 4, 6, 8, 10 and once every two weeks thereafter.

In another broad aspect, netakimab is provided for the treatment of psoriasis at doses of 80 mg of netakimab administered once weekly during weeks 0, 1, 2, 6, and 10.

In another broad aspect, netakimab is provided for the treatment of psoriasis at doses of 80 mg of netakimab administered once weekly for weeks 0, 1, 2, 6, 10 and once every four weeks thereafter.

- 17 046015

In another broad aspect, netakimab is provided for the treatment of psoriasis at doses of 80 mg of netakimab administered once weekly for weeks 0, 1, 2, 6, 10 and once every two weeks thereafter.

In another broad aspect, netakimab is provided for the treatment of psoriasis at doses of 80 mg of netakimab administered once weekly for weeks 0, 1, 2, 4, 6, 8, 10, 12.

Another broad aspect proposes the use of netakimab for the treatment of psoriasis at doses of 80 mg of netakimab administered once weekly for weeks 0, 1, 2, 4, 6, 8, 10, 12 and once every four weeks thereafter. .

Another broad aspect provides the use of netakimab for the treatment of psoriasis at doses of 80 mg of netakimab administered once weekly for weeks 0, 1, 2, 4, 6, 8, 10, 12 and once every two weeks thereafter. .

Another broad aspect provides the use of netakimab for the treatment of psoriasis at doses of 80 mg of netakimab administered once weekly for weeks 0, 1, 2, 4, 6, 8, 10, 12 and once every four weeks for the next 12 weeks thereafter.

Another broad aspect provides the use of netakimab for the treatment of psoriasis at doses of 80 mg netakimab administered once weekly for weeks 0, 1, 2, 4, 6, 8, 10, 12 and once every two weeks for the next 12 weeks thereafter.

In another broad aspect, the use of netakimab for the treatment of psoriasis is proposed in doses of 80 mg of netakimab, which is administered according to the following dosage regimen:

1) administration of a dose of 80 mg netakimab once a week during weeks 0, 1, 2, 4, 6, 8, 10, 12;

2) administering a dose of 80 mg netakimab once every two weeks for the next 12 weeks thereafter;

3) administering a dose of 80 mg netakimab once every four weeks thereafter.

In another broad aspect, the use of netakimab for the treatment of psoriasis is proposed in doses of 80 mg of netakimab, which is administered according to the following dosage regimen:

1) administration of a dose of 80 mg netakimab once a week during weeks 0, 1, 2, 4, 6, 8, 10, 12;

2) administering a dose of 80 mg netakimab once every two weeks for the next 12 weeks thereafter;

3) administering a dose of 80 mg netakimab once every two weeks thereafter.

In another broad aspect, the use of netakimab for the treatment of psoriasis is proposed in doses of 80 mg of netakimab, which is administered according to the following dosage regimen:

1) administration of a dose of 80 mg netakimab once a week during weeks 0, 1, 2, 4, 6, 8, 10, 12;

2) administering a dose of 80 mg netakimab once every four weeks for the next 12 weeks thereafter;

3) administering a dose of 80 mg netakimab once every four weeks thereafter.

In another broad aspect, the use of netakimab for the treatment of psoriasis is proposed in doses of 80 mg of netakimab, which is administered according to the following dosage regimen:

1) administration of a dose of 80 mg netakimab once a week during weeks 0, 1, 2, 4, 6, 8, 10, 12;

2) administering a dose of 80 mg netakimab once every four weeks for the next 12 weeks thereafter;

3) administering a dose of 80 mg netakimab once every two weeks thereafter.

In some embodiments, each of the 80 mg netakimab doses may be administered in two injections containing 40 mg netakimab.

In another broad aspect, netakimab is provided for the treatment of psoriasis at doses of 120 mg of netakimab administered once weekly during weeks 0, 1, 2, 4, 6, 8, and 10.

In another broad aspect, netakimab is provided for the treatment of psoriasis at doses of 120 mg of netakimab administered once weekly during weeks 0, 1, 2, 4, 6, 8, and 10 and once every four weeks thereafter.

In another broad aspect, netakimab is provided for the treatment of psoriasis at doses of 120 mg of netakimab administered once weekly during weeks 0, 1, 2, 4, 6, 8 and 10 and once every two weeks thereafter.

In another broad aspect, netakimab is provided for the treatment of psoriasis at doses of 120 mg of netakimab administered once weekly for weeks 0, 1, 2, 6, 10.

In another broad aspect, netakimab is provided for the treatment of psoriasis at doses of 120 mg of netakimab administered once weekly for weeks 0, 1, 2, 6, 10 and once every four weeks thereafter.

In another broad aspect, netakimab is provided for the treatment of psoriasis at doses of 120 mg of netakimab administered once weekly for weeks 0, 1, 2, 6, 10 and once every two weeks thereafter.

In another broad aspect, netakimab is provided for the treatment of psoriasis at doses of 120 mg netakimab administered once weekly for weeks 0, 1, 2, 4, 6, 8, 10, 12.

- 18 046015

Another broad aspect proposes the use of netakimab for the treatment of psoriasis at doses of 120 mg of netakimab administered once weekly for weeks 0, 1, 2, 4, 6, 8, 10, 12 and once every four weeks thereafter. .

Another broad aspect proposes the use of netakimab for the treatment of psoriasis at doses of 120 mg of netakimab administered once weekly for weeks 0, 1, 2, 4, 6, 8, 10, 12 and once every two weeks thereafter. .

Another broad aspect proposes the use of netakimab for the treatment of psoriasis at doses of 120 mg of netakimab administered once weekly for weeks 0, 1, 2, 4, 6, 8, 10, 12 and once every four weeks for the next 12 weeks thereafter.

Another broad aspect proposes the use of netakimab for the treatment of psoriasis at doses of 120 mg of netakimab administered once weekly for weeks 0, 1, 2, 4, 6, 8, 10, 12 and once every two weeks for the next 12 weeks thereafter.

In another broad aspect, the use of netakimab for the treatment of psoriasis is proposed in doses of 120 mg of netakimab, which is administered according to the following dosage regimen:

1) administration of a dose of 120 mg of netakimab once a week during weeks 0, 1, 2, 4, 6, 8, 10, 12;

2) administering a 120 mg dose of netakimab once every two weeks for the next 12 weeks thereafter;

3) administering a 120 mg dose of netakimab once every four weeks thereafter.

In another broad aspect, the use of netakimab for the treatment of psoriasis is proposed in doses of 120 mg of netakimab, which is administered according to the following dosage regimen:

1) administration of a dose of 120 mg of netakimab once a week during weeks 0, 1, 2, 4, 6, 8, 10, 12;

2) administering a 120 mg dose of netakimab once every two weeks for the next 12 weeks thereafter;

3) administering a 120 mg dose of netakimab once every two weeks thereafter.

In another broad aspect, the use of netakimab for the treatment of psoriasis is proposed in doses of 120 mg of netakimab, which is administered according to the following dosage regimen:

1) administration of a dose of 120 mg netakimab once a week during weeks 0, 1, 2, 4, 6, 8, 10, 12;

2) administering a 120 mg dose of netakimab once every four weeks for the next 12 weeks thereafter;

3) administering a 120 mg dose of netakimab once every four weeks thereafter.

In another broad aspect, the use of netakimab for the treatment of psoriasis is proposed in doses of 120 mg of netakimab, which is administered according to the following dosage regimen:

1) administration of a dose of 120 mg netakimab once a week during weeks 0, 1, 2, 4, 6, 8, 10, 12;

2) administering a 120 mg dose of netakimab once every four weeks for the next 12 weeks thereafter;

3) administering a dose of 120 mg netakimab once every two weeks thereafter.

In some embodiments, each of the 120 mg netakimab doses may be administered in three injections containing 40 mg netakimab.

In some embodiments, each of the 120 mg netakimab doses may be administered as two injections containing 60 mg netakimab.

In some embodiments, netakimab may be administered by subcutaneous injection.

In some embodiments, netakimab may be administered by intravenous injection.

In some embodiments, the psoriasis may be plaque psoriasis.

In another broad aspect, netakimab is provided for the treatment of psoriatic arthritis at doses of 120 mg of netakimab administered once weekly for weeks 0, 1, 2, 4, 6, 8, 10.

In another broad aspect, netakimab is provided for the treatment of psoriatic arthritis at doses of 120 mg of netakimab administered once weekly for weeks 0, 1, 2, 4, 6, 8, 10 and once every four weeks thereafter.

In another broad aspect, netakimab is provided for the treatment of psoriatic arthritis at doses of 120 mg of netakimab administered once weekly for weeks 0, 1, 2, 4, 6, 8, 10 and once every two weeks thereafter.

In another broad aspect, netakimab is provided for the treatment of psoriatic arthritis at doses of 120 mg of netakimab administered once weekly during weeks 0, 1, 2, 6, and 10.

In another broad aspect, netakimab is provided for the treatment of psoriatic arthritis at doses of 120 mg of netakimab administered once weekly for weeks 0, 1, 2, 6, 10 and once every four weeks thereafter.

- 19 046015

In another broad aspect, netakimab is provided for the treatment of psoriatic arthritis at doses of 120 mg of netakimab administered once weekly for weeks 0, 1, 2, 6, 10 and once every two weeks thereafter.

In another broad aspect, netakimab is provided for the treatment of psoriatic arthritis at doses of 120 mg of netakimab administered once weekly for weeks 0, 1, 2, 4, 6, 8, 10, 12.

Another broad aspect provides the use of netakimab for the treatment of psoriatic arthritis at doses of 120 mg netakimab administered once weekly for weeks 0, 1, 2, 4, 6, 8, 10, 12 and once every four weeks thereafter. this.

Another broad aspect provides the use of netakimab for the treatment of psoriatic arthritis at doses of 120 mg of netakimab administered once weekly for weeks 0, 1, 2, 4, 6, 8, 10, 12 and once every two weeks thereafter. this.

In some embodiments, each of the 120 mg netakimab doses may be administered in three injections containing 40 mg netakimab.

In some embodiments, each of the 120 mg netakimab doses may be administered as two injections containing 60 mg netakimab.

In some embodiments, netakimab may be administered by subcutaneous injection.

In some embodiments, netakimab may be administered by intravenous injection.

In another broad aspect, netakimab is provided for the treatment of ankylosing spondylitis at doses of 40 mg of netakimab administered once weekly for weeks 0, 1, 2.

In another broad aspect, netakimab is provided for the treatment of ankylosing spondylitis at doses of 40 mg of netakimab administered once weekly for weeks 0, 1, 2 and once every two weeks thereafter.

In another broad aspect, netakimab is provided for the treatment of ankylosing spondylitis at doses of 40 mg of netakimab administered once weekly for weeks 0, 1, 2, 4, 6, 8, 10, 12.

Another broad aspect proposes the use of netakimab for the treatment of ankylosing spondylitis at doses of 40 mg netakimab administered once weekly for weeks 0, 1, 2, 4, 6, 8, 10, 12 and once every two weeks thereafter. this.

In another broad aspect, netakimab is provided for the treatment of ankylosing spondylitis at doses of 80 mg of netakimab administered once weekly for weeks 0, 1, 2.

In another broad aspect, netakimab is provided for the treatment of ankylosing spondylitis at doses of 80 mg of netakimab administered once weekly for weeks 0, 1, 2 and once every two weeks thereafter.

In another broad aspect, netakimab is provided for the treatment of ankylosing spondylitis at doses of 80 mg of netakimab administered once weekly for weeks 0, 1, 2, 4, 6, 8, 10, 12.

Another broad aspect provides the use of netakimab for the treatment of ankylosing spondylitis at doses of 80 mg netakimab administered once weekly for weeks 0, 1, 2, 4, 6, 8, 10, 12 and once every two weeks thereafter. this.

In another broad aspect, netakimab is proposed for the treatment of ankylosing spondylitis at doses of 80 mg of netakimab administered once weekly for weeks 0, 1, 2, 4, 6, 8, 10, 12, and starting at week 16. in doses of 80 mg of netakimab, which is administered once every two weeks thereafter.

In another broad aspect, netakimab is proposed for the treatment of ankylosing spondylitis at doses of 80 mg of netakimab administered once weekly for weeks 0, 1, 2, 4, 6, 8, 10, 12, and starting at week 16. in doses of 120 mg of netakimab, which is administered once every two weeks thereafter.

In some embodiments, each of the 80 mg netakimab doses may be administered in two injections containing 40 mg netakimab.

In another broad aspect, netakimab is provided for the treatment of ankylosing spondylitis at doses of 120 mg of netakimab administered once weekly for weeks 0, 1, 2.

In another broad aspect, netakimab is provided for the treatment of ankylosing spondylitis at doses of 120 mg of netakimab administered once weekly for weeks 0, 1, 2 and once every two weeks thereafter.

In another broad aspect, netakimab is provided for the treatment of ankylosing spondylitis at doses of 120 mg of netakimab administered once weekly for weeks 0, 1, 2, 4, 6, 8, 10, 12.

Another broad aspect suggests the use of netakimab for the treatment of an

- 20 046015 kylosing spondylitis in doses of 120 mg netakimab administered once weekly for weeks 0, 1, 2, 4, 6, 8, 10, 12 and once every two weeks thereafter.

Another broad aspect proposes the use of netakimab for the treatment of ankylosing spondylitis at doses of 120 mg netakimab administered once weekly for weeks 0, 1, 2, 4, 6, 8, 10, 12, and starting at week 16. in doses of 80 mg of netakimab, which is administered once every two weeks thereafter.

Another broad aspect proposes the use of netakimab for the treatment of ankylosing spondylitis at doses of 120 mg netakimab administered once weekly for weeks 0, 1, 2, 4, 6, 8, 10, 12, and starting at week 16. in doses of 120 mg of netakimab, which is administered once every two weeks thereafter.

In some embodiments, each of the 120 mg netakimab doses may be administered in three injections containing 40 mg netakimab.

In some embodiments, each of the 120 mg netakimab doses may be administered as two injections containing 60 mg netakimab.

In some embodiments, netakimab may be administered by subcutaneous injection.

In some embodiments, netakimab may be administered by intravenous injection.

According to another broad aspect, there is provided the use of a pharmaceutical composition containing, for every 1 ml of the pharmaceutical composition:

Netakimab 40.0 mg

Histidine hydrochloride monohydrate 0.4 mg

L-Histidine 0.4 mg mannitol 54.5 mg water for injection up to 1.0 ml to inhibit the activity of protein 1117a in a subject. In some embodiments, 1 ml of the pharmaceutical composition may be contained in a syringe.

In some embodiments, 2 ml of the pharmaceutical composition may be contained in a syringe.

In some embodiments, the use of the drug may be for the treatment of psoriasis.

In some embodiments, use for treating psoriasis may be accomplished by administering to a subject a 1-milliliter dose of the pharmaceutical composition.

In some embodiments, use for treating psoriasis may be accomplished by administering to the subject a 1-milliliter dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10.

In some embodiments, use for treating psoriasis may be accomplished by administering to the subject a 1-milliliter dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10 and once every four weeks thereafter.

In some embodiments, use for treating psoriasis may be accomplished by administering to the subject a 1-milliliter dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10 and once every two weeks thereafter.

In some embodiments, use for treating psoriasis may be accomplished by administering to a subject a 2-milliliter dose of the pharmaceutical composition.

In some embodiments, use for treating psoriasis may be accomplished by administering to the subject a 2 mL dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10.

In some embodiments, use for treating psoriasis may be accomplished by administering to the subject a 2 mL dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10 and once every four weeks thereafter.

In some embodiments, use for treating psoriasis may be accomplished by administering to the subject a 2-milliliter dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10 and once every two weeks thereafter.

In some embodiments, use for the treatment of psoriasis may be administered by administering to the subject a 2 mL dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 6, 10.

In some embodiments, use for treating psoriasis may be accomplished by administering to the subject a 2-milliliter dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 6, 10 and once every four weeks thereafter.

In some embodiments, use for treating psoriasis may be accomplished by administering to the subject a 2-milliliter dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 6, 10 and once every two weeks thereafter.

In some embodiments, use for treating psoriasis may be

- 21 046015 by administering to the subject a 2 ml dose of the pharmaceutical composition once a week during weeks 0, 1, 2, 4, 6, 8, 10, 12.

In some embodiments, use for the treatment of psoriasis may be administered by administering to the subject a 2 mL dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10, 12 and once every four weeks thereafter.

In some embodiments, use for treating psoriasis may be accomplished by administering to the subject a 2-milliliter dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10, 12 and once every two weeks thereafter.

In some embodiments, use for treating psoriasis may be accomplished by administering to the subject a 2-milliliter dose of the pharmaceutical composition once per week for weeks 0, 1, 2, 4, 6, 8, 10, 12, and once every four weeks for 12 weeks after that.

In some embodiments, use for treating psoriasis may be accomplished by administering to the subject a 2-milliliter dose of the pharmaceutical composition once per week for weeks 0, 1, 2, 4, 6, 8, 10, 12, and once every two weeks for 12 weeks after that.

In some embodiments, use for the treatment of psoriasis may be accomplished by administering to a subject a 2-milliliter dose of the pharmaceutical composition according to the following dosage regimen:

1) administration of 2 ml of the pharmaceutical composition once a week during weeks 0, 1, 2, 4, 6, 8, 10, 12;

2) administering 2 ml of the pharmaceutical composition once every two weeks for the next 12 weeks thereafter;

3) administration of 2 ml of the pharmaceutical composition once every four weeks thereafter.

In some embodiments, use for the treatment of psoriasis may be accomplished by administering to a subject a 2-milliliter dose of the pharmaceutical composition according to the following dosage regimen:

1) administration of 2 ml of the pharmaceutical composition once a week during weeks 0, 1, 2, 4, 6, 8, 10, 12;

2) administering 2 ml of the pharmaceutical composition once every two weeks for the next 12 weeks thereafter;

3) administration of 2 ml of the pharmaceutical composition once every two weeks thereafter.

In some embodiments, use for the treatment of psoriasis may be accomplished by administering to a subject a 2-milliliter dose of the pharmaceutical composition according to the following dosage schedule:

1) administration of 2 ml of the pharmaceutical composition once a week during weeks 0, 1, 2, 4, 6, 8, 10, 12;

2) administering 2 ml of the pharmaceutical composition once every four weeks for the next 12 weeks thereafter;

3) administration of 2 ml of the pharmaceutical composition once every four weeks thereafter.

In some embodiments, use for the treatment of psoriasis may be accomplished by administering to a subject a 2-milliliter dose of the pharmaceutical composition according to the following dosage schedule:

1) administration of 2 ml of the pharmaceutical composition once a week during weeks 0, 1, 2, 4, 6, 8, 10, 12;

2) administering 2 ml of the pharmaceutical composition once every four weeks for the next 12 weeks thereafter;

3) administration of 2 ml of the pharmaceutical composition once every two weeks thereafter.

In some embodiments, each of the 2 ml doses of the pharmaceutical composition can be administered by syringe in two separate 1 ml doses.

In some embodiments, the syringe may be a pre-filled syringe.

In some embodiments, use for treating psoriasis may be accomplished by administering to a subject a 3 mL dose of the pharmaceutical composition.

In some embodiments, use for treating psoriasis may be accomplished by administering to the subject a 3 mL dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10.

In some embodiments, use for the treatment of psoriasis may be accomplished by administering to the subject a 3 mL dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10 and once every four weeks thereafter.

In some embodiments, use for the treatment of psoriasis may be administered by administering to the subject a 3 mL dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10 and once every two weeks thereafter.

In some embodiments, use for treating psoriasis may be

- 22 046015 by administering to the subject a 3 ml dose of the pharmaceutical composition once a week during weeks 0, 1, 2, 6, 10.

In some embodiments, use for the treatment of psoriasis may be administered by administering to the subject a 3 mL dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 6, 10 and once every four weeks thereafter.

In some embodiments, use for treating psoriasis may be accomplished by administering to the subject a 3 mL dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 6, 10 and once every two weeks thereafter.

In some embodiments, use for treating psoriasis may be accomplished by administering to the subject a 3 mL dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10, 12.

In some embodiments, use for the treatment of psoriasis may be administered by administering to the subject a 3 mL dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10, 12 and once every four weeks thereafter.

In some embodiments, use for the treatment of psoriasis may be administered by administering to the subject a 3 mL dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10, 12 and once every two weeks thereafter.

In some embodiments, use for treating psoriasis may be accomplished by administering to the subject a 3 mL dose of the pharmaceutical composition once per week for weeks 0, 1, 2, 4, 6, 8, 10, 12, and once every four weeks for 12 weeks after that.

In some embodiments, use for the treatment of psoriasis may be accomplished by administering to the subject a 3 mL dose of the pharmaceutical composition once per week for weeks 0, 1, 2, 4, 6, 8, 10, 12 and once every two weeks for 12 weeks after that.

In some embodiments, use for the treatment of psoriasis may be accomplished by administering to a subject a 3 mL dose of the pharmaceutical composition according to the following dosage schedule:

1) administration of 3 ml of the pharmaceutical composition once a week during weeks 0, 1, 2, 4, 6, 8, 10, 12;

2) administering 3 ml of the pharmaceutical composition once every two weeks for the next 12 weeks thereafter;

3) administration of 3 ml of the pharmaceutical composition of netakimab once every four weeks thereafter.

In some embodiments, use for the treatment of psoriasis may be accomplished by administering to a subject a 3 mL dose of the pharmaceutical composition according to the following dosage schedule:

1) administration of 3 ml of the pharmaceutical composition once a week during weeks 0, 1, 2, 4, 6, 8, 10, 12;

2) administering 3 ml of the pharmaceutical composition once every two weeks for the next 12 weeks thereafter;

3) administration of 3 ml of the pharmaceutical composition once every two weeks thereafter.

In some embodiments, use for the treatment of psoriasis may be accomplished by administering to a subject a 3 mL dose of the pharmaceutical composition according to the following dosage regimen:

1) administration of 3 ml of the pharmaceutical composition once a week during weeks 0, 1, 2, 4, 6, 8, 10, 12;

2) administering 3 ml of the pharmaceutical composition once every four weeks for the next 12 weeks thereafter;

3) administration of 3 ml of the pharmaceutical composition once every four weeks thereafter.

In some embodiments, use for the treatment of psoriasis may be accomplished by administering to a subject a 3 mL dose of the pharmaceutical composition according to the following dosage schedule:

1) administration of 3 ml of the pharmaceutical composition once a week during weeks 0, 1, 2, 4, 6, 8, 10, 12;

2) administering 3 ml of the pharmaceutical composition once every four weeks for the next 12 weeks thereafter;

3) administration of 3 ml of the pharmaceutical composition once every two weeks thereafter.

In some embodiments, each of the 3 ml doses of the pharmaceutical composition can be administered by syringe in three separate 1 ml doses.

In some embodiments, the syringe may be a pre-filled syringe.

In some embodiments, the pharmaceutical composition may be administered intramuscularly.

- 23 046015

In some embodiments, the pharmaceutical composition may be administered subcutaneously.

In some embodiments, the pharmaceutical composition may be administered intravenously.

In some embodiments, the psoriasis may be plaque psoriasis.

In some embodiments, the use of the drug may be for the treatment of psoriatic arthritis.

In some embodiments, use for the treatment of psoriatic arthritis may be administered by administering a 1 milliliter dose of the pharmaceutical composition to the subject.

In some embodiments, use for the treatment of psoriatic arthritis may be administered by administering a 3 mL dose of the pharmaceutical composition to the subject.

In some embodiments, use for the treatment of psoriatic arthritis may be administered by administering to the subject a 3 mL dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10.

In some embodiments, use for the treatment of psoriatic arthritis may be administered by administering to the subject a 3 mL dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10 and once every four weeks thereafter.

In some embodiments, use for the treatment of psoriatic arthritis may be administered by administering to the subject a 3 mL dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10 and once every two weeks thereafter.

In some embodiments, use for the treatment of psoriatic arthritis may be administered by administering to the subject a 3 mL dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 6, 10.

In some embodiments, use for the treatment of psoriatic arthritis may be administered by administering to the subject a 3 mL dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 6, 10 and once every four weeks thereafter.

In some embodiments, use for the treatment of psoriatic arthritis may be administered by administering to the subject a 3 mL dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 6, 10 and once every two weeks thereafter.

In some embodiments, use for the treatment of psoriatic arthritis may be administered by administering to the subject a 3 mL dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10, 12.

In some embodiments, use for the treatment of psoriatic arthritis may be administered by administering to the subject a 3 mL dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10, 12 and once every four weeks thereafter. .

In some embodiments, use for the treatment of psoriatic arthritis may be administered by administering to the subject a 3 mL dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10, 12 and once every two weeks thereafter. .

In some embodiments, each of the 3 ml doses of the pharmaceutical composition can be administered by syringe in three separate 1 ml doses.

In some embodiments, the syringe may be a pre-filled syringe.

In some embodiments, the pharmaceutical composition may be administered intramuscularly.

In some embodiments, the pharmaceutical composition may be administered subcutaneously.

In some embodiments, the pharmaceutical composition may be administered intravenously.

In some embodiments, the use of the drug may be for the treatment of ankylosing spondylitis.

In some embodiments, use for the treatment of ankylosing spondylitis may be accomplished by administering to a subject a 1-milliliter dose of the pharmaceutical composition.

In some embodiments, use for the treatment of ankylosing spondylitis may be accomplished by administering to the subject a 1-milliliter dose of the pharmaceutical composition once per week during weeks 0, 1, 2.

In some embodiments, use for the treatment of ankylosing spondylitis may be administered by administering to the subject a 1-milliliter dose of the pharmaceutical composition once per week during weeks 0, 1, 2 and once every two weeks thereafter.

In some embodiments, use for the treatment of ankylosing spondylitis may be administered by administering to the subject a 1-milliliter dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10, 12.

- 24 046015

In some embodiments, use for the treatment of ankylosing spondylitis may be administered by administering to the subject a 1-milliliter dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10, 12 and once every two weeks thereafter. .

In some embodiments, use for the treatment of ankylosing spondylitis may be accomplished by administering to a subject a 2-milliliter dose of the pharmaceutical composition.

In some embodiments, use for the treatment of ankylosing spondylitis may be accomplished by administering to the subject a 2-milliliter dose of the pharmaceutical composition once per week during weeks 0, 1, 2.

In some embodiments, use for the treatment of ankylosing spondylitis may be accomplished by administering to the subject a 2-milliliter dose of the pharmaceutical composition once per week during weeks 0, 1, 2 and once every two weeks thereafter.

In some embodiments, use for the treatment of ankylosing spondylitis may be administered by administering to the subject a 2 mL dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10, 12.

In some embodiments, use for the treatment of ankylosing spondylitis may be administered by administering to the subject a 2-milliliter dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10, 12 and once every two weeks thereafter. .

In some embodiments, use for the treatment of ankylosing spondylitis may be administered by administering to the subject a 2-milliliter dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10, 12, and, beginning in week 16, by administering a 2-milliliter dose of the pharmaceutical composition, which is administered once every two weeks thereafter.

In some embodiments, use for the treatment of ankylosing spondylitis may be administered by administering a 2 mL dose of the pharmaceutical composition, which is administered once per week for weeks 0, 1, 2, 4, 6, 8, 10, 12, and beginning in week 16 , by administering a 3 ml dose of the pharmaceutical composition, which is administered once every two weeks thereafter.

In some embodiments, each of the 2 ml doses of the pharmaceutical composition can be administered by syringe in two separate 1 ml doses.

In some embodiments, the syringe may be a pre-filled syringe.

In some embodiments, use for the treatment of ankylosing spondylitis may be accomplished by administering to a subject a 3-milliliter dose of the pharmaceutical composition.

In some embodiments, use for the treatment of ankylosing spondylitis may be administered by administering to the subject a 3 mL dose of the pharmaceutical composition once per week during weeks 0, 1, 2.

In some embodiments, use for the treatment of ankylosing spondylitis may be administered by administering to the subject a 3 mL dose of the pharmaceutical composition once per week during weeks 0, 1, 2 and once every two weeks thereafter.

In some embodiments, use for the treatment of ankylosing spondylitis may be administered by administering to the subject a 3 mL dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10, 12.

In some embodiments, use for the treatment of ankylosing spondylitis may be administered by administering to the subject a 3 mL dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10, 12 and once every two weeks thereafter. .

In some embodiments, use for the treatment of ankylosing spondylitis may be administered by administering to the subject a 3 mL dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10, 12 and, beginning in week 16, by administration of a 3ml dose of the pharmaceutical composition, which is administered once every two weeks thereafter.

In some embodiments, use for the treatment of ankylosing spondylitis may be administered by administering to the subject a 3 mL dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10, 12 and, beginning in week 16, by administering a 2-milliliter dose of the pharmaceutical composition, which is administered once every two weeks thereafter.

In some embodiments, each of the 3 ml doses of the pharmaceutical composition can be administered by syringe in three separate 1 ml doses.

In some embodiments, the syringe may be a pre-filled syringe.

In some embodiments, the pharmaceutical composition may be administered intramuscularly.

In some embodiments, the pharmaceutical composition may be administered under

- 25 046015 skin.

In some embodiments, the pharmaceutical composition may be administered intravenously.

According to another broad aspect, there is provided the use of a pharmaceutical composition containing, for every 1 ml of the pharmaceutical composition:

Netakimab 60.0 mg sodium acetate trihydrate 1.74 mg trehalose dihydrate 80 mg poloxamer (Kolliphor) 188 0.5 mg glacial acetic acid to pH 5.0 water for injection up to 1.0 ml to inhibit IL17a protein activity in a subject.

In some embodiments, 1 ml of the pharmaceutical composition may be contained in a syringe.

In some embodiments, 2 ml of the pharmaceutical composition may be contained in a syringe.

In some embodiments, the use of the drug may be for the treatment of psoriasis.

In some embodiments, use for treating psoriasis may be accomplished by administering to a subject a 1-milliliter dose of the pharmaceutical composition.

In some embodiments, use for treating psoriasis may be accomplished by administering to the subject a 1-milliliter dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10.

In some embodiments, use for treating psoriasis may be accomplished by administering to the subject a 1-milliliter dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10 and once every four weeks thereafter.

In some embodiments, use for treating psoriasis may be accomplished by administering to the subject a 1-milliliter dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10 and once every two weeks thereafter.

In some embodiments, use for treating psoriasis may be accomplished by administering to a subject a 2-milliliter dose of the pharmaceutical composition.

In some embodiments, use for treating psoriasis may be accomplished by administering to the subject a 2 mL dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10.

In some embodiments, use for treating psoriasis may be accomplished by administering to the subject a 2 mL dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10 and once every four weeks thereafter.

In some embodiments, use for treating psoriasis may be accomplished by administering to the subject a 2-milliliter dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10 and once every two weeks thereafter.

In some embodiments, use for the treatment of psoriasis may be administered by administering to the subject a 2 mL dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 6, 10.

In some embodiments, use for treating psoriasis may be accomplished by administering to the subject a 2-milliliter dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 6, 10 and once every four weeks thereafter.

In some embodiments, use for the treatment of psoriasis may be administered by administering to the subject a 2 mL dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 6, 10.

In some embodiments, use for treating psoriasis may be accomplished by administering to the subject a 2-milliliter dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 6, 10 and once every two weeks thereafter.

In some embodiments, use for treating psoriasis may be accomplished by administering to the subject a 2-milliliter dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10, 12.

In some embodiments, use for the treatment of psoriasis may be administered by administering to the subject a 2 mL dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10, 12 and once every four weeks thereafter.

In some embodiments, use for treating psoriasis may be accomplished by administering to the subject a 2-milliliter dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10, 12 and once every two weeks thereafter.

In some embodiments, use for treating psoriasis may be

- 26 046015 by administering to the subject a 2 ml dose of the pharmaceutical composition once per week for weeks 0, 1, 2, 4, 6, 8, 10, 12 and once every four weeks for 12 weeks thereafter.

In some embodiments, use for treating psoriasis may be accomplished by administering to the subject a 2-milliliter dose of the pharmaceutical composition once per week for weeks 0, 1, 2, 4, 6, 8, 10, 12, and once every two weeks for 12 weeks after that.

In some embodiments, use for the treatment of psoriasis may be accomplished by administering to a subject a 2-milliliter dose of the pharmaceutical composition according to the following dosage schedule:

1) administration of 2 ml of the pharmaceutical composition once a week during weeks 0, 1, 2, 4, 6, 8, 10, 12;

2) administering 2 ml of the pharmaceutical composition once every two weeks for the next 12 weeks thereafter;

3) administration of 2 ml of the pharmaceutical composition of netakimab once every four weeks thereafter.

In some embodiments, use for the treatment of psoriasis may be accomplished by administering to a subject a 2-milliliter dose of the pharmaceutical composition according to the following dosage schedule:

1) administration of 2 ml of the pharmaceutical composition once a week during weeks 0, 1, 2, 4, 6, 8, 10, 12;

2) administering 2 ml of the pharmaceutical composition once every two weeks for the next 12 weeks thereafter;

3) administration of 2 ml of the pharmaceutical composition once every two weeks thereafter.

In some embodiments, use for the treatment of psoriasis may be accomplished by administering to a subject a 2-milliliter dose of the pharmaceutical composition according to the following dosage regimen:

1) administration of 2 ml of the pharmaceutical composition once a week during weeks 0, 1, 2, 4, 6, 8, 10, 12;

2) administering 2 ml of the pharmaceutical composition once every four weeks for the next 12 weeks thereafter;

3) administration of 2 ml of the pharmaceutical composition once every four weeks thereafter.

In some embodiments, use for the treatment of psoriasis may be accomplished by administering to a subject a 2-milliliter dose of the pharmaceutical composition according to the following dosage schedule:

1) administration of 2 ml of the pharmaceutical composition once a week during weeks 0, 1, 2, 4, 6, 8, 10, 12;

2) administering 2 ml of the pharmaceutical composition once every four weeks for the next 12 weeks thereafter;

3) administration of 2 ml of the pharmaceutical composition once every two weeks thereafter.

In some embodiments, each of the 2 ml doses of the pharmaceutical composition can be administered by syringe in two separate 1 ml doses.

In some embodiments, the syringe may be a pre-filled syringe.

In some embodiments, the pharmaceutical composition may be administered subcutaneously.

In some embodiments, the pharmaceutical composition may be administered intravenously.

In some embodiments, the use of the drug may be for the treatment of psoriatic arthritis.

In some embodiments, use for the treatment of psoriatic arthritis may be administered by administering a 1 milliliter dose of the pharmaceutical composition to the subject.

In some embodiments, use for the treatment of psoriatic arthritis may be administered by administering a 2 mL dose of the pharmaceutical composition to the subject.

In some embodiments, use for the treatment of psoriatic arthritis may be administered by administering to the subject a 2 mL dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10.

In some embodiments, use for the treatment of psoriatic arthritis may be administered by administering to the subject a 2 mL dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10 and once every four weeks thereafter.

In some embodiments, use for the treatment of psoriatic arthritis may be administered by administering to the subject a 2 mL dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10 and once every two weeks thereafter.

In some embodiments, use for treating psoriatic arthritis may

- 27 046015 carried out by administering to the subject a 2 ml dose of the pharmaceutical composition once a week during weeks 0, 1, 2, 6, 10.

In some embodiments, use for the treatment of psoriatic arthritis may be administered by administering to the subject a 2 mL dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 6, 10 and once every four weeks thereafter.

In some embodiments, use for the treatment of psoriatic arthritis may be administered by administering to the subject a 2 mL dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 6, 10 and once every two weeks thereafter.

In some embodiments, use for the treatment of psoriatic arthritis may be administered by administering to the subject a 2 mL dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10, 12.

In some embodiments, use for the treatment of psoriatic arthritis may be administered by administering to the subject a 2 mL dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10, 12 and once every four weeks thereafter. .

In some embodiments, use for the treatment of psoriatic arthritis may be administered by administering to the subject a 2 mL dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10, 12 and once every two weeks thereafter. .

In some embodiments, each of the 2 ml doses of the pharmaceutical composition can be administered by syringe in two separate 1 ml doses.

In some embodiments, the syringe may be a pre-filled syringe.

In some embodiments, the pharmaceutical composition may be administered intramuscularly.

In some embodiments, the pharmaceutical composition may be administered subcutaneously.

In some embodiments, the pharmaceutical composition may be administered intravenously.

In some embodiments, the use of the drug may be for the treatment of ankylosing spondylitis.

In some embodiments, use for the treatment of ankylosing spondylitis may be accomplished by administering to a subject a 1-milliliter dose of the pharmaceutical composition.

In some embodiments, use for the treatment of ankylosing spondylitis may be accomplished by administering to the subject a 1-milliliter dose of the pharmaceutical composition once per week during weeks 0, 1, 2.

In some embodiments, use for the treatment of ankylosing spondylitis may be administered by administering to the subject a 1-milliliter dose of the pharmaceutical composition once per week during weeks 0, 1, 2 and once every two weeks thereafter.

In some embodiments, use for the treatment of ankylosing spondylitis may be administered by administering to the subject a 1-milliliter dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10, 12.

In some embodiments, use for the treatment of ankylosing spondylitis may be administered by administering to the subject a 1-milliliter dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10, 12 and once every two weeks thereafter. .

In some embodiments, use for the treatment of ankylosing spondylitis may be accomplished by administering to a subject a 2-milliliter dose of the pharmaceutical composition.

In some embodiments, use for the treatment of ankylosing spondylitis may be accomplished by administering to the subject a 2-milliliter dose of the pharmaceutical composition once per week during weeks 0, 1, 2.

In some embodiments, use for the treatment of ankylosing spondylitis may be accomplished by administering to the subject a 2-milliliter dose of the pharmaceutical composition once per week during weeks 0, 1, 2 and once every two weeks thereafter.

In some embodiments, use for the treatment of ankylosing spondylitis may be administered by administering to the subject a 2 mL dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10, 12.

In some embodiments, use for the treatment of ankylosing spondylitis may be administered by administering to the subject a 2-milliliter dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10, 12 and once every two weeks thereafter. .

In some embodiments, use for the treatment of ankylosing spondylitis may be administered by administering to the subject a 2-milliliter dose of the pharmaceutical composition once per week during weeks 0, 1, 2, 4, 6, 8, 10, 12, and, beginning in week 16, by administering a 2-milliliter dose of the pharmaceutical composition, which is administered once every two weeks thereafter.

- 28 046015

In some embodiments, each of the 2 ml doses of the pharmaceutical composition can be administered by syringe in two separate 1 ml doses.

In some embodiments, the syringe may be a pre-filled syringe.

In some embodiments, the pharmaceutical composition may be administered intramuscularly.

In some embodiments, the pharmaceutical composition may be administered subcutaneously.

In some embodiments, the pharmaceutical composition may be administered intravenously.

In another broad aspect, use for the treatment of ankylosing spondylitis may be provided by administering to a subject a 2-milliliter dose of said pharmaceutical composition containing 120 mg of netakimab once per week for weeks 0, 1, 2, 4, 6, 8, 10 , 12 and, starting at week 16, by administering a 2-mL dose of a pharmaceutical composition containing 80 mg of netakimab, administered once every two weeks thereafter.

In another broad aspect, use for the treatment of ankylosing spondylitis may be provided by administering to a subject a 2-milliliter dose of said pharmaceutical composition containing 80 mg of netakimab once weekly for weeks 0, 1, 2, 4, 6, 8, 10 , 12 and, starting at week 16, by administering a 2-mL dose of a pharmaceutical composition containing 120 mg of netakimab, administered once every two weeks thereafter.

Brief description of drawings

The invention will become better understood from the following detailed description of embodiments of the present invention with reference to the accompanying drawings, in which: FIG. 1 is a graph illustrating the absorbance of solutions at 400 nm as a function of PEG concentration in exemplary anti-[E17a antibody compositions with various buffering agents;

fig. 2 is a graph illustrating the absorbance of solutions at 400 nm as a function of PEG concentration in exemplary anti-1L17a antibody compositions with varying concentrations of histidine and/or varying pH;

fig. 3 is a graph illustrating the absorbance of solutions at 400 nm as a function of PEG concentration in exemplary anti-Lb17a antibody compositions with various osmotic agents; and fig. 4 is a graph illustrating the absorbance of solutions at 400 nm as a function of PEG concentration in exemplary anti-1L7a antibody compositions with various solubilizers and/or solubilizer concentrations;

fig. 5 is a graph illustrating the proportion of patients in each study arm who achieved PASI75 by week 12 of treatment (study BCD-085-2);

fig. 6 is a graph illustrating the proportion of patients in each study arm who achieved PASI75 at weeks 4, 8, and 12 of treatment (study BCD-085-2);

fig. 7 is a graph illustrating the percentage improvement value of the PASI index from baseline at weeks 4, 8 and 12 of treatment (study BCD-085-2);

fig. 8 is a graph illustrating the percentage improvement value of NAPSI from baseline at week 12 of treatment (study BCD-085-2);

fig. 9 is a graph illustrating the concentration profile of netakimab after the first injection and showing median and interquartile ranges, minimum and maximum values (study BCD-085-2);

fig. 10 is a graph illustrating the concentration profile of netakimab after multiple injections and showing median and interquartile ranges, minimum and maximum values (study BCD-085-2);

fig. 11 is a graph illustrating the study design (study BCD-085-2ext);

fig. 12 is a graph illustrating the proportion of patients achieving PASI 75 after one year of treatment (week 38 of the BCD-085-2ext study);

fig. 13 is a graph illustrating the proportion of patients achieving PASI90 after 52 weeks of treatment (38 weeks of study BCD-085-2ext);

fig. 14 is a graph illustrating the proportion of patients achieving PASI100 after 52 weeks of treatment (38 weeks of study BCD-085-2ext);

fig. 15 is a graph illustrating the proportion of patients achieving sPGA 0-1 after 52 weeks of treatment (38 weeks of the BCD-085-2ext study);

fig. 16 is a graph illustrating the proportion of patients achieving sPGA 0 (clear skin) after 52 weeks of treatment (38 weeks of the BCD-085-2ext study);

fig. 17 is a graph illustrating the study design (study BCD-085-7);

- 29 046015 fig. 18 is a graph illustrating the determination of PASI 75/90/100 and sPGA 0-1 (ITT population, n=213) (study BCD-085-7);

fig. 19 is a graph illustrating the relative change in PASI scores at weeks 8 and 12 (visits 6 and 8) in the ITT population (n=213) (study BCD-085-7);

fig. 20 is a graph illustrating change in pruritus VAS scores from baseline at weeks 1 and 12 (visits 2 and 8) in the ITT population (n=213) (study BCD-085-7);

fig. 21 is a graph illustrating the change in DLQI scores at weeks 8 and 12 (visits 6 and 8) in the ITT population (n=213) (study BCD-085-7);

fig. 22 is a graph illustrating the change in NAPSI scores at week 12 (N=131) (the figure shows the median value) (study BCD-085-7).

fig. 23 is a graph illustrating the proportion of patients achieving an ACR of 20/50/70 (among patients with psoriatic arthritis, n=15) (study BCD-085-7);

fig. 24 is a graph illustrating the proportion of patients with an ASAS20 response during the study (study BCD-085-3);

fig. 25 is a graph illustrating the proportion of patients with ASAS20, ASAS40 and ASAS5/6 responses during the study (study BCD-085-3);

fig. 26 is a graph illustrating pharmacokinetics after single dose administration (study BCD-085-3);

fig. 27 is a graph illustrating pharmacokinetics after multiple doses (study BCD-085-3);

fig. 28 is a graph illustrating the study design (study BCD-085-3ext);

fig. 29 is a graph illustrating the proportion of patients responding to treatment according to the ASAS20 index (week 16);

fig. 30 is a graph illustrating key secondary outcome measures (mean change from baseline at week 16);

fig. 31 is a graph illustrating the mean change from baseline in MRI scores;

fig. 32 is a graph illustrating the global back pain score determined within 16 weeks of the ASTERA study (mean values) (* P < 0.05 for comparison with placebo);

fig. 33 is a graph illustrating the change in BASDAI, BASFI and QoL scores at week 16 (values).

Detailed description

Definitions.

Monoclonal antibody, as used herein, refers to a llama-derived antibody, a chimeric antibody, a humanized antibody, or a fully human antibody, unless otherwise specified in this application. Monoclonal antibodies of the invention can be produced using, for example, recombinant technologies, phage display technologies, synthetic technologies or combinations of such technologies or other technologies well known in the art.

Monoclonal antibody refers to an antibody produced from a single copy or clone, including, for example, any eukaryotic, prokaryotic or phage clone, and not to the method of its preparation. The monoclonal antibody may be an intact antibody (containing a complete or full-length Fc region), a substantially intact antibody, a portion or fragment of an antibody containing an antigen binding portion, such as a Fab fragment, a Fab' fragment, or an F(ab')2 fragment from llama or chimeric, humanized or human antibody. The Fab' fragment contains a variable and constant domain of the light chain, and a variable domain and the first constant domain (CH1) of the heavy chain. F(ab')2 antibody fragments contain a pair of Fab fragments that are primarily covalently linked near their C-termini by hinge cysteine residues. Other chemical bindings of antibody fragments are also well known in the art.

In addition, the monoclonal antibody as used herein can be a single-chain Fv fragment, which can be produced by linking DNA encoding VHH and V _L with a linker sequence. As long as a protein retains the ability to specifically or preferentially bind to a target (eg, epitope or antigen), it is classified as an antibody. Antibodies may or may not be glycosylated and are within the scope of the invention.

The term antibody derivative or variant as used herein refers to a molecule whose amino acid sequence differs from the amino acid sequence of the parent antibody by addition, deletion and/or substitution of one or more amino acid residues in the sequence of the parent antibody. In a preferred embodiment, the antibody contains at least one amino acid (eg, one to about ten, and preferably 2, 3, 4, 5, 6, 7, or 8) substitutions in the FR or CDR regions of the parent antibody.

- 30 046015

Sequence identity or homology of a variant antibody is defined herein as the percentage of amino acid residues in the variant antibody sequence that are identical to those of the parent antibody, after sequence alignment and the introduction of breaks as necessary to achieve the maximum percentage of sequence identity.

The antibody derivative retains the ability to bind the antigen, or preferably an epitope, to which the parent antibody binds, or preferably has at least one property or biological activity that is superior to that of the parent antibody. For example, the antibody preferably has greater aggregation stability or stronger binding affinity, improved pharmacokinetic properties, or increased ability to inhibit the biological activity of an antigen than the parent antibody.

The term VHH derivative as used herein refers to derivatives of VHH antibodies whose amino acid sequence differs from the amino acid sequence of the parent VHH antibody by substitution of one or more amino acid residues in the sequence of the parent antibody. In a preferred embodiment, the VHH antibody contains at least one amino acid (eg, one to about twenty, and preferably 2, 3, 4, 5, 6, 7, or 8) substitutions in the FR or CDR regions of the parent antibody.

The derived antibody retains the ability to bind the same antigen, or preferably epitope, to which the parent antibody binds or preferably has at least one property or biological activity that is superior to that of the parent antibody. For example, the antibody preferably has greater aggregation stability or stronger binding affinity, improved pharmacokinetic properties, or increased ability to inhibit the biological activity of an antigen than the parent antibody.

A parent VHH antibody, or a parent VHH antibody, or a wild VHH antibody, as used herein, refers to a VHH antibody isolated from an immunized or non-immunized camelid and encoded by the amino acid sequence that is used to produce the VHH variant. The parent antibody may have a framework sequence of camelid origin (with respect to the V _HH variable domain), but preferably the light chain variable domain framework sequence is entirely or substantially human in origin.

A parent or original or wild-type antibody, as used herein, is an antibody encoded by the amino acid sequence that is used to produce the variant. The parent antibody may have a framework sequence of camelid origin (with respect to the VHH variable domain), but preferably the light chain variable domain framework sequence is entirely or substantially human in origin.

The term specifically binds, as used herein, refers to the situation in which one member of a specific binding pair does not significantly bind molecules other than its specific binding partner(s). The term is also applicable when, for example, the antigen binding domain of an antibody of the invention is specific for a particular epitope that is carried by a number of antigens, in which case the specific antibody having the antigen binding domain will be capable of specifically binding to different antigens bearing the epitope. Accordingly, the monoclonal antibody of the invention specifically binds to human IL-17 (IL-17A), while it does not specifically bind to human IL-17B, IL-17C, IL-17D, IL-17E. Moreover, the monoclonal antibody of the invention specifically binds human IL-17 and cynomolgus IL-17, but does not specifically bind rat IL-17 or mouse IL-17.

The term preferably binds, as used herein, refers to the situation in which the antibody binds at least about 20% more, preferably at least about 50%, and 2, 20, 50, or 100 times more, of a specific antigen. than it binds another antigen as measured by techniques known in the art (eg competitive ELISA or KD measurements using an Octet instrument). An antibody may preferentially bind one epitope within an antigen rather than another epitope within the same antigen. Accordingly, the antibody of the invention preferentially binds human IL-17 but not rabbit IL-17.

The term epitope refers to that portion of a molecule that is capable of being recognized and bound by an antibody at one or more antigen-binding sites of the antibody. Epitopes often consist of chemically active surface groups of molecules, such as amino acids or sugar side chains, and have certain 3-D characteristics. By inhibitory epitope and/or neutralizing epitope is meant an epitope that, in the context of an intact antigenic molecule and when bound by an antibody specific for the epitope, results in the loss or reduction of the biological activity of the molecule or the organism that contains the molecule, in vivo or in vitro.

The term epitope, as used herein, further refers to the portion of the polypeptide that

- 31 046015 which has antigenic and/or immunogenic activity in an animal, preferably a mammal, for example a mouse or a human. The term antigenic epitope, as used herein, is the portion of a polypeptide to which an antibody can specifically bind, determined by any method well known in the art, such as a conventional immunoassay. Antigenic epitopes do not necessarily have to be immunogenic, but may also be immunogenic. An immunogenic epitope, as used herein, is defined as that portion of a polypeptide that elicits an antibody response in an animal, as determined by any method known in the art. A non-linear epitope or conformational epitope contains non-contiguous polypeptides (or amino acids) within an antigenic protein to which an epitope-specific antibody binds.

The expressions functional activity or functional characteristic or the terms biological activity or activity towards an antibody of the invention are used interchangeably in this application and include, but are not limited to, epitope/antigen affinity and specificity, ability to neutralize or antagonistize IL-17 in vivo or in vitro, IC50, antibody stability and in vivo immunogenic properties of the antibody. Other biological properties or characteristics of an antibody identifiable in the art include, for example, cross-reactivity (ie, with non-human homologs of the target peptide or with other proteins or targets) and the ability to maintain high levels of protein expression in mammalian cells. The above properties or characteristics may be observed, measured or assessed using techniques known in the art, including, but not limited to, ELISA assay, competitive ELISA assay, Octet assay, in vitro or in vivo neutralization assays without limitation, receptor binding, production and/or cytokine or growth factor secretion, signal transduction and immunohistochemistry of tissue sections obtained from various sources, including human, primate or any other source.

A monoclonal antibody population, as used herein, refers to a homogeneous or substantially homogeneous population of antibodies (i.e., at least about 96%, but more preferably at least about 97 or 98%, or even more preferably at least 99 % of antibodies in the population will compete in an ELISA assay for the same antigen or epitope, or more preferably the antibodies are identical in amino acid sequence).

A full-length antibody found in nature is an immunoglobulin molecule that consists of four polypeptide chains (two heavy (H) chains (approximately 50-70 kDa full length) and two light (L) chains (approximately 25 kDa full length) ), linked by disulfide bridges. The amino-terminal portion of each chain includes a variable domain of approximately 100-110 or more amino acids that is responsible for antigen binding. The carboxy-terminal portion of each chain defines a constant region primarily responsible for effector function. Light chains are classified as kappa or lambda and are characterized by a specific constant region. Each light chain consists of an N-terminal light chain variable region (VL or VK in this application) and a light chain constant region consisting of a single domain (CL or CK). Heavy chains are classified as gamma (γ), delta (δ), alpha (α), mu (μ), or epsilon (ε), and they define the isotype of the antibody, such as IgG, IgM, IgA, IgD, and IgE, respectively, and several of these can be further divided into subclasses (isotypes) such as IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2. Each type of heavy chain is characterized by a specific Fc constant region. Each heavy chain consists of an N-terminal heavy chain variable region (VH in this application) and a CH constant region (heavy chain). The heavy chain constant region consists of three domains (CH1, CH2 and CH3) for IgG, IgD and IgA and 4 domains (CH1, CH2, CH3 and CH4) for IgM and IgE. The VH, VHH and _VL variable domains can be further divided into hypervariable regions (hypervariable regions, CDRs) interspersed with more conserved framework regions (FRs). Each variable domain consists of three CDRs and four FRs, arranged in the following order from N-terminus to C-terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4.

In this application, the 3 heavy chain CDRs are designated HCDR1, HCDR2, and HCDR3, and the 3 light chain CDRs are designated LCDR1, LCDR2, and LCDR3. CDRs contain most of the residues that form specific interactions with the antigen. The numbering and positioning of CDR amino acid residues is carried out according to the Kabat nomenclature.

The term antigen refers to an antigen target against which an antibody may be reactive, is used in the context of this application in its traditional sense as used by those skilled in the art, and includes, among others, polypeptides, peptides, polysaccharides, glycoproteins, polynucleotides (eg , DNA), or chemical antigens, receptors, interleukins. Interleukins may include interleukins of different groups, incl. interleukin 1 (alpha 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, interleukin 33.

The term antigen can also be used to describe a material used to immunize

- 32 046015 of animals (for example, llamas) in the production of antibodies according to the invention. In this context, antigen may have a broader meaning and may include purified forms of the antigen and also crude or incompletely isolated or purified preparations of the antigen, such as, for example, cells, cell lysates or supernatants, cell fractions, for example cell membranes, etc. with the addition of haptens conjugated to an appropriate protein carrier. The antigen used in the immunization process is not necessarily an antigen that is structurally identical to the target antigen to which the antibody of the invention may therefore bind. Typically, the antigen used for immunization may be a truncated version of the target antigen, for example a fragment containing an immunogenic epitope. More detailed characteristics of the antigens used for immunization are described in the literature and may be well known to one skilled in the art.

The variable regions of each light/heavy chain pair form the antigen-binding sites of the antibody. Thus, an intact IgG antibody has two binding sites. With the exception of bifunctional or bispecific antibodies, the two binding sites are the same. As used herein, an antigen-binding moiety, or antigen-binding region, or antigen-binding domain refers, interchangeably, to that part of an antibody molecule that contains amino acid residues that interact with the antigen and determine the specificity and affinity of the antibody for the antigen. This part of the antibody includes framework amino acid residues necessary to maintain the proper conformation of antigen-binding residues.

Preferably, the CDR of the VHH antigen binding region or the entire antigen binding region of the antibody of the present invention is entirely derived from the camelid family or is substantially derived from the camelid family and contains certain amino acid residues modified, for example, replaced by different amino acid residues (see, for example, Table 6) in order to improve specific properties of the antibody, for example KD, koff, IC50. Preferably, the framework regions of the antibody of the invention are of camelid or human origin or substantially human origin (at least 80, 85, 90, 95, 96, 97, 98 or 99% human origin) and correspond to Kabat nomenclature.

The antibody fragment may be an antibody fragment or an antibody fragment having the activity of a full-length antibody. Said antibody fragment may be F(ab')2, F(ab)2, Fab', Fab Fv and scFv.

Interleukin 17, or also IL-17 or IL-17A, is a homodimeric protein with a mass of 20-30 kDa. The human IL-17A gene encodes a 155 amino acid protein that has a 19 amino acid signal sequence and a 136 amino acid mature segment. The amino acid sequence of human IL-17A is 80, 63 and 58% identical to the amino acid sequences of rabbit, mouse and rat, respectively. The amino acid sequence of human IL-17A is 97% identical to the sequence of cynomolgus macaque interleukin-17A.

The term antibody when used in relation to the anti-[k-17 monoclonal antibody of the present invention (hereinafter referred to as the antibody of the present invention), as used in this application, refers to a monoclonal antibody.

The term inhibit or neutralize, as used herein, with respect to the functional activity of an antibody of the invention, means the ability to substantially inhibit, prevent, limit, slow, stop, reduce or reverse, for example, the development or severity of that which is inhibited, including but not limited to the foregoing, a biological activity (eg, IL-17 activity) or property, disease or condition. The inhibition or neutralization of IL-17 activity resulting from binding of an antibody of the invention to IL-17 is preferably at least about 20, 30, 40, 50, 60, 70, 80, 90, 95% or greater.

The term isolated or isolated when used with respect to a nucleic acid or protein preparation (eg, an antibody) refers to a nucleic acid molecule or protein molecule that is identified and separated from at least one contaminant with which it is typically associated in a natural source. Preferably, the isolated antibody is an antibody that is substantially free of other antibodies having distinctive antigen specificity (e.g., the pharmaceutical compositions of the present invention contain an isolated antibody that specifically binds IL-17A and is substantially free of antibodies that specifically bind antigens other than IL-17A).

The terms Kabat nomenclature or Kabat nomenclature are used herein to refer to a numbering system for amino acid residues that are more variable (i.e., hypervariable) than other amino acid residues in the variable regions of an antibody's heavy and light chain (Kabat et al., Ann.N.Y. , Acad. Sci., 190:382-93 (1971); Kabat et al., Sequences of Proteins of Immunol ogical Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242 (1991)).

A polynucleotide is functionally linked if it has functional links with another

- 33 046015 gim polynucleotide. For example, a promoter or enhancer is operably linked to a coding sequence if it affects transcription of the sequence. A polypeptide is operably linked to another polypeptide if the polynucleotides encoding them are operably linked, preferably if they are in the same open reading frame.

The term specific binding between an antibody and target antigen(s) refers to immunological specificity. An antibody can specifically bind to a target antigen if it binds an epitope on the antigen to a greater extent than other epitopes on the antigen. Specific binding does not exclude cross-reactivity with other antigens bearing similar antigen epitopes.

The VL domains in antibodies according to the invention may be of the VL lambda type or the VL kappa type. The term VL domain refers to both VK lambda and VL kappa isotypes that contain one or more amino acid substitutions, insertions or deletions.

The term pharmaceutical composition refers to a composition and/or composition containing an antibody according to the invention in a therapeutically effective amount and excipients (carriers, diluents, fillers, solvents and other excipients, for example).

The term use or method of treatment refers to the possibility of using an antibody according to the invention or a pharmaceutical composition containing it, for the treatment, alleviation of diseases, to accelerate remission, reduce the frequency of relapses due to diseases or disorders mediated by receptors to which the antibody according to the invention can bind.

Exemplary Embodiments

The present invention relates to suitable aqueous pharmaceutical compositions for an anti-IL17a antibody comprising a VHH-derived domain and a _VL variable domain, such as netakimab. One aqueous pharmaceutical composition may contain a histidine-based buffer and mannitol as an osmotic agent. Poloxamer 188 can be added as a solubilizer. Another aqueous pharmaceutical composition may contain an acetate-based buffer and trehalose as an osmotic agent. Poloxamer 188 can be added as a solubilizer.

A histidine-based buffer can be formed by combining L-histidine with histidine hydrochloride monohydrate or, optionally, with hydrochloric acid or other acids. It should be understood that while histidine hydrochloride monohydrate can be used as the salt for the histidine buffer, any other histidine salt can be used for the histidine buffer without departing from the teachings of the present invention.

An acetate buffer can be formed by combining acetic acid with sodium acetate trihydrate. It should be understood that while sodium acetate trihydrate can be used as the salt for the acetate buffer, any other acetate salt, such as potassium acetate, can be used for the acetate buffer without departing from the teachings of the present invention.

In addition, the composition of the present invention may further include one or more other suitable excipients that are well known to those skilled in the art.

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

In some embodiments, the liquid pharmaceutical composition is formulated such that it is shelf stable in the sense that no further protein aggregation or modification occurs beyond the stability at zero time point.

Methods of treatment and use of an aqueous composition.

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

In a preferred embodiment, the mammal is a human.

Diseases or disorders that can be treated with the compositions provided herein 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-associated arthritis; enthesitis; spondyloarthropathy, axial spondyloarthritis; Behçet's disease; inflammatory bowel disease, Crohn's disease, ulcerative colitis; asthma, allergic disorders, atopic allergies; ichthyosis; red hairy pityriasis; papulopustular rosacea; gangrenous pyoderma; hidradenitis suppurativa; psoriasis, psoriatic arthropathy, type I psoriasis, type II psoriasis, plaque psoriasis; dermatitis, atopic dermatitis, autoimmune dermatitis, dermatological conditions; systemic sclerosis; transplantation, graft-versus-host disease, graft rejection, acute or chronic immune disease associated with organ transplantation, acute immune disease

- 34 046015 transplant-related chronic immune disease, graft-related chronic immune disease, small bowel graft rejection, pancreas graft rejection, any organ or tissue graft rejection, heart graft rejection, cartilage graft rejection, kidney graft rejection, liver graft rejection, allograft rejection, skin allograft rejection, heterograft rejection of any organ or tissue, bone graft rejection, bone marrow graft (BMT) rejection, parathyroid graft rejection; bone erosion; sarcoidosis, atherosclerosis, Wegener's disease, microscopic polyangiitis with kidney damage, uveitis, phacogenic uveitis, non-infectious uveitis, cachexia, acute transverse myelitis, primary biliary cirrhosis, autoimmune polyglandular syndrome type I and II, Schmidt's syndrome, acute respiratory distress syndrome; arthropathy, seronegative arthropathy, arthropathy associated with ulcerative colitis, Reiter's syndrome, enteropathic synovitis, atheromatosis/coronary sclerosis, autoimmune bullous disease, pemphigus, pemphigus foliaceus, linear IgA-dependent bullous dermatosis, autoimmune hemolytic anemia, giant cell arteritis, primary th 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 pulmonary disease, dermatomyositis/polymyositis associated with pulmonary disease, Sjögren's syndrome associated with lung disease, ankylosing spondylitis associated with lung disease, vasculitis, diffuse pulmonary vasculitis, primary vasculitis, fibrosis, lymphocyte infiltrating lung disease, autoimmune hepatitis, autoimmune hepatitis type I (classical autoimmune or lupoid hepatitis), autoimmune hepatitis type II (associated with antibody to LKM), autoimmune hypoglycemia, osteoarthritis, primary sclerosing cholangitis, erythematosis; systemic lupus erythematosus, discoid lupus erythematosus, lupus nephritis; multiple sclerosis (all types), sympathetic ophthalmia, pulmonary hypertension secondary to connective tissue disease, Goodpasture's syndrome, pulmonary manifestations of polyarteritis nodosa, acute rheumatic attack, rheumatoid spondylitis, Still's disease, systemic scleroderma, scleroderma disease, scleroderma, Takayasu's disease/arteritis; autoimmune thrombocytopenia, idiopathic thrombocytopenia; autoimmune thyroiditis, hyperthyroidism, autoimmune hypothyroidism (Hashimoto's disease), autoimmune atrophic hypothyroidism; vitiligo, acute liver diseases, chronic liver diseases, cholestasis, diseases mediated by Th2 type and Th1 type, malignant tumors such as lung cancer, breast cancer, stomach cancer, bladder cancer, colorectal cancer, pancreatic cancer, pancreatic carcinoma , ovarian cancer, prostate cancer and malignancies of the hematopoietic system (leukemia and lymphomas), acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, adenocarcinoma, B-cell lymphoma, Burkitt's lymphoma, inflammatory responses to cardiopulmonary bypass, chronic myelocytic leukemia (CML) ), chronic inflammatory pathologies, chronic lymphocytic leukemia (CLL), rectocolytic carcinoma (colorectal carcinoma), cystic fibrosis, malignant lymphoma, malignant histiocytosis, malignant melanoma, multiple myeloma, non-Hodgkin's lymphoma, nasopharyngeal cancer, solid tumors, hairy cell leukemia, Hodgkin's disease, sarcoma, myelodysplastic syndrome, cytokine therapy-related disorders, demyelinating diseases, inflammatory demyelinating disease, pulmonary fibrosis, idiopathic pulmonary fibrosis, usual interstitial pneumonia, iridocyclitis/uveitis/optic neuritis, lymphedema, mixed connective tissue disease, monoclonal gammopathy, chronic neonatal lung diseases, nephritis, nephrotic, neurodegenerative disorders, osteoporosis, paraneoplastic syndrome/hypercalcemia associated with malignancy, phenomenon and Raynaud's disease, skin changes, systemic inflammatory response syndrome, thrombocytopenia, toxic effects, urticaria, acute coronary syndrome , Still's disease developed in adults, aplastic anemia, coronary sclerosis, atopic eczema; autoimmune disorder associated with streptococcal 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 risk of multiple sclerosis, erythema multiforme, severe erythema multiforme, pemphigoid, bullous pemphigoid, cicatricial pemphigoid, mucosal pemphigoid, gestational pemphigoid, iritis, keratitis, motor neuron disease, non-A hepatitis, none B, optic neuritis, oligoarticular JIA, polyarteritis nodosa, polychondritis, poliosis, polymyositis, recurrent neuromyelitis optica, rheumatic heart disease, SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, osteitis), secondary amyloidosis, ankylosing spondylitis, systemic inflammatory response syndrome , cranial arteritis and arthropathy associated with Yersinia or Salmonella.

Additional diseases or disorders that can be treated with the compositions of the present

- 35 046015 invention include the diseases described in patent PCT/RU2015/000163, the relevant parts of which are incorporated herein by reference.

The provided pharmaceutical compositions can be administered to an individual in need of treatment by systemic injection, for example, by intravenous or subcutaneous or intramuscular injection; or by injection or application to the appropriate site, for example, by direct injection or direct application to the site when the site is accessible by surgery; or through topical application.

In one embodiment, the invention provides 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 anti-IL17a antibody compositions of the invention.

In one embodiment, the present invention provides 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 anti-IL17a antibody compositions of the present invention.

In one embodiment, the present invention provides 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 anti-IL17a antibody compositions of the present invention.

In one embodiment, the present invention provides 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 anti-IL17a antibody compositions of the present invention.

In one embodiment, the present invention provides 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 anti-IL17a antibody compositions of the present invention.

In one embodiment, the present invention provides 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 anti-IL17a antibody compositions of the present invention.

In one embodiment, the present invention provides 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 anti-IL17a antibody compositions of the present invention.

In one embodiment, the present invention provides a method of treating and/or preventing palmoplantar psoriasis, comprising administering to a mammal in need thereof a therapeutically effective amount of one of the provided anti-IL17a antibody compositions of the present invention.

In one embodiment, the present invention provides 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 anti-IL17a antibody compositions of the present invention.

In one embodiment, the present invention provides 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 anti-IL17a antibody compositions of the present invention.

In one embodiment, the present invention provides 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 anti-IL17a antibody compositions of the present invention.

In one embodiment, the present invention provides 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 anti-IL17a antibody compositions of the present invention.

The therapeutically effective amount of the anti-IL17a antibodies of the present invention, and aqueous compositions comprising the anti-IL17a antibodies of the present invention, in the present compositions depends on the condition being treated, the severity of the condition, prior therapy and the patient's medical history and response to the therapeutic agent. The appropriate dose can be adjusted according to the discretion of the attending physician so that it can be administered to the patient once or through multiple administrations.

In one embodiment, the effective amount of anti-IL17a antibody per patient dose is from about 0.01 to 10 mg per kilogram of body weight, or about

- 36 046015

0.01 to 5 mg per kilogram of body weight, or approximately 0.01 to 4 mg per kilogram of body weight, or approximately 0.05 to 3 mg per kilogram of body weight, or approximately 0.05 mg per kilogram of body weight, or approximately 0.25 mg per kilogram of body weight, or approximately 0.825 mg per kilogram of body weight, or approximately 1.25 mg per kilogram of body weight, or approximately 1.75 mg per kilogram of body weight, or approximately 2.25 mg per kilogram of body weight body, or approximately 3 mg per kilogram of body weight.

The dosing frequency may typically be about twice a week, or once a week, or about once every 2 weeks, or about once every 4-8 weeks, or about once every 10 weeks, or about once a month. or approximately once every 3 months.

If the dose is to be administered more than once per week, the exemplary dosage range is the same as the above dosage ranges or less, and it is preferably administered two or more times per week with a dosage range of 5-240 mg/dose.

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

The dose may be delivered by one or more than one injection.

The dose can be delivered through one, two or three injections. One injection may contain 1 or 2 ml of the composition disclosed herein.

In one embodiment, the anti-IL17a antibodies of the present invention can be administered at a dose of 40 mg via a single (SC) injection.

In one embodiment, the anti-IL17a antibodies of the present invention can be administered at a dose of 60 mg via a single injection.

In one embodiment, the anti-IL17a antibodies of the present invention can be administered at a dose of 70 mg via a single injection.

In one embodiment, the anti-IL17a antibodies of the present invention can be administered at a dose of 80 mg via a single injection.

In one embodiment, the anti-IL17a antibodies of the present invention can be administered at a dose of 80 mg via two 40 mg injections.

In one embodiment, the anti-IL17a antibodies of the present invention can be administered at a dose of 100 mg via a single injection.

In one embodiment, the anti-IL17a antibodies of the present invention can be administered at a dose of 120 mg via a single injection.

In one embodiment, the anti-IL17a antibodies of the present invention can be administered at a dose of 120 mg via two 60 mg injections.

In some cases, improvement in the patient's condition can be achieved through treatment over an extended period of time. For incurable chronic conditions, the treatment regimen can be continued indefinitely.

In another embodiment, the pharmaceutical compositions of the present invention may be prepared in bulk form and, as such, the components of the pharmaceutical composition are present in amounts greater than may be required for administration and are suitably diluted prior to administration.

Alternatively, the pharmaceutical composition may be frozen, spray dried, or lyophilized and reconstituted in a suitable sterile vehicle before use. Lyophilization can be performed using methods known in the art, which include various steps such as freezing, annealing, primary and secondary drying.

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

Administration of the proposed pharmaceutical compositions can be carried out in a variety of ways, including parenteral, oral, buccal, nasal, rectal and topical administration. Parenteral administration may include, without limitation, transdermal, subcutaneous, intravenous, intraarterial, intraperitoneal, intradermal, intracardiac, intraventricular, intracranial, intratracheal, intrathecal, intramuscular injection, intravitreal injection.

The pharmaceutical compositions of the present invention are particularly suitable for parenteral

- 37 046015 new introduction, i.e. subcutaneously, intramuscularly, intravenously, intraperitoneally, into the spinal cord, into the joints, intrasynovially and/or intrathecally. Parenteral administration can be done by bolus injection or continuous infusion. Pharmaceutical compositions for injection may be in unit dosage form, such as, but not limited to, ampoules, vials, prefilled syringes, or multi-dose containers with an added preservative. In addition, a number of recent approaches to drug delivery have been developed, and the pharmaceutical compositions of the present invention are suitable for administration by these new routes, for example, BD Physioject™, Inject-ease®, Genject®, injector pens such as GenPen®, and needleless devices such as MediJector®40 and BioJector®. The pharmaceutical composition of the present invention can also be adapted for as yet undiscovered routes of administration.

Also see Langer, 1990, Science, 249:1527-1533.

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

Pharmaceutical compositions may optionally be provided in a vial, package, or dispenser, 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 liquid formulation ready for injection. The syringe may be accompanied by instructions for administration.

In another embodiment, the present invention relates to a kit or container containing an aqueous pharmaceutical composition according to the invention. The concentration of the polypeptide in the aqueous pharmaceutical composition can vary widely, but is typically within the range of about 1 mg/ml to about 200 mg/ml of the aqueous composition. The kit may also come with instructions for use.

The method of obtaining the above compositions involves adding acetate buffering agents to the aqueous phase, followed by adding, in any order, the following components: an osmolytic selected from disaccharides (such as trehalose, sucrose or a combination thereof), an anti-IL17a antibody containing a VHH- domain derivative and VL variable domain, and/or a solubilizer selected from the group: polysorbate 20, polysorbate 80, poloxamer 188, or a combination thereof.

The method of obtaining the above compositions involves adding histidine buffering agents to the aqueous phase, followed by adding, in any order, the following components: an osmolytic selected from sugar alcohols (such as mannitol, sorbitol or a combination thereof), an anti-IL17a antibody containing a VHH-derived domain and a VL variable domain, and/or a solubilizer selected from the group: polysorbate 20, polysorbate 80, poloxamer 188, or a combination thereof.

Case study

Below is an example of a study to determine the reagents and their concentrations for the preparation of an aqueous anti-IL17a antibody composition of the present invention, such as netakimab.

The experiments and methods described herein are intended to relate to an anti-IL17a antibody of the present invention, such as netakimab, with a VHH variable domain and a VL variable domain. Examples of suitable antibodies are described in patent application No. PCT/RU2015/000163.

It is understood that while the illustrative studies and examples presented herein relate to netakimab, which is intended as an exemplary antibody, the illustrative studies and examples may be applied to another antibody of the present invention without departing from the teachings of the present invention ( for example, in particular in view of the structural similarities of the antibodies of the present invention, a VHH variable domain linked to a _VL variable domain).

The studies and examples presented herein are for illustrative purposes only, which demonstrate the suitability of certain components used in the aqueous anti-IL17a antibody compositions of the present invention. It is understood that other methods may be used by one of ordinary skill in the art without departing from the teachings of the present invention.

The suitability of the aqueous compositions of the present invention was tested through the illustrative methods described herein.

Method 1. Preparation of stable anti-HE17 antibody compositions.

Antibody samples with a concentration of 10 mg/ml were prepared in Stirred Cell concentration cells (Millipore) under pressure. To do this, the antibody in its original composition was placed in cells

- 38 046015 ku, with continuous stirring, the protein was concentrated under a stream of compressed air to a concentration of 10 mg/ml, after which at least a 10-fold volume of an aqueous solution with the target composition was added to the cell, including buffering agents, osmotic agents and, if necessary, additional water-soluble stabilizers. Upon completion of the diafiltration process, the antibody was concentrated to a concentration of about 12-20 mg/ml, unloaded from the cell, and the exact protein concentration was determined by UV spectrophotometry. The sample was then spiked with the appropriate placebo solution to obtain a solution with a target protein concentration of 10 ± 0.5 mg/mL.

Protein samples with a concentration of more than 40 mg/ml were obtained in Pellicon cassettes (Millipore) in tangential flow mode. To do this, the antibody in the original composition was placed in a container for diafiltration, the protein was concentrated to a concentration of 40-100 mg/ml, after which the system was connected to a supply of at least 10 times the volume of a solution with the target composition containing buffering agents, osmotic agents and, if necessary , additional water-soluble stabilizers. It is allowed to add a concentrate of osmotic agents and water-soluble stabilizers after completion of diafiltration. Upon completion of the diafiltration process, the antibody was concentrated to a concentration above the target, discharged from the system, and the exact protein concentration was determined. The appropriate placebo solution was then added to the sample to obtain a solution with the target protein concentration.

When preparing formulations containing solubilizers, surfactant concentrates were added to the antibody after completion of diafiltration and concentration with a final dilution of the antibody with placebo solution to the target concentration.

Before aseptic filling into the final container (eg, glass or polymer vessel, vial or syringe), the antibody solution was filtered through a 0.22 μm pore size membrane.

Method 2. Determination of protein concentration in the test samples.

Protein concentration was determined using UV spectrophotometry at 280 nm in UV transparent plates.

Each sample was diluted with the appropriate placebo solution to a concentration of approximately 0.5 mg/ml. 150 μl of the diluted sample was placed into the well of the UV spectrophotometry plate. The optical density of the solutions placed in the plate was measured using a plate spectrophotometer at a wavelength of 280 nm. The corresponding placebo solution was used as a reference solution.

Protein concentration (C) in mg/ml was calculated using the formula _ A(28O) *

С = ε * I

A ₂₈₀ is the optical density value at a wavelength of 280 nm;

s is the extinction coefficient of the protein under study;

b is the total dilution factor of the sample;

l is the thickness of the layer in the well of the tablet;

for 150 µl l=0.42 cm.

Method 3. PEG aggregation.

A solution of PEG 6000 was prepared with a mass concentration of 20-25% in the studied composition of excipients. The final solutions were filtered through a 0.45 µm Durapore filter.

The calculated amount of sample, solution of excipients and 20-25% PEG 6000 solution was transferred into 96-well plates for UV spectrophotometry so that in a number of wells there was a PEG6000 concentration from 0 to 18%, and the protein concentration in each well was 1 mg/ ml. All solutions obtained in the wells were mixed well by pipetting.

After this, the degree of turbidity of the solutions was assessed visually, and the optical density of the solutions was measured at a wavelength of 400 nm.

Protein precipitation in the presence of PEG is associated with a volume displacement effect, i.e. the protein is sterically displaced from solvent regions by the polymer. This causes the protein to concentrate until its solubility is exceeded and a precipitate forms. The less stable the sample, the lower the concentration of PEG 6000 it will form visible aggregates (opalescence).

Method 4. Determination of colloidal stability using the shake test method.

The test samples were divided into 2 parts of 200 μl and placed in glass vials, 1 vial for each composition was placed in the refrigerator for storage at 2-8°C, the rest were placed in a shaker and shaken at a speed of 800 rpm at a temperature of 2-8°C. 8°C for the specified time. After the end of the stress, the tubes were shaken on a vortex and transferred for analysis.

Method 5. Determination of colloidal stability by cryoconcentration method.

The test samples were divided into 2 parts and placed in plastic vials: 1 vial for each composition was placed in the refrigerator for storage at 2-8°C, the rest were placed in the freezer and stored at a temperature of minus 16-20°C for the specified time. After the end of the stress, the tubes were removed from the freezer, kept at room temperature until the contents were completely thawed, the solutions were mixed by vortex and transferred for analysis.

Method 6. Determination of thermal stability using the thermostress method.

- 39 046015

The test samples were divided into 2 parts and placed in separate glass vials: 1 vial for each composition was placed in a refrigerator for storage at 2-8°C, the rest were placed in a thermostat and incubated at the required temperature for the specified time. After heating was completed, the vials were removed from the thermostat, kept at room temperature for about 15 minutes, and submitted for analysis.

Method 7. Determination of protein homogeneity and aggregation point using the dynamic light scattering (DLS) method.

Determination of the homogeneity of the studied samples was carried out on a Zetasizer Nano ZSP device in the Size measurement mode. To do this, 0.5 ml of the solution was placed in a dust-free disposable plastic cuvette.

Analytical model: Protein analysis.

Maintain at temperature before starting measurement for 30 s.

At each point, the average value of 13 measurements in 3 replicates.

Determination of the aggregation point of the studied proteins was carried out using a Zetasizer Nano ZSP device. To do this, the solution was placed in a dust-free quartz cuvette, which was gradually heated in the device while constantly measuring the intensity of scattered light in the Temperature trend measurement mode.

Analytical model: Protein analysis.

Temperature trend mode, mod: Protein aggregation point. From 50 to 85°C with heating steps of 1°C.

Maintain at temperature before starting measurement for 60 s. At each point, the average value is from 15 measurements in 1 repetition.

We built a temperature trend using the device software, which automatically calculates the protein aggregation point.

Method 8. Determination of sample homogeneity using the size exclusion (E) high performance liquid chromatography (HPLC) method.

The homogeneity of the samples was then determined using high performance liquid chromatography (HPLC) with the following characteristics.

Column Tosoh TSK-GelG3000SWXL 7.8 mm IDx30 cm, cat. No. 08541.

Column temperature: 25°C.

Mobile phase flow rate: 0.7 ml/min.

Injection volume: 10 µl.

Sample concentration: 5 mg/ml.

Detector wavelength: 220 nm.

Elution duration: 25 min.

Mobile phase: disodium hydrogen phosphate b/v 7.1 mg/ml.

Sodium chloride 17.54 mg/ml.

The pH of the mobile phase was adjusted to 7.0 with orthophosphoric acid.

The change in purity after stress was calculated using the formula

Δ=(proportion of the main peak after stress - fraction of the main peak before stress)

Method 9. Determination of the acid-base profile of samples using ion exchange (IO) HPLC.

The acid-base profile of the samples was then determined using the ion exchange (IO) HPLC method with the following characteristics.

Column ProPac WCX-10 Analytical, 4x250 mm.

Pre-column Pro Race WCX-10G, 4x50 mm.

Column temperature: 25°C.

Mobile phase flow rate: 0.7 ml/min.

Injection volume: 50 µl.

Sample concentration: 1 mg/ml.

Detector wavelength: 280 nm.

Elution duration: 60 min.

Mobile phase.

Eluent A: 20 mM 2-(N-morpholino)ethanesulfonic acid (MES), pH 6.0.

Eluent B: 20 mM 2-(N-morpholino)ethanesulfonic acid (MES), 400 mM NaCl, pH 6.0.

Phase A gradient: 87-0-90%.

The absolute change in the acid-base profile after stress was calculated using the formula Δ=|content of acidic fractions before stress - content of acidic fractions after stress|+|content of the dominant fraction before stress - content of the dominant fraction after stress|+|content of alkaline fractions before stress - content of alkaline fractions after stress|

Method 10. Determination of low molecular weight impurities by polyacrylamide gel electrophoresis (SDS-PAGE) under reducing and non-reducing conditions.

Polyacrylamide gel (PAGE) was prepared in glass plates in the presence of sodium dodecyl

- 40 046015 sulfate, consisting of a concentrating layer - 4% PAAG and a separating layer: under reducing conditions - 12.5% PAAG, under non-reducing conditions - 8% PAAG.

The electrophoresis chamber was assembled and installed in accordance with the operating instructions for the device for vertical electrophoresis. Samples were prepared by diluting samples with purified water to a final concentration of 1 mg/mL. A volume equivalent to 40 μg was taken and the prepared samples of the test sample were mixed in a ratio of 3:1 (volume/volume) with a 4-fold sample loading buffer solution containing 2-mercaptoethanol (reducing conditions) and not containing 2-mercaptoethanol (non-reducing conditions) , mixed. The resulting solutions were incubated at a temperature of (99±1)°C for 3 minutes (samples containing 2-mercaptoethanol) and at a temperature of (99±1)°C for 1 minute (samples not containing 2-mercaptoethanol). The solutions were cooled to room temperature, mixed and applied to PAGE wells under a layer of electrode buffer solution.

Electrophoresis was carried out in constant current mode using a water cooling system. The operating parameters of the power source were set: when the dye front passed through the concentrating gel, the current voltage was 110 V. After the dye front entered the lower separating gel by 5-7 mm, the current voltage was increased to 180 V. The power source was turned off when the dye front reached the lower boundary of the gel .

After completion of electrophoresis, the gels were separated from the glasses and the proteins were fixed in a fixing solution for 16-18 hours at room temperature. Then the gels were stained (in acid blue 83 solution) and washed until the bands were clearly visualized. The gels were scanned. The purity and impurities of the test samples were assessed using GelPro software.

Method 11. Determination of specific activity.

The specific activity of monoclonal anti-P.17 antibody samples was assessed by the ability to specifically bind IL17a protein and neutralize IL17a-dependent IL6 production by HT1080 cells. The HT1080 cell suspension 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 ₂ . Using the Freedom Evo robotic station, serial dilutions of the standard and test samples were prepared, mixed with the IL17a + TNFa solution, and incubated for 1 hour at room temperature. After incubation, the mixture was transferred into culture plates in a volume of 50 μl/well. The plates were incubated for 16-18 hours at 37°C, 5% CO ₂ . All procedures described above were carried out under aseptic conditions.

Detection of the level of IL17a-dependent IL6 production was carried out using ELISA analysis, using an ELISA kit for determining the concentration of IL6 Human IL-6 DuoSet ELISA, R&D System, USA, cat. No. DY206.

Using Magellan 7.2 software, four-parameter curves of the dependence of the average optical density on the protein concentration were constructed for solutions of the standard sample and the test samples located on the same plate.

The relative specific activity of the test sample in percent (RP) was calculated using the formula

RP = ^ED x ^st -100%.

ED^jest where ED ₅₀ st is the value of the half effective dose of the standard sample, ng/ml;

ED ₅₀ test - the value of the half effective dose of the test sample, ng/ml.

The final result was taken as the average value of relative specific activity, calculated from 3 independent determinations (determined on 3 different culture plates).

Examples

Example 1. Selecting a buffer solution.

In the present illustrative study, two four typical antibody buffer solutions of the present invention are selected, suitable for, for example, parenteral, including subcutaneous administration. The tested compositions (per 1 ml) are as follows.

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Designation Compound 5 mM Acet, pH 5.0 Netakimab 2.°.^ tt ζ, h 0.44 mg Sodium acetate trihydrate (t/g) Acetic acid ice. _{tt from} „ ' to pH 5.0 4.5 mM His, pH 6.0 Netakimab 10 mg L-histidine 0.4 mg L-histidine hydrochloride 0.4 mg monohydrate (m/g) 5 mM PB, pH 6.0 Netakimab 10 mg Sodium dihydrogen phosphate 0.59 mg monohydrate (m/g) Sodium hydrogen phosphate anhydrous 0.10 mg (w/w) 5 mM Cit, pH 5.0 Netakimab 10 mg Sodium citrate dihydrate (d/g) 0.93 mg Anhydrous citric acid 0.35 mg (w/w)

Determination of colloidal stability by PEG aggregation method.

The results are presented in table. 1 and Fig. 1.

water and acetate buffer solutions. The composition based on phosphate and citrate was excluded from further study because aggregation at 12% PEG is an unsatisfactory indicator when developing concentrated GDF for subcutaneous administration. Based on the results obtained, acetate and histidine buffer solutions were selected for further development.

Example 2. Development of the composition of anti-TY excipients? based on histidine buffer solution.

Optimization of pH and ionic strength of the buffer solution.

Compositions studied (per 1 ml)

4.5 mM His, pH 6.0 Netakimab L-histidine L-histidine hydrochloride m/g 10 mg 0.4 mg 0.4 mg IOmMHis, pH 6.0 Netakimab L-histidine L-histidine hydrochloride m/g 10 mg 0.9 mg 0.9 mg 20 mM His, pH 6.0 Netakimab L-histidine L-histidine hydrochloride m/g 10 mg 1.8 mg 1.8 mg IOmMHis, pH 5.5 Netakimab L-histidine L-histidine hydrochloride m/g 10 mg 0.46 mg 1.48 mg IOmMHis, pH 6.5 Netakimab L-histidine L-histidine hydrochloride m/g 10 mg 1.16 mg 0.54 mg

Determination of colloidal stability by PEG aggregation method.

The results are presented in table. 2 and fig. 2. Changes in pH and histidine concentration do not affect the colloidal stability and theoretical solubility of the protein.

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table 2

Average optical density data for solutions

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

Determination of thermal stability and protein aggregation temperature.

Table 3

Summary results

Samples studied Change in purity, % Total change in acid-base profile, % pH change Aggregation temperature, °C Thermostress 50°C, 48 h evezhh iovezhkh DLS 4.5 mM His, pH 6.0 -(>.42 IMMIMIIIIMMY 6 0 MIIIIIII 10 mM His, pH 6.0 -O. 4 14.33 (>.14 75 20 MMHis, pH 6.0 -1 24 16.70 72 10 mM His, pH 5.5 -I) “S 14.62 74 10 MMHis, pH 6.5 -Oh 15.83 6.5 ί 74

Positive / better result

Average result

Negative/worst result

It has been experimentally confirmed that an increase in the buffer capacity of the histidine buffer solution leads to a decrease in the thermal stability of the anti-P.17 antibody. At the same time, reducing the histidine/histidine hydrochloride ratio to 0.4 mg/ml/0.4 mg/ml does not lead to a noticeable pH shift after diafiltration and thermal stress. Increasing the pH of the buffer solution to 6.5 slightly reduces the thermal stability of the protein; the stability of anti-I.17 in the pH range 5.5-6.0 does not have significant differences.

For further development, let's assume the following placebo composition (per 1 ml):

L-histidine 0.4 mg

L-histidine hydrochloride m/g 0.4 mg pH 6.0 ±0.5

Choice of osmotic agent.

Four typical excipients were selected as osmolytics.

When choosing their concentration, restrictions on parenteral administration were taken into account. The tested compositions (per 1 ml) are as follows: ____________________________________________________________

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

Determination of colloidal stability by PEG aggregation method.

The results are presented in table. 4 and fig. 3.

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Table 4

Average optical density data for solutions 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

Determination of thermal stability and protein aggregation temperature.

The results of determining the thermal stability and temperature of protein aggregation are presented in table. 5.

Table 5 _______________________________Summary results________________________________

Samples studied Change in purity, % Total change in acid-base profile, % Aggregation temperature, °C Thermostress 50°С, 48 h HPLC IO HPLC DLS His + TRE -0.73 16.31 72 His + SUC -0.54 16.21 71 His + MAN NWIIIIII|SH| NI|I|11|||II|||N|||I|I ~ ⁴ His + SORB -Ϊ 4S 1*>4<» 71 ^Positive / best „ , „ SHI with _a Average result Οι ριιtsative / worst result

All proposed compositions provide sufficient thermal and colloidal stability of the protein. Nevertheless, the composition with mannitol has good heat-stabilizing properties, because over 48 hours of thermal stress, the increase in protein impurities in this composition when analyzed by E-HPLC, as well as the total changes in the isoform profile, was the minimum value among all those obtained.

Based on the data obtained, the following placebo composition is acceptable for use as a pharmaceutical composition:

L-histidine 0.4 mg/ml

L-histidine hydrochloride m/g 0.4 mg/ml

Mannitol 54.5 mg/ml pH 6.0 ±0.5

Selection of solubilizer and optimization of its content.

To reduce the level of aggregation of the concentrated form of the monoclonal anti-Th17 antibody, the use of solubilizers polysorbate 80 and poloxamer 188 was considered. The tested compositions (per 1 ml) are as follows: _____________________________________________________________________

Netakimab 10 mg His + MAN pH 6.0 L-histidine 0.4 mg L-histidine hydrochloride m/g 0.4 mg Mannitol 54.5 mg Netakimab 10 mg L-histidine 0.4 mg His+ MAN + 0.1 PS80 pH 6.0 L-histidine hydrochloride m/g 0.4 mg Mannitol 54.5 mg Polysorbate 80 0.1 mg Netakimab 10 mg L-histidine 0.4 mg His+ MAN + 0.2 PS80 pH 6.0 L-histidine hydrochloride m/g 0.4 mg Mannitol 54.5 mg Polysorbate 80 0.2 mg His+ MAN + 0.5 PS80 pH 6.0 Netakimab 10 mg L-histidine 0.4 mg

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L-histidine hydrochloride m/g Mannitol Polysorbate 80 0.4 mg 54.5 mg 0.5 mg His+ MAN+ 1.0PS80 pH 6.0 Netakimab L-histidine L-histidine hydrochloride m/g Mannitol Polysorbate 80 10 mg 0.4 mg 0.4 mg 54.5 mg 1.0 mg His+ MAN + 0.1 poly oxamer pH 6.0 Netakimab L-histidine L-histidine hydrochloride m/g Mannitol Poloxamer 188 10 mg 0.4 mg 0.4 mg 54.5 mg 0.1 mg His+ MAN + 1.0 poloxamer pH 6.0 Netakimab L-histidine L-histidine hydrochloride m/g Mannitol Poloxamer 188 10 mg 0.4 mg 0.4 mg 54.5 mg 1.0 mg

Determination of colloidal stability by PEG aggregation method.

Then colloidal stability was determined by PEG aggregation of solutions. The results are presented in table. 6 and FIG. 4.

Table 6

Average optical density data for solutions

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 + 0.1 PS80 0.0483 0.0520 0.0537 0.0552 0.0635 0.0603 0.0628 0.0687 His + MAN + 0.2 PS80 0.0524 0.0551 0.0578 0.0591 0.0583 0.0642 0.0736 0.0802 His + MAN + 0.5 PS80 0.0526 0.0551 0.0557 0.0570 0.0710 0.0692 0.0701 0.0721 His + MAN + 1.0 PS80 0.0512 0.0576 0.0583 0.0572 0.0638 0.0653 0.0687 0.0734 His + MAN+ 0.1 poloxamer 0.0534 0.0539 0.0576 0.0582 0.0639 0.0663 0.0658 0.0740 His + MAN + 1.0 poloxamer 0.0514 0.0534 0.0581 0.0522 0.0611 0.0678 0.0619 0.0730

Determination of thermal stability and protein aggregation temperature.

The thermal stability and aggregation temperature of the protein were then determined; the results are presented in table. 7.

Table 7

Summary results

Samples studied Total change Change in purity, % acid-base profile, % Aggregation temperature, °C Thermostress 50°C, 48 h HPLC IO HPLC DLS His + MAN ... 15.67 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 His+MAN + 1.0 ESSO 16.30 His + MAN + 0.1 poloxamer INIMIII1 15.55 1I111NNV1 His+ MAN + 1.0 poloxamer 16.87 72

»positive / best ~ „ '3 lt Average result

Negative/worst result

The negative effect of polysorbate 80 on the aggregation stability of the anti-11.17 antibody was shown. With an increase in the content of this surfactant in the composition, the increase in impurities during thermal stress increases when analyzed by E-HPLC. The content of poloxamer 188 in the anti-P.17 antibody does not have a significant effect on the stability of the antibody. The acid-base profile of the studied protein does not significantly depend on the content of surfactants.

- 45 046015

Based on the study results, the following placebo composition is acceptable for the dosage form, presented as an example:

L-histidine 0.4 mg/ml

L-histidine hydrochloride m/g 0.4 mg/ml

Mannitol 54.5 mg/ml

Poloxamer 188 0- 1.0 mg/ml pH 6.0 ±0.5

Example 3. Development of a composition of anti IL17 excipients based on an acetate buffer solution.

Next, optimization of the pH and ionic strength of the buffer solution was investigated.

The following test compositions were prepared (per 1 ml)._____________________

5 mM Acet, pH 5.0 Netakimab Sodium acetate trihydrate Acetic acid, ice. 10 mg 0.44 mg up to pH 5.0 10 mM Acet, pH 5.0 Netakimab Sodium acetate trihydrate Acetic acid, ice. 10 mg 0.87 mg to pH 5.0 20 mM Acet, pH 5.0 Netakimab Sodium acetate trihydrate Acetic acid ice. 10 mg 1.74 mg up to pH 5.0 20 mM Acet, pH 4.0 Netakimab Sodium acetate trihydrate Acetic acid ice. 10 mg 0.98 mg to pH 4.5 20 mM Acet, pH 6.0 Netakimab Sodium acetate trihydrate Acetic acid, ice. 10 mg 2.31 mg to pH 5.5

In example 2 it is shown that the pH and buffer capacity of the solution do not have a significant effect on the results of PEG aggregation, therefore in example 3 for the acetate buffer solution the results of this experiment are not shown.

Determination of thermal stability and protein aggregation temperature.

Then the thermal stability and aggregation temperature of the protein were determined; the results are presented in table. 8.

Table 8

Summary results of samples before and after stress

Samples studied Change in purity, % Total change in acid-base profile, % pH change Aggregation temperature, °C Thermostress 50°С, 48 h HPLC IO HPLC DLS 5 mM Acet, pH 5.0 MMVI^N| 14.74 5.23 74 10 mM Acet, pH 5.0 IIIIIM 14.68 5.18 74 20 mM Acet, pH 5.0 -0 11 15.81 5.01 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

Average result: positive / worst result (positive / best result

It has been experimentally confirmed that increasing the buffer capacity stabilizes the pH of the acetate buffer solution, but does not have a significant effect on the thermal stability of the anti-I.17 antibody. It was also shown that the protein under study is stable in the pH range of 4.5-5.5.

For further development, we allow the placebo composition (per 1 ml): Sodium acetate trihydrate 1.74 mg

Acetic acid, ice. up to pH 5.0 ± 1.0

Choice of osmotic agent.

In the present study, four typical osmolytics were selected. When choosing the concentration of osmolytics, restrictions on possible parenteral administration were taken into account.

- 46 046015

The following test compositions were prepared (per 1 ml).

Designation Compound 20 mM ACET+TRE Netakimab 10 mg Sodium acetate trihydrate 1.74 mg Trehalose d/g 100 mg Acetic acid, ice. up to pH 5.0 20 mM ACET+SUC Netakimab 10 mg Sodium acetate trihydrate 1.74 mg Sucrose 100 mg Acetic acid, ice. up to pH 5.0 20 mM ACET+MAN Netakimab 10 mg Sodium acetate trihydrate 1.74 mg Mannitol 54.5 mg Acetic acid, ice. up to pH 5.0 20 mM ACET+SORB Netakimab 10 mg Sodium acetate trihydrate 1.74 mg Sorbitol 54.5 mg Acetic acid, ice. up to pH 5.0 20 mM ACET+PROL Netakimab 10 mg Sodium acetate trihydrate 1.74 mg L-proline 27 mg Acetic acid, ice. up to pH 5.0

Table 9

Summary results of samples before and after stress

No. Protein, mg/ml Composition designation Change in purity, % Total change in acid-base profile modulo, % Thermostress 50°C, 96 h evezhh IO HPLC 1 10 Acet+Tre - _________________________22 90____________________ | 2 10 Acet+Suc - : 3 10 Acet+Man 26.18 4 10 Acet+Sorb -0.29 25.52 5 10 Acet+Prol -0.44 111III11IIII1^D^OYA1111Я11ЯИ11И1

Negative/worst result

Positive / better result

Average result

Based on the results of this study, the following acceptable illustrative placebo composition (excluding additional excipients):

Sodium acetate trihydrate Trehalose dihydrate Acetic acid ice.

1.74 mg/ml 100 mg/ml up to pH 5.0

This composition showed good stabilizing properties during thermal stress at 50°C, shaketest and freezing among the studied samples. It showed the smallest change in purity using E-HPLC after stressing and acceptable indicators of changes in the acid-base profile of the samples.

Selection of stabilizers.

In order to obtain a stable dosage form with a maximum concentration of anti-GN7 antibody, screening of stabilizers was carried out for samples at protein concentrations of 60, 100 and 120 mg/ml. To ensure the physiology 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.

The compositions containing histidine developed in example 2 were used as a reference solution. However, the maximum concentration at which it was possible to obtain a stable solution with histidine was limited to 70 mg/ml.

Due to the increased aggregation of highly concentrated protein solutions during thermal stress, in this section the thermal stress temperature was reduced, which was compensated by an increase in the duration of thermostatting.

- 47 046015

The following test compositions were prepared (per 1 ml).

Designation Compound 4.5 mM His + mannitol Netakimab L-histidine Mannitol 40, 60, 70 mg 0.4 mg 54.5 mg 4.5 mM His + mannitol Netakimab L-histidine Mannitol Poloxamer 188 40, 60, 70 mg 0.4 mg 54.5 mg 1.0 mg 20 mM acetate 80 trehalose Netakimab Sodium acetate trihydrate Acetic acid ice. 60, 100, 120 mg 1.74 mg up to pH 5.0 20 mM acetate 80 trehalose 0.5 Pol oxamer 188 Netakimab Sodium acetate trihydrate Trehalose d/g Poloxamer 188 Acetic acid ice. 60, 100, 120 mg 1.74 mg 80 mg 0.5 mg up to pH 5.0 20 mM acetate 80 trehalose 1.0 Pol oxamer 188 Netakimab Sodium acetate trihydrate Trehalose d/g Poloxamer 188 Acetic acid ice. 60, 100, 120 mg 1.74 mg 80 mg 1.0 mg up to pH 5.0 20 mM acetate 80 trehalose 0.5 Polysorbate 20 Netakimab Sodium acetate trihydrate Trehalose d/g Polysorbate 20 Acetic acid ice. 60, 100, 120 mg 1.74 mg 80 mg 0.5 mg up to pH 5.0 20 mM acetate 80 trehalose NRB 10 Netakimab Sodium acetate trihydrate 60, 100, 120 mg 1.74 mg

- 48 046015

Trehalose d/g cyclodextrin NRV Acetic acid ice. 80 mg 10 mg up to pH 5.0 Netakimab 60, 100, 120 mg 20 mM acetate 80 trehalose HPB20 Sodium acetate trihydrate Trehalose d/g NRV cyclodextrin 1.74 mg 80 mg 20 mg Acetic acid, ice. up to pH 5.0 Netakimab 60, 100, 120 mg 20 mM acetate 80 trehalose 5 mM methionine Sodium acetate trihydrate Trehalose d/g L-methionine 1.74 mg 80 mg 0.746 mg Acetic acid, ice. up to pH 5.0 Netakimab 60, 100, 120 mg 20 mM acetate 80 methionine 10 mM methionine Sodium acetate trihydrate Trehalose d/g L-methionine 1.74 mg 80 mg 1.492 mg Acetic acid, ice. up to pH 5.0 Netakimab 60, 100, 120 mg 20 mM acetate 80 trehalose 20 mM methionine Sodium acetate trihydrate Trehalose d/g L-methionine 1.74 mg 80 mg 2.984 mg Acetic acid, ice. up to pH 5.0 Netakimab 60, 100, 120 mg 20 mM acetate 50 trehalose 3 NaCl Sodium acetate trihydrate Trehalose d/g 1.74 mg 50 mg Sodium chloride 3 mg Acetic acid, ice. up to pH 5.0 Netakimab 60, 100, 120 mg 20 mM acetate 50 trehalose 100 mM glycine Sodium acetate trihydrate Trehalose d/g Glycine 1.74 mg 50 mg 7.507 mg Acetic acid, ice. up to pH 5.0 Netakimab 60, 100, 120 mg Sodium acetate trihydrate 1.74 mg 20 mM acetate 50 trehalose Trehalose d/g 50 mg 100 mM glycine +10 mM met Glycine 7.507 mg L-methionine 1.492 mg Acetic acid, ice. up to pH 5.0 Netakimab 60, 100, 120 mg 20 mM acetate 50 trehalose 100 mM lysine Sodium acetate trihydrate Trehalose d/g Lysine monohydrate-L 1.74 mg 50 mg 16.42 mg Acetic acid, ice. up to pH 5.0 Netakimab 60, 100, 120 mg 20 mM acetate 50 trehalose 100 mM serine Sodium acetate trihydrate Trehalose d/g Serin-L 1.74 mg 50 mg 10.91 mg Acetic acid, ice. up to pH 5.0 20 mM acetate 50 trehalose Netakimab 60, 100, 120 mg 100 mM guanidine Sodium acetate trihydrate 1.74 mg hydrochloride Trehalose d/g 50 mg

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Guanidine hydrochloride Acetic acid ice. 9.55 mg up to pH 5.0 20 mM acetate 50 25 mM leucine trehalose Netakimab Sodium acetate trihydrate Trehalose d/g Leucine-L Acetic acid, ice. 60, 100, 120 mg 1.74 mg 50 mg 3.28 mg to pH 5.0 20 mM acetate 50 trehalose 5 mM tryptophan Netakimab Sodium acetate trihydrate Trehalose d/g Tryptophan-L Acetic acid, ice. 60, 100, 120 mg 1.74 mg 50 mg 1.02 mg up to pH 5.0 20 mM acetate 50 100 mM glutamate trehalose Netakimab Sodium acetate trihydrate Trehalose d/g Monosodium glutamate Acetic acid ice. 60, 100, 120 mg 1.74 mg 50 mg 16.91 mg up to pH 5.0 20 mM acetate 50 100 mM hydrochloride trehalose arginine Netakimab Sodium acetate trihydrate Trehalose d/g L-Arginine hydrochloride Acetic acid ice. 60, 100, 120 mg 1.74 mg 50 mg 21.07 mg up to pH 5.0 20 mM acetate 50 trehalose 50 mM glutamate 50 mM arginine Netakimab Sodium acetate trihydrate Trehalose d/g Monosodium glutamate L-Arginine hydrochloride Acetic acid ice. 60, 100, 120 mg 1.74 mg 50 mg 8.46 mg 10.53 mg up to pH 5.0

Table 10

Summary results of E-HPLC samples before and after stress

No. Protein, mg/ml Composition designation Change in monomer content, HPLC E, % Thermo-stress, 42°C, 96 h Thermo-stress 42°C, 10 days Thermo-stress, 37°C, 1 week. Thermo-stress, 37°C, 2 weeks. Compositions based on histidine buffer solution (4.5 mM) 1 40 54.5 mg/ml mannitol -P.68 -1 2ι> -o 2 -0 zc 2 60 -0 84 -2 mi -1 I. -eleven 3 70 -1 O -1 23 -> (G 4 40 54.5 mg/ml mannitol + 1.0 mg/ml poloxamer -0.55 -1 22 -and 65 -0 29 5 60 -I 38 -l.u.3 -1.28 -1.54 6 70 -1.72 -3.38 -1.39 -1.98 Compositions based on acetate buffer solution (20 mM) 7 60 80 mg/ml trehalose d/g -II 1 1 -1 50 -o 18 -and 56 8 80 mg/ml trehalose d/g + 0.5 mg/ml poloxamer NNISHII|| 9 80 mg/ml trehalose d/g + 1 mg/ml poloxamer 10 eleven 50 mg/ml trehalose d/g 100 mM Gly 50 mg/ml trehalose d/g 10 MMMeth III^iIVn i^INp Βι^ΗΜΗη and|miN^n| 12 50 mg/ml trehalose d/g 100 mM glutamate -2 '8 |·Μ№|μΒ IINImNi 13 50 mg/ml trehalose d/g 50 mM glutamate 50 mM arginine -odz -3 82 -2 9b -1 zx -1181 14 100 80 mg/ml trehalose d/g 15 80 mg/ml trehalose d/g 0.5 mg/ml poloxamer 188 -z 54 I|IiN|| 16 80 mg/ml trehalose d/g + 1 mg/ml poloxamer |NIVI|I|II -2 hh ^shi|N|IN 17 80 mg/ml trehalose d/g 0.5 mg/ml Polysorbate 20 -1.43 -4.46 -1.94 18 30 mg/ml trehalose d/g 10 mg/ml NRP cyclodextrin -1.11 -3.38 -1.67 -1.84 19 80 mg/ml trehalose d/g 20 mg/ml NRB cyclodextrin -1.37 -3.22 -1.72 20 80 mg/ml trehalose d/g 5 mM methionine N|MI|NINV l 46 -1.88 21 80 mg/ml trehalose d/g 10 mM methionine IMImNN| -1.63 institutes

- 50 046015

22 80 mg/ml trehalose d/g 20 mM methionine WINNN · ³ ' ⁷⁰ -2 pi -2 '4 23 50 mg/ml trehalose d/g 3 mg/ml NaCl -2.9 -6 34 24 50 mg/ml trehalose d/g 100 mM glycine -1 O -3 45 -2 '11 schishchin 25 50 mg/ml trehalose d/g 100 mH glycine +10 mM methionine -14' aaaaaand -2 04 26 50 mg/ml trehalose d/g 100 mM lysine -4.58 |D|||ID||I| -4 0 27 50 mg/ml trehalose d/g 100 mM Serine -12 -2 2 NO NO· 29 50 mg/ml trehalose d/g 100 mM guanidine hydrochloride -5.84 -8 118 -4'4 -'ς- 29 50 mg/ml trehalose d/g 25 mM leucine nsmts -' 8<. -2 -2 1‘> thirty 50 mg/ml trehalose d/g 5 mM tryptophan -14 -3 38 NNIi -1 8'1 31 100 50 mg/ml trehalose d/g 100 mM glutamate -12 D1I^M|II|| -2 42 -1 32 50 mg/ml trehalose d/g 100 mM arginine hydrochloride iiiiii ||||I^M||||| -4 26 -5 58 33 50 mg/ml trehalose d/g 50 mM glutamate 50 mM arginine -6 94 -2 -3 84 34 120 30 mg/ml trehalose d/g -1128 -4.13 -1 8<. -1 94 35 80 mg/ml trehalose d/g + 0.5 mg/ml poloxamer VNII|I ninschv NSCH|Shchi ininv 36 80 mg/ml trehalose d/g + 1 mg/ml poloxamer AI|SHN iNNShchts SCHII| NO NO· 37 50 mg/ml trehalose d/g 100 mM Gly -2 32 NIMI| -eleven' -2 29 behind 50 mg/ml trehalose d/g 10 mM methionine -2 45 NSHNN| INVNN -2 39 39 50 mg/ml trehalose d/g 100 mM glutamate !||DD1I|I| -o 18 -1 88 -2 69 40 50 mg/ml trehalose d/g 50 mM glutamate 50 mM arginine Research Institute··· -1 18 -3 73

The E-HPLC method confirmed that in the concentration range of aHTu-IL17 antibodies according to the invention 60-120 mg/ml, compositions with trehalose dihydrate and poloxamer 188 exhibit good stabilizing properties. The stabilizing effect of L-methionine and glycine on the test protein under thermal stress was also noted. The composition based on histidine buffer solution has lower solubility, but sufficient thermal stability for further use.

Selection of stabilizers.

In order to confirm the stability of the anti-IL17a antibody according to the invention in the recommended compositions, samples were placed in accelerated storage at +37°C. At this stage, the compositions were examined for quality indicators such as specific activity, low molecular weight impurities, acid-base profile, and purity. The results are presented in table. eleven.

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Table 11

Sample Quality indicator Norm Protein concentration, mg/ml Incoming control 2 weeks at 37°C 4 weeks at 37°C Change after 4 weeks Placebo composition: pH 6.0 ±0.5 40 6.17 - 6.11 -0.05 L-Histidine 0.4 mg/ml L-Histidine hydrochloride monohydrate 0.4 mg/ml Mannitol 54.5 mg/ml 60 6.17 - 6.15 -0.02 70 6.18 - 6.14 -0.04 Purity, E HPLC (aggregate content upper value, monomer content lower value) At least 95% 40 97.02 96.72 95.60 -1.42 60 97.22 95.46 94.28 -2.94 70 97.31 94.95 93.67 -3.64 SDS-PAGE Not less than 95% in reducing conditions 40 95.66 95.26 94.37 -1.29 60 95.64 95.10 93.71 -1.93 70 95.70 94.58 94.25 -1.45 At least 90% in non-reducing conditions 40 95.90 94.15 92.32 -3.58 60 95.88 93.67 92.00 -3.88. 70 95.12 93.68 92.09 -3.03 Acid-base profile, AI HPLC - 40 12.64 17.02 22.30 23.54 75.99 70.39 64.22 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 Activity 80 - 125% of control sample 40 111 - 102 -9 60 109 - 98 -eleven 70 105 - 96 -9 Placebo composition: pH 6.0 ±0.5 40 6.15 - 6.13 -0.02 L-Histidine 0.4 mg/ml L-Histidine hydrochloride monohydrate 0.4 mg/ml Mannitol 54.5 mg/ml Poloxamer 188 1 mg/ml 60 6.20 - 6.18 -0.02 70 6.22 - 6.16 -0.06 Purity, E HPLC (aggregate content upper value, monomer content lower value) At least 95% 40 97.11 96.16 95.44 -1.67 60 97.28 95.12 94.69 -2.59 70 97.52 94.29 93.89 -3.63

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Placebo composition:

Sodium acetate trihydrate 1.74 mg/ml

Acetic acid up to pH 5.0

Trehalose dihydrate 80 mg/ml

SDS-PAGE Not less than 95% in reducing conditions 40 95.23 94.76 94.12 -1.11 60 95.39 95.02 93.48 -1.91 70 95.42 94.67 94.12 -1.30 At least 90% in non-reducing conditions 40 95.64 94.87 92.75 -2.89 60 95.43 93.58 92.49 -2.94 70 95.29 93.45 92.19 -3.10 Acid-base profile, AI HPLC - 40 12.32 17.02 21.69 21.98 75.68 70.39 64.69 12.00 12.59 13.62 60 12.09 19.20 23.44 24.42 75.31 69.26 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 Activity 80 - 125% control sample 40 100 - 96 -4 60 102 - 92 -10 70 106 - 94 -12 pH 6.0 ±0.5 60 5.21 - 5.24 0.03 100 5.34 - 5.40 0.06 120 5.34 - 5.41 0.07 Purity, E HPLC (aggregate content upper value, monomer content lower value) At least 95% 60 95.98 95.41 96.22 0.25 100 95.96 95.16 94.15 -1.81 120 95.48 94.04 93.97 -1.51 SDS-PAGE Not less than 95% in reducing conditions 60 95.57 95.13 94.60 -0.97 100 95.30 94.99 94.58 -0.72 120 95.44 95.26 94.58 -0.86 At least 90% in non-reducing conditions 60 95.31 95.06 94.58 -0.73 100 95.42 94.77 94.46 -0.94 120 95.67 94.23 94.21 -1.46 Acid-base profile, AI HPLC - 60 13.33 20.34 22.63 26.60 76.17 66.32 62.87 10.50 13.34 14.30

- 53 046015

Placebo composition:

Sodium acetate trihydrate 1.74 mg/ml

Acetic acid up to pH 5.0

Trehalose d/g mg/ml

Poloxamer 188 1 mg/ml

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 18.69 Activity 80 - 125% control sample 60 98 - 95 -3 100 99 - 92 -7 120 104 - 97 -7 pH 6.0 ±0.5 60 5.21 - 5.28 0.07 100 5.33 - 5.41 0.08 120 5.32 - 5.42 0.10 Purity, E HPLC (aggregate content upper value, monomer content lower value) At least 95% 60 95.98 96.02 96.04 0.07 100 95.98 94.89 93.83 -2.15 120 95.98 94.71 94.00 -1.97 SDS-PAGE Not less than 95% in reducing conditions 60 94.98 94.58 94.21 -0.77 100 94.89 94.60 94.37 -0.52 120 95.35 95.10 94.37 -0.98 At least 90% in non-reducing conditions 60 95.01 93.54 92.91 -2.10 100 94.58 93.15 92.06 -2.52 120 95.55 94.34 93.66 -1.89 Acid-base profile, AI HPLC - 60 13.56 20.34 22.99 28.02 76.02 65.03 62.01 10.42 14.63 15.00 100 13.49 19.98 23.67 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 Activity 80 - 125% of control sample 60 108 - 101 -7 100 103 - 97 -6 120 BY - 99 -eleven

As a result of accelerated aging of samples for 1 month at +37°C, the preservation of homogeneity and specific activity of the anti-P.17 antibody according to the invention was proven in the following illustrative acceptable storage compositions:

Anti-1H7 antibody

L-histidine

L-Γhistidine hydrochloride monohydrate Mannitol

Pol oxamer 188 pH 6.0 ±0.5

10-70 mg/ml

0.4 mg/ml

0.4 mg/ml

54.5 mg/ml

0-1 mg/ml

- 54 046015

Anti-1H7 antibody

Sodium acetate trihydrate Trehalose d/g Poloxamer 188 Acetic acid ice. pH 5.0 ±0.5

- 120 mg/ml 0.44 - 1.74 mg/ml 80- 100 mg/ml 0-1 mg/ml up to pH 5.0

While the invention has been described with reference to preferred embodiments, it should be understood that changes and modifications may be made as will be apparent to those skilled in the art. Such changes and modifications should be considered within the scope and scope of the present invention.

Illustrative, non-limiting examples of the present invention have been described in detail above with reference to the accompanying drawings. This detailed description is provided merely to provide one skilled in the art with additional details for the practice of preferred aspects of the present teachings, and is not intended to limit the scope of the present invention. In addition, each of the additional features and ideas disclosed above and below may be used individually or in combination with other features or ideas.

Moreover, the combinations of features and steps disclosed in the detailed description below, as well as the experimental examples, may not be necessary for the practice of the invention in the broadest sense, and are provided only to describe in detail specific examples for the present invention. Moreover, the features of the specific examples described above and the independent and dependent claims set forth herein may be combined in ways not specifically and directly indicated to realize additional useful embodiments of the present invention.

Additional research examples.

Additional exemplary studies have been conducted using various pharmaceutical compositions, including an anti-IL17a antibody as described herein (eg, netakimab), for the treatment of various IL17a-mediated diseases. Typical pharmaceutical compositions used for these studies are described in table. 11.1.

Table 11.1

Code K'. llllliriCCK'Ol about her. le.ioBiiniBi IIOK'SI hissing Teranov tnch eskne up to 1y. Ml <1>a w Made 1 m.1 solution BCD-085-2 plaque psoriasis 40, 80, 120 II monoclonal anti-1N7 antibody 40.0 mg, histidine hydrochloride monohydrate 0.4 mg, L-histidine 0.4 mg, mannitol 54.5 mg, water for injection up to 1.0 ml BCD-085-2ext plaque psoriasis 80, 120 BCD-085-3 ankylosing spondylitis 40, 80, 120 BCD-085-3ext ankylosing spondylitis 80, 120 BCD-085-7, BCD-085-4 plaque psoriasis 120 III monoclonal anti-1N7 antibody 60.0 mg, sodium acetate trihydrate 1.74 mg, trehalose dihydrate 80 mg, poloxamer (Kolliphor) 188 0.5 mg, glacial acetic acid to pH 5.0 water for injection up to 1.0 ml BCD-085-5 ankylosing spondylitis 120 BCD-085-8 psoriatic arthritis 120

In some examples, 80 mg was administered in 2 syringes (1 ml each, 40 mg BCD-085), in other examples, 120 mg was administered in 3 syringes (1 ml each, 40 mg BCD-085) or 120 mg was administered in 2 - two syringes (1 ml each, 60 mg BCD-085).

It has been shown that various doses of pharmaceutical compositions and/or the drug Netakimab, described in table. 11.1 are suitable for the treatment of corresponding diseases mediated by IL17a, as described in table. 11.1, and subject to the drug dosage regimen described in detail later in this document. In fact, various dosages/schedules of Netakimab and its pharmaceutical compositions as described herein may be used to treat a study participant.

The results of the case studies are presented here.

Example 4: Use of Netakimab at different doses for the treatment of plaque psoriasis (PP), a proof-of-concept study (study BCD-085-2).

Clinical trial design.

Study BCD-085-2 is a phase II, double-blind, randomized, multicenter, placebo-controlled clinical trial in patients with moderate to severe plaque psoriasis. The primary goal was to find an effective and

- 55 046015 safe dose of BCD-085 for multiple injections in patients with moderate to severe plaque psoriasis. Pharmacokinetic and immunogenicity assessments were included in the secondary objectives of the study.

The study population was represented by adult patients (aged 18 to 65 years inclusive) with moderate to severe plaque psoriasis diagnosed at least 6 months before screening, with a baseline level of BSA (body surface area) covered by psoriasis >10 %, psoriasis severity index of 12 or higher, disease severity on the sPGA scale of 3 or more, who are candidates for systemic or phototherapy or have undergone previous biological therapy to no avail. Patients with previous monoclonal antibody use were allowed to participate (except for previous use of IL17/IL17R inhibitors) after completion of the appropriate washout periods.

120 Patients were randomly assigned (1:1:1:1 ratio) to 4 treatment groups: 1) BCD-085 40 mg; 2) BCD-085 80 mg; 3) BCD-085 120 mg; and 4) placebo. The BCD-085-2 study used BCD-085 at a dose of 40 mg/1 ml in prefilled syringes. BCD-085/placebo was used on day 1 of weeks 0, 1, 2, 4, 6, 8, and 10 of treatment. For blinding purposes, patients in the 40 and 80 mg dose groups received 2 or 1 subcutaneous placebo injections (1 ml each), respectively. Patients in the control group received 3 subcutaneous injections of placebo (each injection 1.0 ml). To ensure safety, patients were observed until the 14th week.

The study hypothesis was that BCD-085 was superior to placebo in patients with moderate to severe plaque psoriasis. The marginal performance criterion (δ) was 0.1 (10%), type 1 error (α) -5% (0.05), type 2 error (β) 20% (0.2) and power 80 %. The primary outcome measure in this study was the proportion of patients who achieved PASI75 by week 12 of treatment. Achieving a PASI 75 was defined as a decrease in PASI value of at least 75% by week 12 of treatment compared to baseline. Secondary evaluation criteria include assessment of the PASI 50 and PASI 90 indices, sPGA 0-1, percentage improvement in PASI, PPT and nail plate condition according to the NAPSI index, reduction in the severity of itching on the VAS scale (mm), assessment of quality of life QoL (SF-36 questionnaires and DLQI). Efficacy criteria were assessed at 0, 4, 8 and 12 weeks of treatment. Safety criteria included the incidence of adverse events (AEs), serious adverse events (SAEs), grade 3-4 AEs according to CTCAE 4.03 criteria, and the incidence of early study termination due to AEs. The pharmacokinetic criteria assessed included standard pharmacokinetic parameters ( _Cmin , AUC( _0-168 ), AUC( _0-672 ), _Tmax , T1/2, Vd, _Kel , CL). The immunogenicity analysis included determining the frequency of binding and neutralization of antibodies to the drug BCD-085 after multiple injections of the drug.

Research results.

The groups were comparable to each other in terms of demographic and baseline characteristics (Table 12).

- 56 046015

Table 12

Original ha Patient characteristics (study BCD-085-2) Parameter BCD-085 40 mi (11=30) BCD-085 80 mi (11=30) BCD-085 120 mi (11=28) Placebo (11=26) Age (years), median FIQR1 41.50 [32.00-50.00] 35.00 [29.00-45.00] 45.00 [35.00-54.00] 41.50 [32.00-48.00] Body mass index (kg/ ^m2 ), median [IQR] 25.81 [23.7-28.09] 26.85 [23.62-29.59] 29.72 [24.15-31.94] 24.95 [22.95-30.12] Male gender, number (%) 23 (76.67%) 19 (63.33%) 22 (78.57%) 15 (57.69%) Disease duration (months), median [IQR] 178 [76.00-224.00] 137 [73.00-187.00] 137 [46.00-191.00] 112 [69.00-211.00] PASI index, median [IQR] 25.7 [17.4-30.7] 21.9 [17.4-28.2] 23.55 [16.4-30.6] 26.4 [17.8-31.1] BSA%, median [IQR] 31 [18-39] 23.05 [17.5-36] 31.8 [21.9-40] 31 [16-38] sPGA index, median (IQR1 4 [3-4] 4 [3-4] 4 [3-4] 4 [3-4] Previous use of systemic glucocorticoids, number (%) 6 (20%) 4 (14.33%) 4 (14.29%) 3 (11.54%) Previous use of phototherapy, number (%) 21 (70%) 19 (63%) 19 (67.86%) 20 (76.92%) Previous biological treatment, number (%) 1 (3.33%) 1 (3.33%) 1 (3.57%) 0 (0.00%) Note: IQR - interquartile range

The efficacy population included 114 patients. Six of the 120 randomized subjects were not included in the efficacy study for the following reasons: Dropped out of the study early before the first dose (1 patient in the BCD-085 80 mg group and 2 patients in the BCD-085 group at dose of 120 mg), violated the inclusion/exclusion criteria (1 patient in the BCD-085 group at a dose of 40 mg) and violated the drug dosage regimen (2 patients in the placebo group). The analysis showed that BCD-085 was superior to placebo at all doses tested in patients with moderate to severe plaque psoriasis. More than 90% of patients in the highest dose group (120 mg) responded to treatment. The main results of the effectiveness of the action are presented in table. 13, fig. 5, 6, 7.

Table 13

Comparative assessment of PASI75 clinical response rates at week 12 of treatment (study BCD-085-2)

1 pymia . Iei<apci venny prenara i Papist share. .loci in iiiiix PASI 75. n (<.) p-value 1 (n=30) BCD-085 (40 mg) 24 (80.0%) pi<0.0001 rg<0.0001 2 (n=30) BCD-085 (80 mg) 25 (83.33%) 3 (n=28) BCD-085 (120 mg) 26 (92.86%) 4 (n=26) Placebo 6(23.08%)

Note: 1 - two-sided exact version of Fisher's test; 2 - test

X ² with Yates' correction.

To support the protocol hypothesis that BCD-085 is superior to placebo, 95% CIs were calculated for the difference in proportions achieving PASI 75 (individual pairwise comparisons were conducted for the placebo group versus each BCD-085 group). A hypothesis was accepted if the lower bound of the estimated 95% CI for the difference in PASI 75 achievement ratios was greater than the prespecified clinically insignificant difference (δ) limit of 10% (0.10). The results are presented in table. 14.

Table 14

Comparative assessment of PASI75 response rates at week 12 of treatment (study BCD-085-2)

Difference in achieving \.i\ reading but PASI index 75 ' Completed1st and । grater, ι ¹ ->5 ⁰ «> p-values ¹ Groups 1 and 5 56.92% [31.72%; 82.13%] <0.0001 Groups 2 and 4 60.25% [35.69%; 84.83%] <0.0001 Groups 3 and 4 69.78% [47.28%; 92.28%] <0.0001 Note: 1 - two-tailed / ² test with Yates correction.

This table shows that the lower bounds of the 95% CI for all pairwise comparisons (placebo vs. BCD-085) are outside the prespecified cutoff.

- 57 046015 efficiency. In summary, the hypothesis that BCD-085 is superior to placebo in the treatment of patients with moderate to severe plaque psoriasis was accepted and the primary objective of the clinical trial was achieved. It should be noted that higher efficacy of BCD-085 over placebo was proven for all doses tested (40, 80 and 120 mg). Dynamic assessment of the percentage improvement in PASI 75 and PASI scores compared to baseline showed clear results from week 4 of treatment (Figs. 6, 7).

The PASI90 index was recorded in 66.7, 60.0, 78.6% of patients taking BCD-085, respectively, in contrast to 19.2% for the placebo group by week 12 of treatment (p < 0.0001 for groups 1, 2, 3 compared to the placebo group). In addition, 83.3, 90.0, 89.3% of patients taking BCD-085 achieved clear or almost clear skin (sPGA 0/1) in groups 1, 2, 3, respectively, in contrast to 30.8 % for the placebo group (p<0.0001 for groups 1, 2, 3 compared with the placebo group) by week 12 of treatment. The mean percentage reduction in affected BSA by week 12 of treatment 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%) versus 27.1% for placebo group (range 0 to 69.7%), p<0.0001 for groups 1, 2, 3 versus placebo groups.

BCD-085 also showed significant efficacy in the treatment of nail psoriasis (Figure 8). The population size for evaluation of nail psoriasis was 66 patients (other patients had no evidence of nail psoriasis during the study period). Mean percentage change in NAPSI scores by week 12 of treatment: 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%) versus 0 for placebo group (range -9.3 to 0%), p=0.0002 for group 1, 2, 3 respectively versus group placebo.

Quality of life (QoL) assessments showed that the DLQI score decreased significantly over time, indicating improved quality of life (QoL) in the BCD-085 groups, and did not change in the placebo group. It was proven that BCD-085 was more effective than placebo, and the main goal of the study was achieved. Although there were no differences between the three BCD-085 doses for most endpoints, the best overall reduction in psoriasis signs/symptoms was found in the 120 mg BCD-085 dose group.

Pharmacokinetics.

After a single dose of 40, 80 and 120 mg of BCD-085, Netakimab was detected in the serum within 0.5-4 hours after dosing. Its concentration changed over time in the same way for all doses. Changes in Netakimab drug concentrations were proportional to the dose administered. Slow absorption was observed with a gradual linear increase in serum concentrations of BCD-085 with a maximum observed at the end of the 1st week of treatment. Higher doses (80 and 120 mg) were characterized by higher _Cmax and AUC( _{0- i68} ) compared to the 40 mg dose (Fig. 9).

Long-term absorption resulted in BCD-085 Cmax at 144 [78-168] hours post-dose, which is close to the time of the second injection. The lack of terminal half-life of BCD-085 after a single dose in this trial indicated that PK parameters such as AUC( _0-M ), T1/2 and Kel could not be calculated and therefore data for these endpoints are not presented.

With repeated injections of BCD-085 at doses of 40, 80 and 120 mg, trough serum concentrations were quite high (>60% _Cmax ) and were achieved before the second injection of BCD-085. With repeated administrations, BCD-085 accumulated in the blood serum, and its concentration increased by 1.8-3.6 times. Administration of higher doses (80 and 120 mg) demonstrates a higher induction potential compared to the 40 mg dose, since fewer injections are required to achieve concentrations around Cmax _-mult (Fig. 10).

Safety.

The safety analysis was performed on 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 assessed in 19.35% of patients in group 1, 10.00% of patients in group 2, 7.14% of patients in group 3 and 10.71% of patients in group 4 (p=0.534). No grade 4 AEs or SAEs were reported. No patient had to discontinue study treatment due to an AE/SAE. Grade 3 AEs were reported in 3.23% of patients in group 1, 3.33% of patients in group 2, 3.57% of patients in group 3 and 7.14% of patients in group 4 (p=0.872, two-sided Fisher's exact test ). The most common AEs were neutropenia, acute respiratory tract infections, increased blood pressure and increased liver transaminases. Most AEs were mild. Only one focal reaction (grade 1) was detected in group 1 (BCD-085, 40 mg).

- 58 046015

Table 15

Summary of safety data (study BCD-085-2)

11arame r BCD-085. 40 mi BCD-085. 80 mi BCD-085. 120 mi Nlanebo (n=28) p-niil'ICIIlIC (11=31 > (11=30) (11=28( Any and szhs late l and ys phenomena (AE) 14 (45.16%) eleven ,!.-%,! 7 (25.00%) 1 1 1 _x 'o 2'L,p 0.443 Any serious adverse events (SAEs) NO Adverse events related to therapy 6 (19.35%) 3 (10.00%) 2(7.14%) 3 (10.71%) 0.534 adverse events with toxicity grade 3 1 (3.23%) 1 (3.33%) 1 (3.47%) 2 (7.14%) 0.872 adverse events with toxicity grade 4 NO Reactions at the injection site 1 (3.23%) 0 O O 1.000 Discontinuation of therapy due to AEs or SAEs NO Typical adverse events Neutropenia 4 (12.90%) 2 (6.67%) 1 (3.57%) 1 (3.57%) 0.539 Upper respiratory tract infection 3 (9.68%) 1 (3.33%) 1 (3.57%) 1 (3.57%) 0.721 Increased serum gammaglutamyltransferase (GGT) 0 3 (10.00%) 1 (3.57%) 2(7.14%) 0.291

Immunogenicity.

The immunogenicity assessment population consisted of 117 patients (those who received at least one injection of the study product and provided at least two blood samples for analysis, one of which was drawn before the first dose on day 1, week 0). Blood samples were taken at week 0 before injection and at week 14 of treatment. Immunogenicity assessment did not reveal the presence of any binding antibodies against BCD-085 in any patient.

Conclusion.

The analysis showed that BCD-085 was superior to placebo at all doses tested. The greatest efficacy was shown for the 120 mg dose: 92.86% of patients achieved PASI75 by week 12 of treatment (compared to 23.08% in the placebo group, two-sided 95% CI [47.28, 92.28%] p<0.0001, chi-square test with Yates correction). Toxicity of BCD-085 was moderate: the frequency of AEs did not differ between groups (including placebo), the most common types of AEs being grade 1-2 laboratory abnormalities and increased blood pressure. There were no cases of SAEs, premature discontinuation of study participation due to safety concerns, or the formation of antibodies to the drug.

Example 5: Long-term use of Netakimab in patients with moderate to severe plaque psoriasis (study BCD-085-2ext).

Research plan.

The BCD-085-2ext study is a multicenter, 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 protocol. The main objective was to evaluate the effectiveness and safety of maintenance therapy (up to 1 year) using BCD-085.

When the duration of follow-up in the main study BCD-085-2 (14 weeks) and its extension phase BCD-085-2ext (42 weeks) are combined, the total follow-up time per subject in both studies was 56 weeks (about 1 year).

Patient population and study design.

This study included 103 patients who completed the BCD-085-2 study as per protocol. Patients who achieved a PASI of 50 or less (non-responders) after the BCD-085-2 study received BCD-085 subcutaneously at a dose of 120 mg according to the Q2W regimen (BCD-085 is given once every 2 weeks), patients who achieved improvement in PASI 50 or more, received BCD-085 subcutaneously at a dose of 80 mg according to the 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) at the same doses. Patients who did not achieve PASI 100 were considered poor responders and continued to receive the same dose of BCD-085 on a Q2W schedule until the end of the study (Figure 11).

During the 12 weeks of the BCD-085-2ext study, patients were treated with the Q2W regimen in two groups:

group 1: BCD-085 at a dose of 80 mg;

group 2: BCD-085 at a dose of 120 mg.

Since the Q4W regimen was introduced after 6 months of treatment (12 weeks study

- 59 046015 BCD-085-2ext), patients were divided into 4 groups: group 1: BCD-085 at a dose of 120 mg (Q2W/Q4W); group 2: BCD-085 at a dose of 80 mg (Q2W/Q4W); group 3: BCD-085 at a dose of 120 mg (Q2W); group 4: BCD-085 at a dose of 80 mg (Q2W).

Study BCD-085-2 used baseline characteristics. The primary outcome measure was the proportion of patients who achieved PASI 75 by week 38 of this study (or week 52 if participation in the main BCD-085-2 trial was included). Secondary evaluation criteria include PASI 90, PASI 100, and sPGA 0-1 scores. Primary efficacy endpoints were assessed at weeks 12 and 38 of the BCD-085-2ext study (weeks 24 and 52 of treatment). Immunogenicity parameters included the frequency of antibody binding and neutralization to BCD-085 after one year of treatment (week 56).

The study involved 86 patients from the Russian Federation and 17 patients from the Republic of Belarus.

Results.

Efficiency.

The primary outcome measure for this study was the proportion of patients who achieved PASI 75 by week 38 of this study (or week 52 if participation in the pivotal study BCD-085-2 was included). Achieving a PASI 75 was defined as an improvement in PASI score of at least 75% by week 38 of treatment compared with the baseline value before initiation of BCD-085 therapy (as screened for the BCD-085-2 trial). Efficacy was assessed in the ITT population (efficacy analysis included all patients, even those who dropped out and did not receive the full course of treatment, total population, n=103).

The analysis showed that the proportion of patients who achieved PASI 75 after 1 year of treatment with BCD-085 was 98.06% (including patients without clinical response to therapy - patients who did not achieve PASI 50 at the time of inclusion in the additional treatment phase).

Efficacy data after 6 months of study treatment (i.e., 12 weeks of the BCD-085-2ext study) were obtained in two groups of patients who received BCD-085 at doses of 80 and 120 mg.

Efficacy data after 1 year of treatment (i.e., after 38 weeks of the BCD-0852ext study) were obtained in 4 groups:

group 1: BCD-085 at a dose of 120 mg (Q2W/Q4W);

group 2: BCD-085 at a dose of 80 mg (Q2W/Q4W);

group 3: BCD-085 at a dose of 120 mg (Q2W);

group 4: BCD-085 at a dose of 80 mg (Q2W).

In this study, two subgroups were compared: a subgroup that was very sensitive to the study treatment (groups 1 and 2, where patients received BCD-085 according to the Q2W regimen, and then, after 12 weeks, according to the Q4W regimen, n = 45) and a subgroup of patients , whose response to treatment was slower (groups 3 and 4, where patients received BCD-085 according to the Q2W regimen throughout the study; n=58).

The results of the PASI 75 assessment in the ITT population are presented in Table. 16 and fig. 12.

Table 16

Proportion of patients achieving PASI 75 after one year of treatment (38th week of BCD-085-2ext study) (BCD-085-2ext study)

1 healing ruin Proportion of Nazis, losin iihix PASI 75 by week 38 '(one yule treatment) R-shaceppe ¹ died Total number of patients, n=103 101 98.06 - Group 1, n=6 6 100 1,000 Group 2, n=39 38 97.44 Group 3, n=21 20 95.24 0.3621 Group 4, n=37 37 100 ¹ - two-sided exact version of Fisher's test.

¹ The 38-week time point in the BCD-085-2ext study is equal to 52 weeks when combined with the duration of the previous BCD-085-2 study (hereinafter).

Comparisons in the subgroup of patients more responsive to treatment (groups 1 and 2) showed no significant differences (p=1000, two-tailed Fisher's exact test) between the 80 and 120 mg doses of BCD-085. However, efficacy was highest with BCD-085 120 mg (Group 1): 100% of patients achieved PASI75.

Comparison in the subgroup of patients less sensitive to therapy (groups 3 and 4) also showed no significant differences. Group 3 had a lower response rate because it included the sickest patients who did not have minimal response

- 60 046015 (PASI 50) when entering the extension phase and did not reach PASI 100 after 12 weeks of extension. However, 95.24% of patients in this group achieved PASI 75, which confirms the high effectiveness of therapy even in responders with a delayed response to treatment.

Assessment of loss of response to the drug after one year of treatment.

Biological therapy for psoriasis using TNF-alpha inhibitors is known to be associated with loss of response to the drug over time. Monoclonal antibodies to interleukin-17 have been shown to have high levels of efficacy over a long period of time. To confirm this fact, loss of response to the drug was assessed in patients receiving BCD-085 for one year. The proportion of patients with a decrease in PASI 75/90/100 after 1 year of therapy was compared with a PASI 75/90/100 at week 12 of the BCD-085-2 study among patients receiving BCD-085 in both studies (n=77). This group did not include patients who received placebo during the BCD-085-2 study.

Table 17

Proportion of patients with decreased PASI 75/90/100 response after one year of treatment (BCD-085-2ext study)

1 ruins Share of iiamieiiioB with noiepeii oiBeia at week 38 (52 nc.ie.ui treatments) Absolute value PASI 75 n=77 2 2.60 Group 2, n=33 1 3.03 Group 3, n=13 1 7.69 Group 4, n=31 0 0 PASI 90 n=77 3 3.90 Group 2, n=33 1 3.03 Group 3, n=13 0 0 Group 4, n=31 4 12.90 PASI 100 n=77 7 9.09 Group 2, n=33 6 18.18 Group 3, n=13 0 0 Group 4, n=31 1 3.23 In group 1, all patients received placebo during the study period.

As can be seen from the table above. 17, loss of response to the drug was found in few patients. Failure to achieve PASI90 was observed primarily in Group 4 (12.9% of patients), where subjects received BCD-085 80 mg Q2W. The decrease in PASI 100 value was observed mainly in group 2 (18.18%), where patients received 80 mg BCD-085 according to the Q2W/Q4W regimen.

A decrease in PASI 75 score was observed in only 2 patients (2.6%) of the total population (n=77, excluding patients receiving placebo in the main study). This shows that the majority of patients maintained a sustained response during long-term treatment with BCD-085. Cases of decreased PASI 90/100 in groups receiving BCD-085 at a dose of 80 mg may indicate that this dose was not sufficiently effective.

The effect of switching from a more frequent dosing regimen (Q2W) to a less frequent dosing regimen (Q4W) on maintaining clinical response was studied. This parameter was assessed using the proportion of patients in groups 1 and 2 (n=45) who maintained a PASI value of 100 at the end of the observation period (Table 18).

Table 18

Proportion of patients who maintained/decreased PASI 100 after dosage switch (Q2W/Q4W) (BCD-085-2ext Study)

1 pvniia Share iiamiieiiioB. \ which were preserved in PASI 1 (κι IiamieiiioB share with PASI 100 wobble reduction P-value ¹ Absolute and I am magnitude Absolute and I am magnitude O/ η = 45 (patients of groups 1 and 2) 38 84.44 7 15.56 - Group 1, n=6 6 100 0 0 0.5686 Group 2, n=39 32 82.05 7 17.95 ¹ - two-sided exact version of Fisher's test

There were no patients in Group 1 (patients receiving BCD-085 120 mg Q2W/Q4W) with a decrease in PASI 100 response at the end of the extension study, and

- 61 046015

17.95% of patients experienced a decrease in PASI 100 response in group 2 (patients receiving BCD-085 80 mg Q2W/q4). Thus, the use of BCD-085 at a dose of 120 mg in the Q4W regimen allowed us to maintain a higher response rate to treatment in more patients than the use of BCD-085 at a dose of 80 mg at the same dosing frequency.

Evaluation of the effectiveness of BCD-085 after 6 months of treatment (12 weeks of the BCD-085-2ext study).

In table Figure 19 presents efficacy data at week 12 of the BCD-085-2ext study (ie, after 6 months of enrollment in the previous BCD-085-2 study and initiation of study treatment) in the ITT population (n=103). Comparisons were made between the two groups based on the dose of BCD-085 received during the first 12 weeks of the BCD-085-2ext study (80 or 120 mg).

Table 19

Proportion of patients achieving PASI 75 after 6 months of treatment (study BCD-085-2ext)

1 healing ruin Additional salt value 0/ 0 R-shacheppe ¹ Proportion of patients achieving PASI 75 by week 12 (after 6 months of treatment) Total number of patients, n=103 92 89.32 - 80 mg dose group, n=76 75 98.68 <0.0001 dose group 120 mg, n=27 17 62.96 Proportion of patients achieving PASI 90 at week 12 (after 6 months of treatment) Total number of patients, n=103 63 61.17 - 80 mg dose group, n=76 56 73.68 <0.0001 dose group 120 mg, n=27 7 25.93 Proportion of patients achieving PASI 100 at week 12 (after 6 months of treatment) Total number of patients, n=103 45 43.69 80 mg dose group, n=76 39 51.32 0.0167 dose group 120 mg, n=27 6 22.22 ¹ - two-sided exact version of Fisher's test.

Disease severity on the sPGA scale at 0-1 (clear or almost clear skin) was achieved by 87.38% after 6 months of therapy (Table 20).

Table 20

Proportion of patients who achieved an sPGA score of 0-1 after 6 months of treatment (BCD-085-2ext Study)

1 |P she treats number R- Hia4ciHie ¹ Proportion of patients achieving sPGA 0-1 at week 12 (after 6 months of treatment) Total number of patients, n=103 90 87.38 - 80 mg dose group, n=76 73 96.05 <0.0001 dose group 120 mg, n=27 17 62.96

Data show that the proportion of patients with PASI75/90/100 and sPGA 0-1 at 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 value (PASI 50) in patients in the BCD-085 120 mg group at enrollment in the BCD-085-2ext study, i.e. they had the most severe condition at the start of the study and responded more slowly to treatment.

Evaluation of the effectiveness of BCD-085 after one year of treatment.

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

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Table 21

Proportion of patients who achieved PASI 90 and PASI 100 after one year of treatment (38 weeks of BCD-085-2ext study)

1 r\n treatment number % R-shachepne ¹ Proportion of patients achieving PASI 90 by week 38 (one year of treatment) Total number of patients, n=103 95 92.23 - Group 1, n=6 6 100 1,000 ¹ Group 2, n=39 38 97.44 Group 3, n=21 17 80.95 0.241 ¹ Group 4, n=37 34 91.89 Proportion of patients achieving PASI 100 by week 38 (one year of treatment) Total number of patients, n=103 61 59.22 Group 1, n=6 6 100 0.5686 ¹ Group 2, n=39 32 82.05 Group 3, n=21 7 33.33 0.6439 ² Group 4, n=37 16 43.24 ¹ - two-sided exact version of Fisher's test; ² - test with Yates correction / ² .

The highest treatment response rate was shown in group 1, where all subjects achieved PASI 90/100. No significant differences were found between groups (groups 1 and 2, groups 3 and 4) in any parameter.

After one year of treatment, disease severity scores sPGA 0-1 were achieved in 95.15% of patients, and sPGA 0 (clear skin) was achieved in 59.22% of patients (Table 22, Figs. 15, 16).

Table 22

Proportion of patients achieving sPGA 0-1 and sPGA 0 (clear skin) after 52 weeks of treatment (38 weeks of BCD-085-2ext study) treatment breakdown_________| Aoco.iioi share velipiιиia |________»________| P-'.beginning I

Proportion of patients achieving sPGA of 0-1 at week 38 (52 weeks of treatment) Total number of patients, n=103 98 95.15 - Group 1, n=6 6 100 1,000 Group 2, n=39 38 97.44 Group 3, n=21 20 95.24 1,000 Group 4, n=37 34 91.89 Proportion of patients achieving sPGA 0 by week 38 (52 weeks of treatment) Total number of patients, n=103 61 59.22 - Group 1, n=6 6 100.00 0.5719 Group 2, n=39 31 79.49 Group 3, n=21 7 33.33 0.4135 Group 4, n=37 17 45.95 ¹ - two-sided exact version of Fisher's test.

The best results for sPGA assessment were observed in patients receiving BCD-085 at a dose of 120 mg in a Q2W/Q4W regimen.

Safety.

The safety analysis was performed on all patients who received at least one dose of BCD-085 (n=103, Table 23).

Regardless of dose and dosage schedule, BCD-085 showed a favorable safety profile that did not differ between groups.

During the study period, at least one case of AE/SAE was recorded in 36.89% of patients (38 out of 103): 33.33% of patients in group 1 (2 out of 6), 35.90% of patients in group 2 ( 14 of 39), 38.10% of patients in group 3 (8 of 21) and 37.84% of patients in group 4 (14 of 37) (p=1.0000, Fisher's exact test).

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Summary of safety data (study BCD-085-2ext)

Table 23

Total NUM. ICHI IOC II. napnsn1ov Group 1 (n=6) 2 (11=39) 3(n=21) 4 (11=3 ⁷ ) II % "''O II II % η % Any AE/SAE 38 36.89 2 33.33 14 35.90 8 38.10 14 37.84 P-value ¹ 1.0000 Adverse events related to therapy 6 5.83 0 0 4 10.26 1 4.76 1 2.70 P-value ¹ 0.6542 Any SAE 1 0.97 0 0 1 2.56 0 0 0 0 P-value ¹ 1.0000 SAEs related to No therapy AE, severity level 3/4 5 4.85 1 16.67 2 5.13 0 0 2 5.41 P-value ¹ 0.3528 Grade 3/4 treatment-related AEs 5 4.85 1 16.67 2 5.13 0 0 2 5.41 P-value ¹ 1.0000 Focal reactions No Cancellation of therapy due to AEs or SAEs

Note: ¹ - two-sided Fisher's exact test.

Study treatment-related AEs/SAEs were reported in 5.83% of patients (6/103): four patients in group 2 (10.26%), one patient in group 3 (4.76%) and one patient in group 4 (2.70%) (p=0.6542, two-sided Fisher's exact test).

During the study, one patient from group 2 (2.56%) had two cases of SAEs not related to study therapy: left-sided obstructive pyelonephritis (kidney stones) and acute pancreatitis. In both cases, the criterion for severity was hospitalization. Grade 3/4 AEs unrelated to study therapy were reported in 4.85% of patients (5/103): one patient in group 1, two patients in groups 2 and 4, and none in group 3.

The most common AEs were lymphocytosis, increased liver function tests, increased indirect bilirubin levels, and increased blood pressure (Table 24).

AEs were mostly mild or moderate (grade 1/2 according to CTCAE 4.03 scale).

Table 24

Most common AEs (more than 1 case per arm) (BCD-085-2ext Study)

About 1 K. lOIICIIIIC Group 1 (u = 6) Group 2 (u = 39) Group 3 (n = 21) Group 4 (11 =37) Rvalue 1 ^eleven % % % N % Disorders of the blood and lymphatic system Lymphocytosis (grade 2) 0 0.00 2 5.13 0 0.00 1 2.70 0.8287 Disorders of the liver and biliary tract Increased ALT (total quantity) 0 0.00 0 0.00 0 0.00 5 13.51 0.0434 Degree 1 0 0.00 0 0.00 0 0.00 4 10.81 0.1018 Degree 2 0 0.00 0 0.00 0 0.00 1 2.70 0.6214 ACT Improvement (Grade 1) 0 0.00 0 0.00 2 9.52 1 2.70 0.2127 Increase in GGT (total quantity) 0 0.00 4 10.26 1 4.76 2 5.41 0.7992 Degree 1 0 0.00 1 2.56 0 0.00 1 2.70 1.0000 Degree 2 0 0.00 2 5.13 1 4.76 1 2.70 1.0000 Degree 3 0 0.00 1 2.56 0 0.00 0 0.00 1.0000 Increased indirect bilirubin (grade 2) 0 0.00 2 5.13 0 0.00 0 0.00 0.4215 Cardiovascular disorders Increased blood pressure (total number) 0 0.00 0 0.00 2 9.52 3 8.11 0.1613 Degree 2 0 0.00 0 0.00 2 9.52 1 2.70 0.2127 Degree 3 0 0.00 0 0.00 0 0.00 2 5.41 0.2804 Note: ¹ - exact version of Fisher's test.

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Grade 3 adverse events, with the exception of 2 cases of increased blood pressure (group 4: 5.41%) were recorded as isolated events: increased diastolic blood pressure in 1 patient from group 2 (2.56%), increased GGTP in 1 patient from group 2 (2.56%); deforming osteoarthritis of the right knee joint and bilateral gonarthrosis (psoriatic arthropathy, pain syndrome) in 1 patient from group 1 (16.67%).

There were no cases of discontinuation of therapy due to AEs or SAEs.

There were no focal reactions associated with the study drug.

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 increased incidence of AEs with long-term use of BCD-085, the exposure-adjusted incidence rate (EAIR) of AEs was assessed during the BCD-085-2ext study (42 weeks) and compared with the rate during the BCD-085-2 study. (14 weeks). Data from patients who received BCD-085 at a dose of 80 and 120 mg were taken into account (Table 25).

Table 25

Exposure-adjusted incidence rate of AEs in Study BCD-085-2ext compared to Study BCD-085-2 (Study BCD-085-2ext)

.Ιο ia. mi co 120 SO 120 1 lapanci 1" K'o. iipieci and about s. lx seagulls but no time iicc.ie by whom 01 about nerno οι. η Hour i o I and g.ernfp nirova and us\ s.lyiacit K'o. iipiccih about s. |hchaen but no time iicc.ie |chem 01 about nerno ia. η Hour· οι and vsrnfnpironan us\ s.iviaen K'o. iipiccih about s. |hchaen but time iicc.ie ιχ eat 01 about nerno ia. η Chasnia vsrnfin propane us\s. pchasv K'o. iipiccih about s. pchaen but nremya iiee.ie ixexi 01 o nerno ia. η Hour ιοι a nsrnfnnnnrovan ιιι.ιι s.IIchaev NA SPY eleven 12-1 - i.i.S51 28 1.1.4211 111 0.4233 Related AE/SAE 3 0.3429 2 0.2449 4 0.0602 1 0.0423 AE grade 3-4 1 0.1143 1 0.1224 2 0.0301 2 0.0847 AE related to investigational therapy, grade 3-4 severity 1 0.1143 0 0.0000 0 0.0000 0 0

The exposure-adjusted incidence rates of AEs/SAEs were 1.2571 and 0.8571 AEs per patient per year for BCD-085 80 and 120 mg, respectively, during the BCD-085-2 study and 0.4211 and 0. 4233 AEs per 1 patient per year for BCD-085 at a dose of 80 and 120 mg, respectively, during the BCD-085-2ext study. Thus, the incidence of AEs/SAEs did not increase during the extension study period. The results obtained suggest that long-term use of the drug BCD-085 at a dose of 80 and 120 mg is possible without the risk of increasing the incidence of adverse events.

Immunogenicity.

The immunogenicity analysis was based on data obtained from 101 patients who received at least one dose of BCD-085 starting from week 0 of this study and did not miss/lose/spoilt serum samples collected on any day 42 weeks of study BCD-085-2-ext.

The immunogenicity assay did not detect the presence of binding antibodies after 42 weeks of the BCD-085-2ext study (ie, 56 weeks from the start of the BCD-085-2 study).

Conclusion.

The high effectiveness of the drug BCD-085 with long-term use was established based on the following data: in 98.06% of patients, significant clinical improvement in the course of psoriasis was achieved, regardless of the dose and regimen of use of the drug BCD-085.

The greatest effectiveness was observed in patients who received BCD-085 at a dose of 120 mg in the Q2W/Q4W regimen: by the end of the BCD-085-2ext study, 100% of these patients achieved a PASI 100 and an sPGA score of 0-1.

In the population of patients treated with BCD-085 for 1 year (during the previous BCD-085-2 study and the current BCD-085-2ext study), a decrease in PASI 75 was observed in only 2.6% of study participants. Cases of decreased PASI90/100 values were more often observed in groups in which study participants received BCD-085 at a dose of 80 mg, which indicates that this dosage is insufficiently effective.

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Among patients who were switched from Q2W to Q4W using BCD-085 (Q2W/Q4W dosing regimen), the best response was seen with BCD-085 at a dose of 120 mg, and no patients experienced a decrease in PASI 100 response.

In summary, the overall analysis demonstrated the high efficacy of BCD-085 when used long-term in patients with moderate to severe plaque psoriasis who had failed previous standard treatment. It has been demonstrated that BCD-085 can be used less frequently (once per month) after 6 months of treatment when administered at a dose of 120 mg.

Example 6. Use of Netakimab according to standard and low-frequency dosing regimens in patients with moderate to severe plaque psoriasis (study BCD-085-7).

Clinical trial plan.

BCD-085-7 is an ongoing, double-blind, multicenter, placebo-controlled, phase III study in patients with moderate to severe plaque psoriasis. The purpose of the study is to evaluate the efficacy and safety of BCD-085 administered once every four weeks (Q4W regimen) compared with BCD-085 administered once every 2 weeks (Q2W regimen).

The BCD-085-7 study uses a 60 mg/1 mL formulation of BCD-085 in prefilled syringes. Method of administration: subcutaneous injections with 2 pre-filled syringes (2 subcutaneous injections over 15 minutes). The study is currently ongoing and results from the first 12 weeks of treatment are available.

Patient population and clinical trial design.

The patient population included 213 patients with moderate to severe plaque psoriasis (PASI > 10, BSA > 10, and sPGA > 3) aged 18 years or older who met other eligibility criteria. The study did not include patients who had previously received treatment with monoclonal antibodies that bind to IL17 (or the IL17 receptor), and patients who had previously taken 2 or more drugs containing monoclonal antibodies or their fragments. After the screening examination, patients were randomly divided in a 2:2:1 ratio into 3 groups: 1) BCD-085 group, Q2W regimen; 2) group BCD-085, Q4W regimen; and 3) placebo group. Patients received BCD-085/placebo in a blinded manner for 12 weeks. Group 1 received BCD-085 at a dose of 120 mg at 0, 1, 2 weeks, then at 4, 6, 8, 10 weeks. Group 2 received BCD-085 at a dose of 120 mg at weeks 0, 1, 2, then at weeks 6, 10 (for the purpose of blinding, patients received placebo at weeks 4 and 8). Patients in group 3 received placebo at weeks 0, 1, 2, 4, 6, 8, and 10 of treatment. At week 12 of treatment, PASI 75 was assessed for primary outcome and treatment was de-blinded.

Starting from the 14th week, all patients in groups 1 and 2 will receive BCD-085 according to the Q4W regimen until the 50th week. All patients in Group 3 (placebo) will receive BCD-085 at weeks 12, 13, 14, and then every 4 weeks from week 14 until week 50. Beginning at week 54, only responders (achieving PASI75 or greater at week 52) will continue treatment in the Q4W extension study beginning at week 54. Patients in Groups 1 and 2 will receive BCD-085 until week 154, and patients in Group 3 will receive BCD-085 until week 166. The observation period for all patients is 4 weeks (Fig. 17).

The primary outcome measure is the proportion of patients in each study arm who achieved PASI 75 by week 12 of the study. Secondary evaluation criteria include assessment of the PASI 50 and PASI 90 indices, sPGA 0-1, percentage improvement in PASI, PPT and nail plate condition according to the NAPSI index, reduction in the severity of itching on the VAS scale (mm), assessment of the dermatological quality of life index QoL (DLQI questionnaire ). Study BCD-085-7 evaluates psoriatic arthritis (PsA) by assessing ACR20/50/70 response according to American College of Rheumatology criteria (among patients with active PsA at baseline). Efficacy criteria are assessed at 0, 8, 12, 24, 42 and 52 weeks of study in the main period and at 62, 74, 86, 98, 110, 122, 134, 146 and 154 weeks of treatment with BCD-085 during the open-label extension study. . Safety criteria include the incidence of adverse events (AEs), PCOS, grade 3-4 AEs in accordance with CTCAE 4.03 criteria, rates of early study termination due to the occurrence of AEs. Immunogenicity parameters include the frequency of binding and neutralization of antibodies to BCD-085 at 0, 12, 24 and 54 weeks of study in the main period and at 86, 98, 110, 134, 154 weeks of BCD-085 treatment during the open-label extension period (OLE- period).

The BCD-085-7 study was based on sequential testing of hypotheses: BCD-085 is more effective than placebo in any dosage regimen; efficiency criterion (δ) 0 (0%), type I error 0.025, type II error 80%; the drug BCD-085 with the Q4W dosing regimen is no less effective than the Q2W dosing regimen; efficiency criterion (δ) -0.2038 (-20.38%), type I error 0.05 (significance level with a two-sided test),

- 66 046015 type II error 80%.

Testing the superiority hypothesis.

The statistical hypothesis that BCD-085 is superior to placebo was tested sequentially by comparing the lower limit of the 95% confidence interval for the difference in the proportion of patients with PASI 75 at week 12 of treatment in the BCD-085 Q2W group and the placebo group, then in the BCD-085 Q4W group and the placebo group with a prespecified efficacy cutoff (8.0%).

Results.

Efficacy was assessed in 2 patient populations: the ITT population using the NRI method (n=213) and the PP population (a group of patients who completed participation in the study in accordance with the protocol) (n=210). Two patients discontinued the study early and one patient was lost to follow-up before week 12.

The groups did not differ from each other in demographic and baseline characteristics (Tables 26, 27).

Table 26

Patient demographics and baseline characteristics (study BCD-085-7)

IhipiiMcip 1I 1)-OX5 Q2W (n=X5) 1I 1)-0Х5 Q4W (p=Х4) 11. laneoo (11=44) P-Miii chenne Views (1 types), median [IQR] 42 [35 - 49] 41.5 [32-53] 39 [33-53] 0.9344 ¹ Body weight (kg), median [IQR] 87.3 [75-96.1] 89.5 [78-98] 83.5 [70-95] 0.3078 ¹ Height (cm), median [IQR] 178 [170-184] 176 [168-182] 175.5 [168-180] 0.6110 ² Body mass index (kg/ ^m2 ), median [IQR] 27.9 [24.5-31.5] 28.5 [25.5-32.5] 27.1 [24.2-30.0] 0.3958 ¹ Women (%) 22 (22.58) 26(30.95) 9 (20.45) 0.4319 ³ Men (%) 63(74.12) 58(69.05) 35 (79.55) reproductive potential in women (%) 13 (59.09) 18(69.23) 4 (44.44) 0.4114 ⁴ Disease duration (months), median [IQR] 120 [36-204] 111 [36- 183] 100 [34- 193] 0.8727 ¹ BSA, % 20 [13-42] 22 [14.5-43] 22.5 [13-44] 0.9136 ¹ PASI index 18.4 [14.2-27] 17.9 [15.1-28.6] 19.7 [16.3-29.4] 0.3469 ¹ NAPSI index 7 [0-29] 14 [2-28] 14 [0-37] 0.5001 ¹ sPGA index 3 [3-4] 4 [3-4] 4 [3-4] 0.1210 ¹ Itch Score (VAS) 47 [27-67] 48 [27-71] 45.5 [23 - 70] 0.961 ¹ Beck Depression Ratings, points 6 [2-9] 6 [2-11] 6.5 [2-10] 0.7388 ¹ DLQI indicator 13 [10-20] 13 [9-18] 15 [9-20] 0.7450 ² History of psoriatic arthritis, and (%) 6 (7.06) 10(11.9) 2(4.55) 0.3478 ⁴ Psoriatic arthritis at the time of examination, and (%) 6 (7.06) 7 (8.33) 2(4.55) 0.7883 ⁴

Kruskal-Wallis test, ² - analysis of variance, ³ - test with Yates's X2 correction, ⁴ - Fisher's exact test.

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Table 27

Previous treatment for psoriasis (study BCD-085-7)

Previous therapy BCD-085 Q2W (n=85) BCD-085 Q4W (n=84) Placebo (n=44) P-value % -....:. _n :.. , % : : P ^: . % Monoclonal antibodies and Janus kinase inhibitors 5 5.88 6 7.14 1 2.27 0.6389 ² • Adalimumab 3 3.53 2 2.38 1 2.27 1.0000 ² • Infliximab 0 0.00 1 1.19 0 0.00 0.6009 ² • Ustekinumab 0 0.00 2 2.38 0 0.00 0.1963 ² • Guselkimab 1 1.18 0 0.00 0 0.00 1.0000 ² • Tofacitinib 1 1.18 1 1.19 0 0.00 1.0000 ² GKS 23 27.06 32 38.10 16 36.36 0.2802 ¹ • Systemic application 10 11.76 8 9.52 5 11.36 0.8820 ² • Local application 15 17.65 22 26.19 12 27.27 0.3149 ¹ Other systemic treatments 22 25.88 29 34.52 21 47.73 0.0447 ¹ • Methotrexate 17 20.00 24 28.57 19 43.18 0.0212 ¹ • Cyclosporine A 4 4.71 3 3.57 1 2.27 0.9032 ² • Apremilast 1 1.18 0 0.00 0 0.00 1.0000 ² • Acetrine 1 1.18 3 3.57 0 0.00 0.4366 ² Phototherapy 47 55.29 50 59.52 thirty 68.18 0.3677 ¹

Note: ¹ - Pearson X2 test with Yates correction; ² - Fisher's exact test

Efficacy study results (first 12 weeks).

The difference in the proportion of patients responding to treatment according to the PASI 75 index at week 12 was 77.65% (BCD-085 Q2W and placebo) with a 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 indicate that the lower bounds of the 95% CI for the BCD-085 Q4W and BCD-085 Q2W groups (73.63 and 67.07%, respectively) exceed the effectiveness cutoff criterion (0%). In conclusion, both regimens of BCD-085 were superior to placebo in patients with moderate to severe plaque psoriasis.

Consistent with the statistical methods used to evaluate efficacy, the study hypothesis of noninferiority of BCD-085 once every 4 weeks versus BCD-085 once every 2 weeks was tested by comparing the lower 95% confidence limit interval to determine the difference in the proportion of patients with a PASI 75 at week 12 between BCD-085 in the Q4W regimen and BCD-085 in the Q2W regimen, with a prespecified non-inferiority margin (δ) of -20.38%.

The difference in the proportion of patients with PASI 75 at week 12 between the BCD-085 Q4W and BCD-085 Q2W groups was 5.68 with 95% CI [-7.41; 18.78%] (P=0.4603, Pearson test with Yates correction χ2). The lower bound of the 95% CI (−7.41%) is within the prespecified bound of −20.38%. This fact indicates that the effectiveness of taking BCD-085 every 4 weeks was not inferior to the effectiveness of taking BCD-085 every 2 weeks (Table 28).

Table 28

Primary outcome measure (PASI75 at week 12) with 95% CI (ITT population, n=213) (study BCD-085-7)

group PASI 75 in week 12. n=213 P-iiianeine . (.overit, ibiibiii shrnal 95% X ⁿ /n BCD-005 Q2W (85) 66 77.65 0.4603 ¹ -7.41; 18.78] ¹ BCD-085 Q4W (84) 70 83.33 Placebo(44) 0 0 0.0001 ² <0.0001 ³ 67.07; 88.23] ² 73.63; 93.03] ³

Q4W (Yates' chi-square test), ² BCD-085 Q2W vs. placebo (Fisher's exact test), ³ BCD-085 Q4W vs. placebo (Fisher's exact test)

Comparison of secondary effectiveness measures (proportion of patients who achieved PASI 75, PASI 90, PASI 100, sPGA 0-1, relative change expressed in PASI scores, reduction in the severity of itching on the VAS scale, improvement in the condition of the nail plates on the NAPSI index, changes quality of life according to the DLQI questionnaire, criteria of the American College of Rheumatology 20/50/70, reduction of symptoms in patients with psoriatic arthritis) confirmed the results obtained after assessing the main criterion (Table 29, Fig. 18-23).

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Efficacy of BCD-085 in the BCD-085-7 study at weeks 8 and 12 of treatment (ITT population, n=213)

Table 29

Evaluation criterion 1 ruin 1 le.ie. io 8 Pedelya 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 ¹ <0.0001 ² <0.0001 ³ 0.4603 ¹ <0.0001 ² <0.0001 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 ¹ <0.0001 ² <0.0001 ³ 1.0000 ¹ O.OOO ² <0.0001 ³ PASI 100 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 ¹ 0.0012 ² 0.0012 ³ 0.7013 ¹ <0.0001 ² <0.0001 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 ¹ <0.0001 ² <0.0001 ³ 0.9698 ¹ <0.0001 ² <0.0001 ³

^CD-OSS Q2W vs. BCD-085 Q4W (Chi-square test with Yates correction), ² BCD-085 Q2W vs. placebo (Fisher's exact test), ³ BCD-085 Q4W vs. placebo (Fisher's exact test)

Safety study results (first 12 weeks).

The use of BCD-085 during the 12-week study was well tolerated and demonstrated a favorable safety profile (Table 30). There were no cases of premature discontinuation of study participation due to safety concerns during the study. A focal reaction was found in one patient (2.27%) in the placebo group (redness at the injection site). No cases of unexpected toxicity were observed.

There was one grade 3 treatment-related SAE (pneumonia) per CTCAE 4.03 criteria in the BCD-085 Q4W arm. Grade 3 neutropenia was observed in 1 patient in the BCD-085 Q2W group, and elevated creatinine was observed in 1 patient in the placebo group. Other AEs were mild or moderate. There were no statistically significant differences in the frequency of registration of AEs between the groups (Table 31).

Table 30

Evaluation of drug safety results after 12 weeks of treatment (study BCD-085-7)

llapaneip BCD-085 Q2W (11=85) BCD-085 Q4W (11=84) 11. laneoo (11=44) r-shaceppe \ η O eleven η Proportion of patients who developed AEs 15 17.65 14 16, 67 8 18.18 0.9735 ¹ Proportion of patients who developed SAEs 0 0.00 1 1.19 0 0.00 0.60092 ² Proportion of patients who developed grade 3-4 AEs 1 1.18 1 1.19 1 2.27 1.0000 ² Proportion of patients with injection site reactions 0 0.00 0 0.00 1 2.27 0.2066 ² Proportion of patients who discontinued study treatment due to an AE/SAE. 0 0.00 0 0.00 0 0.00 1.0000 ²

¹ -X ² Pearson test with Yates correction, ² - exact version of Fisher test.

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Table 31

Safety profile after 12 weeks of treatment (study BCD-085-7)

11same. ia io. ibiioe manifestly BCD-085 Q2W (11=85) BCD-085 Q4W (11=84) 11.1 and the sky (11=44) rummaging % % λ Cardiovascular diseases High blood pressure (grade 2) 0 0.00% 1 1.19% 0 0.00% 0.60 ¹ Elevated systolic blood pressure (grade 2) 1 1.18% 0 0.00% 0 0.00% 1.00 ¹ Elevated diastolic blood pressure (grade 2) 0 0.00% 1 1.19% 0 0.00% 0.60 ¹ Signs of focal myocardial ischemia on ECG (grade 1) 1 1.18% 0 0.00% 0 0.00% 1.00 ¹ Infectious diseases Upper respiratory tract infection (grade 2) 0 0.00% 0 0.00% 1 2.27% 0.21 ¹ Upper respiratory tract infection (grade 2) 0 0.00% 0 0.00% 1 2.27% 0.2 G Follicular tonsillitis (grade 2) 1 1.18% 0 0.00% 0 0.00% 1.00 ¹ Pneumonia (grade 3) 0 0.00% 1 1.19% 0 0.00% 0.60 ¹ Urinary tract infection (grade 2) 1 1.18% 0 0.00% 0 0.00% 1.00 ¹ Diseases of the skin and subcutaneous tissue Erythema (1st degree) 0 0.00% 0 0.00% 1 2.27% 0.21 ¹ Eczema (2 degrees) 1 1.18% 0 0.00% 0 0.00% 1.00 ¹ General reactions and reactions to injection Injection reaction: dizziness (1 tbsp.) 1 1.18% 1 1.19% 0 0.00% 1.00 ¹ Abdominal pain (grade 2) 0 0.00% 1 1.19% 0 0.00% 0.60 ¹ Laboratory abnormalities Hyperhemoglobinemia (grade 2) 1 1.18% 0 0.00% 0 0.00% 1.00 ¹ Thrombocytopenia (1st degree) 0 0.00% 1 1.19% 0 0.00% 0.60 ¹ Leukopenia (total number) 1 1.18% 2 2.38% 0 0.00% 0.6 G • 1 tbsp. 0 0.00% 1 1.19% 0 0.00% 0.60 ¹ • 2 tbsp. 1 1.18% 1 1.19% 0 0.00% 1.00 ¹ Neutropenia (total number) 3 3.53% 1 1.19% 0 0.00% 0.54 ¹ • 2 tbsp. 2 2.35% 1 1.19% 0 0.00% 0.80 ¹ • 3 tbsp. 1 1.18% 0 0.00% 0 0.00% 1.00 ¹ Lymphocytosis (grade 2) 1 1.18% 0 0.00% 1 2.27% 0.68 ¹ Hyperbilirubinemia (grade 2) 4 4.71% 2 2.38% 1 2.27% 0.70 ¹ Increased ACT activity (2 tbsp.) 1 1.18% 1 1.19% 0 0.00% 1.00 ¹ Increased ALT activity (2 degrees) 1 1.18% 0 0.00% 0 0.00% 1.00 ¹ Hypercholesterolemia (2 degrees) 1 1.18% 1 1.19% 0 0.00% 1.00 ¹ Hyperglycemia (2 degrees) 0 0.00% 3 3.57% 0 0.00% 0.17 ¹ Increase in serum creatinine (3 tbsp.) 0 0.00% 0 0.00% 1 2.27% 0.2 G Proteinuria (total quantity) 1 1.18% 0 0.00% 2 4.55% 0.11 ¹ • 1 tbsp. 1 1.18% 0 0.00% 1 2.27% 0.68 ¹ • 2 tbsp. 0 0.00% 0 0.00% 1 2.27% 0.2 G Τι deputies Thermal burn (1st degree) |0 0.00% |0 |0.00% |1 |2.27% 10.21 ^{1 1} - exact version of Fisher's test.

Immunogenicity study results (first 12 weeks).

The immunogenicity assay was based on data obtained from 209 patients who received at least one dose of study drug and provided at least two blood samples for analysis, one of which was collected before the first dose 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 collected at week 0 before injection and at week 12 of treatment.

Table 32

Immunogenicity assessment after 12 weeks of treatment (study BCD-085-7)

BCD-085 Q2W BCD-085 Q4W 11. laneoo p-value ¹ (11=85) (n=81) (n=43) \ ABOUT η ABOUT \ P Proportion of patients with VAL 1 1.18 0 0 0 0 1,000 Proportion of patients with NAb undefined ¹ - exact version of Fisher's test.

Immunogenicity assessment showed the presence of binding antibodies in one patient from the group at

- 70 046015 administration of the drug BCD-085 according to the Q2W regimen after 12 weeks of treatment. No neutralizing activity was detected (Table 32).

Conclusion.

83.3 and 77.7% of Patients from the BCD-085-Q4W, BCD-085-Q2W groups achieved PASI75 by week 12 of treatment (p = 0.46 for BCD-085-Q4W compared with BCD-085-Q2W) by Compared with 0% in the placebo group (p<0.0001), sPGA (0-1) was achieved in 79.8, 81.2 and 2.27% of patients in the BCD-085-Q4W, BCD-085- Q2W and placebo, respectively. Adverse events (AEs) were recorded in 17.7, 16.7 and 18.2% of patients in the BCD-085-Q4W, BCD-085-Q2W, placebo groups (p=1.0), respectively. There was one treatment-related grade 3 SAE (pneumonia) (according to CTCAE 4.03 criteria) in the BCD-085-Q4W group. Grade 3 neutropenia was observed in 1 patient in the BCD-085-Q2W group, and elevated creatinine was observed in 1 patient in the placebo group. Other AEs were mild or moderate (abnormalities in laboratory parameters were most often recorded); no focal reactions were observed in the BCD-085 treatment groups. Drug binding antibodies were detected in one patient (1.18%, BCD-085-Q2W group). No neutralizing antibodies were detected.

Example 7. Efficacy of Netakimab with standard and low-frequency dosing regimens in the treatment of psoriatic arthritis (PsA), additional proof-of-concept study (BCD-085-7).

Clinical trial design.

Study BCD-085-7, described in Example 6, assessed the efficacy of Netakimab compared to placebo in a limited population of patients with psoriatic arthritis at baseline. The endpoint for assessing psoriatic arthritis during this period was the proportion of patients (patients with psoriatic arthritis) who achieved 20, 50, 70% symptom reduction according to American College of Rheumatology criteria (ACR 20/50/70) by week 12 of treatment. This parameter was assessed by determining the number of swollen/tender joints 66/68, functional activity (HAQ-DI, patient-rated), disease activity assessment (assessed by physician and patient), patient pain score (VAS), and determination of inflammatory markers (CRP and ESR ).

Results.

The psoriatic arthritis evaluation population included 15 patients (6 in the BCD-085 Q2W group, 7 in the BCD-085 Q4W group, and 2 in the placebo group). One patient (BCD-085 Q4W group) included in this population (case ID 10-131) was withdrawn at visit 7 (week 10), i.e. before assessment at visit 8 (week 12). This patient was classified as having no clinical response to treatment.

Table 33

Proportion of patients achieving 20% symptom reduction according to American College of Rheumatology (ACR 20) criteria (among patients with psoriatic arthritis, n=15)

1 r\ppa treatment Share iiaiuieinoB. losin shp\ 2<)o reduction simi ι oma ι ikn coi.iacuo krterpyam Kmerpkanskop co. i.iei nor rheumay.101 pi (ACR 20) at visit 8 (week 12). η 15 R-'.painting Aoco.noi share value O Group BCD-085 taking the drug according to the Q2W regimen, n=6 5 83.33 1.0001 ¹ Group BCD-085 taking the drug according to the Q4W regimen, n=7 6 85.71 Placebo group, n=2 0 0 0.10712 ² 0.08333 ³

¹ Comparison of the BCD-085 Q2W group with the BCD-085 Q4W group (Fisher's exact test), ² Comparison of the BCD-085 Q2W group with the placebo group (Fisher's exact test), ³ Comparison of the BCD-085 Q4W group with the placebo group (Fisher's exact test)

- 71 046015

Table 34

Proportion of patients achieving 50% symptom reduction according to American College of Rheumatology (ACR 50) criteria (among patients with psoriatic arthritis, n=15)

1 treatment per treatment Share of papists, losin quiet 5o ^1, <> reduction of sim। oma । iki coi lasno krternyam Kmerpkapskop ko.i.ici ni revmayu.101 mon (\CR 5()) at iioceiiieiiini X (week 12). η 15 R- '.started Aoco.iioi share value °." Group BCD-085 taking the drug according to the Q2W regimen, n=6 3 50 0.59211 ¹ Group BCD-085 taking the drug according to the Q4W regimen, n=7 2 28.57 Placebo group, n=2 0 0 0.46432 ² 1.0003 ^{3 1} Comparison of the BCD-085 Q2W group with the BCD-085 Q4W group (Fisher's exact test), ² Comparison of the BCD-085 Q2W group with the placebo group (Fisher's exact test), ³ Comparison of the BCD-085 Q4W group with the placebo group (Fisher's exact test)

Table 35

Proportion of patients achieving 70% symptom reduction according to American College of Rheumatology (ACR 70) criteria (among patients with psoriatic arthritis, n=15)

1 healing ruin Papist share. dosι ιιι ιιπιχ 70% reduction in ci 1mijoma11ικιi coi.iacuo krternam American ko.i.ici nor rheumay.101 ιπι (ACR 70) at visit 8 (week I2).n 15 R-shaceppe Aoco.iioia value 0/ o Group BCD-085 taking the drug according to the Q2W regimen, n=6 1 16.67 1.0001 ¹ Group BCD-085 taking the drug according to the Q4W regimen, n=7 1 14.29 Placebo group, n=2 0 0 1.0002 ² 1.0003 ³

¹ Comparison of the BCD-085 Q2W group with the BCD-085 Q4W group (Fisher's exact test), ² Comparison of the BCD-085 Q2W group with the placebo group (Fisher's exact test), ³ Comparison of the BCD-085 Q4W group with the placebo group (Fisher's exact test)

Conclusion.

Analysis of patients with psoriatic arthritis (n=15) showed that ACR 20 by week 12 of treatment was achieved in 83.33, 85.71 and 0% of patients in the BCD-085 Q2W group, the BCD-085 Q4W group and the placebo, respectively (Table 33, Fig. 23). ACR 50 was achieved in 50, 28.57 and 0% of patients in the BCD-085 Q2W group, BCD-085 Q4W group and placebo group, respectively (Table 34, Fig. 23). ACR 70 was achieved in 16.67, 14.29 and 0% of patients in the BCD-085 Q2W group, BCD-085 Q4W group and placebo group, respectively (Table 35, Fig. 23). Assessment at 12 weeks of treatment showed no significant differences between groups on any parameter. This may be due to the small number of patients or the assessment being carried out too early. However, the response according to the ACR 20 criterion demonstrates pronounced positive dynamics in almost all patients with psoriatic arthritis who received the drug BCD-085.

Example 8: Netakimab at different doses for the treatment of ankylosing spondylitis (AS), proof of concept study (BCD-085-3).

Clinical trial plan.

BCD-085-3 (NCT02763111) is a phase II, double-blind, randomized, multicenter study in patients with acute ankylosing spondylitis. The primary goal was to establish a therapeutically effective and safe dose of BCD-085 that can be administered as multiple injections to patients with acute ankylosing spondylitis.

Patient population and clinical trial design.

The study included 88 patients with ankylosing spondylitis in the acute stage, aged 18 to 65 years inclusive, who were diagnosed with AS (modified New York criteria, 1984), level 4 on the BASDAI scale or higher, with an inadequate response to NSAIDs taken for a period of time. less than 3 months before screening who met other eligibility criteria. Patients who had previously received treatment with monoclonal antibodies that bind to IL17 (or the IL17 receptor) and patients who had previously received

- 72 046015 treatment with 2 or more therapeutic monoclonal antibodies. After the examination, patients were randomly distributed into groups in a ratio of 1:1:1:1 into 4 groups: 1) BCD-085 at a dose of 40 mg; 2) BCD-085 at a dose of 80 mg; 3) BCD-085 at a dose of 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 in the 40 mg and 80 mg dose groups received 2 or 1 subcutaneous placebo injections (1 ml each), respectively. Patients in the control group received 3 subcutaneous injections of placebo (each injection 1.0 ml). The placebo used in all three groups had a similar composition, which includes excipients from the dosage form of the drug BCD-085. Patients were observed until 16 weeks.

The study hypothesis was that BCD-085 was superior to placebo in terms of efficacy in patients with acute ankylosing spondylitis. The marginal performance criterion (δ) was 0.1 (10%), type 1 error (α) -5% (0.05), type 2 error (β) 20% (0.2) and power 80 %.

The primary outcome measure is the proportion of patients in each study arm who achieved ASAS20 improvement criterion 75 by week 16 of the study. Secondary outcome measures include assessment of improvement criteria ASAS40 and ASAS5/6, mean change from baseline in BASDAI, BASMI, MASES, BASFI, ASDAS-CRP and chest expansion, change in 24-hour pain scale and mean C-reactive concentration protein, as well as quality of life (QoL) assessment. Primary efficacy endpoints were assessed at weeks 0, 4, 8, 12 and 16. Safety criteria included the incidence of adverse events (AEs), serious adverse events (SAEs), grade 3-4 AEs according to CTCAE 4.03 criteria, and the incidence of early study termination due to AEs. The pharmacokinetic criteria assessed included standard pharmacokinetic parameters (Cmin, AUC( _0-168 ), AUC( _0-672 ), Tmax, T1/2, Vd, Kel, CL). The immunogenicity analysis included determining the frequency of binding and neutralization of antibodies to the drug BCD-085 after multiple injections of the drug.

Results.

The groups did not differ from each other in demographic and baseline characteristics (Table 36).

Table 36

Baseline patient characteristics (study BCD-085-3)

Parameter 1)(1)-085 40 mg X=22 1)(1)-085 80 mg X=22 1)(1)-085 120 mg X=22 Placebo X=22 Age (years), median [IQR] 40.0 [33.0-44.0] 34.0 [31.0-36.0] 38.0 [35.0-44.0] 41.0 [32.0-47.0] Map, n (%) 17 [77.27] 19 [86.36] 22 [100.0] 15 [68.18] Body weight (kg), median [IQR] 75.5 [61.0-93.0] 79.0 [63.0-86.1] 79.1 [71.5-85.0] 81.3 [75.0-90.0] Duration of AS (months), median [IQR] 26.5 [11-75] 37.5 [20-56] 46.5 [13-96] 26.5 [10-48] Back pain, total (0-10 scale), median [IQR] 7.5 [6-8] 7 [6-8] 7 [6-8] 7 [6-7] BASDAI, total score, median [IQR] 6.45 [5.4-7.4] 6.7 [5.8-7.1] 6.45 [4.7-7.3] 5.95 [5.1-7] BASFI, total score, median [IQR] 5.9 [4.3-7.2] 5.95 [4.5-6.9] 5.55 [3.9-6.8] 6 [4-6.7] BASMI, total score, median [IQR] 4.65 [3.2-5.2] 4.5 [2.8-5.1] 4.15 [3.5-5.4] 4.55 [3.3-5.1] Chest expansion, cm, median [IQR] 3.5 [3-4] 3.5 [2-4] 3 [3-4] 3 [3-5] Previous use of anti-TNFa, n(%) 4 [18.18] 2 [9.09] 3 [13.64] 4 [18.18] Note: IQR - interquartile range

The main outcome measure was the proportion of patients responding to treatment according to the ASAS20 index at week 16. In all groups taking BCD-085, the proportion of patients responding to treatment according to the ASAS20 index at week 16 was above 70%, while in the placebo group only about 40% of patients were responding to treatment.

The analysis showed that BCD-085 in doses of 80 and 120 mg was superior to placebo in patients with ankylosing spondylitis in the acute stage. The results of achieving the ASAS20 criterion are shown below. To prove the hypothesis recorded in the protocol that the drug

- 73 046015

BCD-085 is superior to placebo, 95% CIs for the difference in proportions of ASAS20 criterion achievement were calculated (individual pairwise comparisons were conducted for the placebo group versus each BCD-085 group). A hypothesis was accepted if the lower bound of the estimated 95% CI for the difference in ASAS 20 achievement ratios was greater than the prespecified clinically insignificant difference (δ) limit of 10% (0.10). The results are presented in table. 37.

Table 37

Difference in quantitative ratios of the ASAS20 indicator (study BCD-085-3)

Rashina in dos ι nzhepnn AS.AS2O . 1overp ι elnyn shperva. ι 95% r-shachenpe ¹ Groups 1 and 4 29.87% [1.69%; 58.05%] 0.0472 Groups 2 and 4 38.96% [12.36%; 65.56%] 0.0082 Groups 3 and 4 48.05% [23.71%; 72.39%] 0.0008

Note: 1 - bilateral X2 test

Table 37 indicates that the lower bounds of the 95% CI for pairwise comparisons (placebo and BCD-085) between groups 2, 4 and groups 3, 4 are outside the prespecified efficacy criterion. Thus, the hypothesis that BCD-085 is superior to placebo in the treatment of patients with acute ankylosing spondylitis was accepted and the primary objective of the clinical trial was achieved. It should be noted that higher efficacy of BCD-085 over placebo was proven for the tested doses of 80 and 120 mg.

ASAS20 at week 12 was recorded in 72.73% of patients in group 1, 81.82% in group 2 and 90.91% in group 3 versus 23.1% receiving placebo (p=0.0043 for groups 1, 2, 3 versus placebo, Fig. 24).

Table 38

Proportion of patients with ASAS20, ASAS40 and ASAS5/6 responses during the study (study BCD-085-3)

1 ruin ASAS2Oη (%) ASAS4O η (%) ASAS5/6 η (%) R-shachenpe 1 Week 4 1 (n=22) 16 (72.73%) 9 (40.91%) 10 (45.45%) /<=0.0039 P;=0.0246 /<=0.0024 2(n=22) 17 (77.27%) 14(63.64%) 12 (54.55%) 3 (n=22) 18 (81.82%) 11 (50.00%) 13 (59.09%) 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%) /<=0.0140 /<=0.0593 /<=0.0007 2 (n=22) 16 (72.73%) 13 (59.09%) 12 (54.55%) 3 (n=22) 17 (77.27%) 10(45.45%) 11 (50.0%) 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%) /<=0.0214 /<=0.0069 /<=0.0809 2 (n=22) 16 (72.73%) 13 (59.09%) 12 (54.55%) 3 (n=22) 19 (86.36%) 15 (68.18%) 13 (59.09%) 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%) /<=0.0043 Рз= 0.0004 /<=0.0027 2 (n=22) 18 (81.82%) 14 (63.64%) 12 (54.55%) 3 (n=22) 20 (90.91%) 16 (72.73%) 15 (68.18%) 4 (n=21) 9 (42.86%) 3 (14.29%) 3 (14.29%) Note: 1 - two-sided Fisher's exact test / two-sided x2 test; P2 - assessment ASAS20; RZ - ASAS40 score; P4 - ASAS score 5/6 *Group 1: BCD-085 40 mg; Group 2 - BCD-085 80 mg; Group 3 - BCD-085 120 mg; Group 4 - placebo)

The results of indicators ASAS20, ASAS40, ASAS 5/6 are presented in table. 38 (Fig. 25).

The percentage of patients achieving ASAS20, ASAS40, ASAS 5/6 criteria was higher in the BCD-085 groups, especially in the 120 mg dose group. Other secondary endpoints showed similar changes, with all BCD-085 groups demonstrating better response to treatment compared with the placebo group. All secondary indicators showed significant improvement by the time of the second control compared to screening. The achieved response to the treatment was maintained throughout the entire study period.

- 74 046015

Pharmacokinetics.

Following single administration of BCD-085 at doses of 40, 80 and 120 mg, the drug was detectable in the serum for 0.5-4 hours post-dose. Its concentration changed over time in the same way for all doses (Fig. 26). Changes in BCD-085 drug concentrations were proportional to the dose administered. Cmax and _AUC ( _0.168 ) had strong dose-dependent effects.

Subsequent use of the drug BCD-085 led to a gradual increase in its concentration without obvious signs of accumulation (Fig. 27).

Safety.

The safety analysis included all patients who received at least one dose of BCD-085 (n=88, Table 39). At least one case of AE/SAE was reported in 45.45% of patients (group 1), 27.27% of patients (group 2), 18.18% of patients (group 3) and 31.82% of patients (group 4) (p=0.298). Treatment-related AEs were assessed in 22.73% of patients in group 1, 18.18% of patients in group 2, 4.55% of patients in group 3 and 22.73% of patients in group 4 (p=0.354) . Grade 3-4 AEs were recorded in 4.55% of patients in groups 1 and 4, and in 9.09% in group 2. The most common AEs were neutropenia and increased lower blood pressure. Most AEs were mild. No focal reactions were reported.

One patient withdrew from the clinical study prematurely due to an AE in the BCD-085 80 mg group. No serious adverse events, focal reactions, or deaths were reported.

Table 39

Summary of safety data (study BCD-085-3)

Variables BCD-085 40 mi Х=22 BCD-085 80 mi X=22 В(1)-085 120 mi Х=22 Plapebo X=22 rshachenne ¹ At least 1 AE 11 (5i.i.) 0 (27.27) 4 (18.18) 7 (31.82) i.183 At least 1 TN 5 (22.73) 4 (18.18) 1 (4.55) 5 (22.73) 0.354 Severe AE 1 (4.55) 2 (9.09) 0 1 (4.55) 0.900 Severe TN 0 1 (4.55) 0 1 (4.55) 1.00 Withdrawal from the study due to AEs 0 1 (4.55) 0 0 1.00 List of severe AEs Anemia (grade 3) 0 0 0 1 (4.55) 1.00 Neutropenia (grade 4) 0 1 (4.55) 0 0 1.00 Erosive colitis (grade 3) 0 1 (4.55) 0 0 1.00 Episcleritis (grade 3) 1 (4.55) 0 0 0 1.00

Immunogenicity.

The immunogenicity assessment population consisted of 85 patients (those who received at least one injection of study drug and provided at least two blood samples for analysis, one of which was drawn before the first dose on day 1, week 0). Blood samples were collected at week 0 before injection, at weeks 8, and at week 16 of treatment. Immunogenicity assessment did not reveal the presence of any binding antibodies against BCD-085 in any patient.

Conclusion.

Treatment with BCD-085 leads to a significant improvement in all symptoms of AS compared to placebo. The drug BCD-085 at a dose of 120 mg showed the most pronounced effect. This drug was well tolerated at all doses with no difference in safety profile compared to placebo.

Example 9. Long-term use of the drug Netakimab in patients with ankylosing spondylitis (study BCD-085-3ext).

Clinical trial design.

The BCD-085-3ext study is a multicenter, open-label, Phase II extension study of the efficacy and safety of BCD-085 80 mg and 120 mg in patients with ankylosing spondylitis who completed the BCD-085-3 study as per protocol. The main objective was to evaluate the effectiveness and safety of maintenance therapy (up to 1 year) using BCD-085. The study has been completed and the results have been analyzed.

When the duration of follow-up in the main study BCD-085-2 (16 weeks) and its extension phase BCD-085-2ext (40 weeks) are combined, the total follow-up time per subject in both studies was 56 weeks (about 1 year) ( Fig. 28).

Patient population and clinical trial design.

This study included 81 patients who completed the BCD-085-3 study at

- 75 046015 in accordance with the protocol. Patients who did not achieve ASAS20 (non-responder) after the BCD-085-3 study received BCD-085 at a dose of 120 mg according to the Q2W regimen for up to 1 year, patients who achieved ASAS20 after the BCD-085-3 study , received BCD-085 at a dose of 80 mg according to the Q2W regimen for up to 1 year.

During the BCD-085-2ext study, patients were treated in two groups:

group 1: BCD-085 at a dose of 80 mg;

group 2: BCD-085 at a dose of 120 mg.

The primary outcome measure was the proportion of patients in each study arm who achieved ASAS20 criterion at week 36 of the BCD-085-ext study. Secondary outcome measures include assessment of ASAS40 and ASAS5/6 criteria, mean change from baseline in BASDAI, BASMI, MASES, BASFI, ASDAS-CRP and chest expansion, change in 24-hour pain scale, and quality of life assessment ( QoL). Primary efficacy endpoints were assessed at weeks 12, 24 and 36 of the BCD-085-2ext study (weeks 28, 40 and 52 of treatment). Safety criteria included the incidence of adverse events (AEs), serious adverse events (SAEs), grade 3-4 AEs according to CTCAE 4.03 criteria, and the incidence of early study termination due to AEs. Immunogenicity parameters included the frequency of binding and neutralization of antibodies to BCD-085 after one year of treatment (week 40 of the BCD-085-3ext study).

Results.

In general, based on the results of the effectiveness assessment, it was established that long-term (more than a year) therapy with BCD-085 provides high efficiency that persists over time;

long-term use of BCD-085 was not associated with high rates of loss of efficacy;

Using the study drug at a dose of 120 mg allows more patients to respond to therapy, including patients in whom the use of BCD-085 for 16 weeks did not lead to a clinical response.

Response assessment according to ASAS criteria (ASAS20/40, ASAS5/6) showed that more than 70% of patients at each time point of the open-label extension study achieved an appropriate response to therapy, regardless of the dose used. In addition, the proportion of patients achieving ASAS20 criterion at week 52 of the open-label extension study was 79.01% (86.42% using the last documented value method). The proportion of patients achieving ASAS40 within one year of therapy was 71.60% (77.78% using the last documented value method).

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

Table 40

Key efficacy data from the BCD-085-3ext study (regardless of dosage regimen)

11a frame ι r BCD-08 Initial characteristics of the neck >-3 Pedelya 16 11food 1st 28 BCD-085-Zeh 11food 1st 40 11food (I'm 52 r ¹ siia'iemie Index BASDAI 6.3 2.9 2.1 2.2 2.25 <0.0001 Index BASMI 4.5 3.6 3.4 3.2 3 <0.0001 MASES indicator 3 0 0 0 0 <0.0001

- 76 046015

Breathing excursion 3 4 4 4 4 <0.0001 Index BASFI 5.9 3.2 2.2 2.3 1.9 <0.0001 Index ASDAS-CRP 3.92 2.25 1.83 1.825 1.845 <0.0001 SF-36 (physical component) 31.2 39.5 41.6 n/a 43, 9 <0.0001 SF-36 (psychological component) 40.5 49.4 53.4 n/a 54.1 <0.0001 Pain Rating, NRS 7 3 2 2 2 <0.0001 Nyctalgia Rating, NRS 7 2 2 2 1 <0.0001 Note: Friedman test

Thus, we can conclude that treatment with BCD-085 leads to a significant improvement in most symptoms of AS, which develops mainly within the first month after the start of therapy and persists throughout the year of treatment.

Assessment of the loss of the achieved effect with increasing duration of therapy.

Analysis of the dynamics of responses to the ASAS20/40 criterion did not reveal a trend towards a decrease in response during the open-label additional study. Overall, loss of response to treatment was noted in 4.76% of patients.

Data on the long-term effectiveness of BCD-085 in doses of 80 and 120 mg.

Long-term use of BCD-085 at a maximum dose of 120 mg results in high efficacy in patients who did not respond sufficiently to treatment within the first 16 weeks. At the end of the open-label extension study period, responses according to ASAS20/40, ASAS5/6 criteria were achieved in 63.16, 52.66 and 52.66% of patients, respectively.

For other secondary indicators, the presence of similar dynamics over a long period of time was shown (Table 41).

Table 41

Key efficacy parameters of BCD-085 at doses of 80 and 120 mg in phase 2 studies (BCD-085-3 and BCD-085-3ext)

1 (parameter BCD-O85-3 BCD-085-ZeM P ¹ value Pedelya 16 Week 2S Week 40 Week 52 Index BASDAI BCD-O85 80 mg 2.45 1.U 2 1.9 <0.0001 BCD-085 120 mg 5.8 3.3 3 3.2 <0.0001 BASMI indicator 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 indicator BCD-085 80 mg 0 0 0 0 0.0003 BCD-085 120 mg 1 0 0 0.0007 Breathing excursion BCD-085 80 mg 4 4.5 4 4 0.1759 BCD-085 120 mg 4 4 4 4 0.3012 BASFI indicator 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 score BCD-085 80 mg 2.135 1.695 1.65 1.61 <0.0001 BCD-085 120 mg 3.77 2.48 2.45 2.5 <0.0001 SF-36 (physical component) BCD-085 80 mg 40.1 42.95 n/a 44.6 0.0018 BCD-085 120 mg 34.2 36.9 n/a 38.3 0.1504 SF-36 (psychological component) BCD-085 80 mg 50.80 53.35 n/a 54.6 0.0477 BCD-085 120 mg 43.5 54 n/a 50.3 0.0032 NRS Pain Rating (NRS) BCD-085 80 mg 3 2 2 2 <0.0001 BCD-085 120 mg 7 3 3 3 <0.0001 NRS Pain Rating (NRS) BCD-085 80 mg 2 1.5 1 1 <0.0001 BCD-085 120 mg 5 3 3 3 0.0001

Note: ¹ - Friedman test; repeated observations analysis of variance

Data indicate that patients in arm 1 (80 mg) had low values for all major measures of ankylosing spondylitis activity at enrollment in the BCD-085-3ext study (week 16 of the BCD-085-3 study). Further use of the drug led to a stabilization of the effect (the average values of most indicators reached a plateau).

Patients from group 2 (120 mg) were characterized by initially higher values of all

- 77 046015 new indicators at inclusion in the study (1.5-2 times higher than in the 80 mg group), which is associated with insufficiency of ASAS20 in the previous 16 weeks of treatment in the main study. The use of BCD-085 at a dose of 120 mg during the open-label additional study leads to a pronounced and statistically significant decrease in BASDAI, BASFI, BASMI and pain scores. Thus, the BASDAI index, which reflects the activity of ankylosing spondylitis, in this group was 3.2, which corresponds to the inactive stage of the disease. According to ASAS-EULAR2016 recommendations, changes in ASDAS scores >1.1 and BASDAI scores >2 are considered clinically significant. The data presented in the table above indicate the presence of these changes in the 120 mg BCD-085 group, confirming the significance of the effects.

Safety.

The safety analysis was performed on all patients who received at least one dose of BCD-085 in the BCD-085-3ext study (n=81).

Overall, at least one AE was reported in 40.74% (33) of participants, while treatment-related AEs were reported in 28.40% (23) of patients. During the entire study period, there were no cases of SAEs, grade 4 AEs, or deaths (Table 42).

During the BCD-085-3ext study, two cases of early withdrawal from the study were recorded due to the occurrence of AEs (microbial eczema, positive blood test for tuberculosis).

Table 42

Key drug safety data from the BCD-085-3ext study

Description οι κ.ιοιιοιιιιιί Share iiamieiiiOB (η 81) Any AE 33 (40.74%) Any SAE 0 (0.00%) Treatment-related AEs 23 (28.40%) AE grade 3 4 (4.94%) Grade 3 AEs related to treatment 2 (2.47%) Focal reactions 1 (1.23%) Withdrawal from the study due to AEs 2 (2.47%)

Most AEs were isolated cases throughout the study. Reported AEs were mainly related to infectious diseases, disorders of the blood and lymphatic system, as well as disorders of the liver and biliary tract. Cardiovascular disorders were less common.

Reported AEs, including treatment-related ones, were mostly mild to moderate (grade 1-2 according to CTCAE 4.03 criteria), which allows us to conclude that BCD-085 showed a favorable safety profile. There were four patients with high-grade AEs such as neutropenia, elevated GGT, acute upper respiratory tract infection, and elevated blood pressure. Two cases of increased blood pressure (grade 3), recorded in one patient, required drug therapy and were eliminated without consequences.

The likelihood of AEs was considered based on the 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). BCD-085-3ext, the only unexpected AE reported was facial paresthesia.However, nervous system disorders accompanied by sensory impairment (facial palsy, sciatica) have been previously described for Secukinumab and Ixekizumab, which may indicate some likelihood of such an AE occurring in patients treated with IL-17 inhibitors.

A case series of AEs has been reported and is of interest as part of the safety assessment of therapeutic monoclonal antibodies in general and interleukin-17 inhibitors in particular.

Two cases of positive blood tests for tuberculosis were reported in the presence of a normal chest radiograph and without any other evidence of active tuberculosis.

One case of stage 2 mycosis (esophageal candidiasis) (1.23%) was identified. This AE was treated without consequences as part of standard therapy.

According to the presented protocol, no manifestations of such an AE as ankylosing spondylitis were recorded. In this regard, it is necessary to note the case of iridocyclitis, which was interpreted by researchers as a manifestation of ankylosing spondylitis and was not registered as an AE. Iridocyclitis was cured without consequences as part of standard therapy.

Given the route of administration of BCD-085 (subcutaneous injection), focal reactions were expected. The proportion of patients with focal reactions was 1.23% (2 focal reactions were registered

- 78 046015 were observed in one patient, represented by hyperemia, edema, itching, pain and the formation of focal infiltrate), which indicates a low incidence of this unfavorable phenomenon.

During the entire study period, there were no cases of the formation of antibodies to narcotic substances.

Thus, the use of BCD-085 throughout the year in patients with AS demonstrates a favorable safety profile and good tolerability. This drug is characterized by a low likelihood of focal reactions and SAEs; the incidence of SAEs did not increase during therapy. Comparison with available safety data for other monoclonal antibodies against interleukin-17 (secukinumab, ikekizumab) indicates comparability of their safety profiles.

Conclusion.

Long-term use of BCD-085 at a dose of 120 mg has been shown to achieve treatment response even in patients with a delayed response (who did not achieve the ASAS20 score at 16 weeks), for example, after 1 year of treatment, ASAS20/40 scores and ASAS5/6 were obtained in 63.16, 52.66 and 52.66% of patients, respectively. The safety analysis showed that long-term use of BCD-085 was well tolerated by patients; the immunogenicity analysis did not reveal any cases of the formation of antibodies to the drug.

Example 10. Efficacy of Netakimab in the treatment of patients with ankylosing spondylitis (study BCD-085-5).

Clinical trial design.

BCD-085-5 is an ongoing, double-blind, multicenter, placebo-controlled, Phase III study in patients with acute ankylosing spondylitis. The main objective of the study is to evaluate the effectiveness and safety of BCD-085 compared to placebo in the treatment of patients with ankylosing spondylitis in the acute stage.

The BCD-085-5 study uses 60 mg/1 mL of BCD-085 in prefilled syringes. Route of administration: subcutaneous injections with 2 pre-filled syringes (2 subcutaneous injections over 15 minutes) at 0, 1, 2 weeks and then every other week for 3 years of treatment.

Patient population and clinical trial design.

The study included 228 patients with acute ankylosing spondylitis, aged 18 to 65 years inclusive, who met the eligibility criteria. Patients must have been diagnosed with ankylosing spondylitis according to the modified New York criteria (1984) at least 3 months before signing the FIS (informed consent form). Patients previously treated with monoclonal antibodies that bind to IL17 (or IL17 receptor) and patients previously treated with 2 or more anti-TNF-alpha antibody drugs were not included in the study. After the examination, patients were randomly distributed into groups in a 1:1 ratio into 2 groups: 1) BCD-085 at a dose of 120 mg; and 2) placebo. Patients received BCD-085/placebo in a blinded manner on day 1 at weeks 0, 1, 2, 4, 6, 8, 10, 12, and 14. Beginning at week 16 of treatment, the study is open-label and patients in both arms begin receiving BCD-085 120 mg on a Q2W schedule (except for placebo responders: patients achieving ASAS20 at week 14 in this arm excluded from the study). Upon completion of the control treatment at week 154 (week 170 for patients initially randomized to placebo), patients will undergo a 4-week follow-up to assess safety.

Results.

Data are presented for the first 16 weeks.

Patient characteristics at baseline were similar between treatment groups. The mean age at baseline was 39.14 ± 9.99 years, 75.88% of patients were male, and the mean duration of symptoms was 4.3 ± 4.48 years. All patients had AS in the acute stage (average BASDAI score: 6.21±1.55); 76.8% of patients did not receive any biological treatment. At week 16, ASAS40 response was higher in the BCD-085 group compared with placebo: 40.35% and 2.63% of patients, respectively (95% CI for difference in ASAS40 response rate was [27.37 ; 48.07%] (p < 0.0001, Fig. 29) The superior efficacy of BCD-085 was also confirmed by comparison of all other secondary efficacy measures (Fig. 30), and the improvement in BASDAI, MASES and BASFI scores was significant from week 4 and values remained low throughout this study.

At the time of inclusion in the study, both groups were comparable on the Berlin spine score (4.18±4.58 in the BCD-085 group versus 4.19±4.32 in the placebo group) and on the SPARCC scale (5.67±8. 33 in the BCD-085 group versus 5.23±7.86 in the placebo group) (p>0.05). Analysis of data at week 16 of treatment showed that in the BCD-085 group there was a significant reduction in bone marrow edema during immediate

-

Claims (31)

compared with the placebo group: at week 16, the mean change from baseline in the Berlin spine score was -2.16±2.87 in the BCD-085 group compared to -0.30±1.55 in placebo group (p < 0.0001), and the mean change from baseline in the SPARCC score was -3.80 ± 6.68 in the BCD-085 group compared with -1.82 ± 4.12 in the placebo group ( p<0.01, Fig. 31). At week 1, the difference in the total back pain score between the study groups became statistically significant (Fig. 32). At week 16, the use of BCD-085 is accompanied by a statistically significant improvement compared to the initial level of BASDAI (-2.8 versus 0.2, p<0.0001), BASFI (-0.9 versus 0.9, p<0 .0001) and the physical component SF36 (6.3 versus - 2.6, p<0.0001) (Fig. 33). At week 16, response as assessed by the WPAI (Work and Activities of Daily Living Impairment) scale in the BCD-085 group was significantly better than in the placebo group (Table 43). Table 43 Change in WPAT at week 16 (medians: upper and lower quartiles) 1lapa.xie। R B('1)-O85 (n=114) Placebo (ιι=Ι 14) Initial characteristic ICP 1 imputation οι fasting. ιι>ιιο original characteristics shk to pedele 16 Original characteristic IKN 11{menen1В1 t post, ικιιο initial characteristic ik to week 16% missed working time due to health reasons 0 [0; 18.4] 0[-11,1;0] 0 [0; 15.8] 0 [0; 29.9]% disability due to health reasons 50 [30; 70] -80 [-40; 0] 50 [40; 70] 10 [-10; 20]% general disability due to health conditions 55.1 [40; 84] -15.6 [-40; 0] 60 [50; 75] 1.2 [-10.3; 20]% impairment of daily activities due to health reasons 60 [40; 80] -20 [-40; -10] 60 [50; 70] 0 [-10; 20] Safety of the drug. The majority of reported adverse events (AEs) and treatment-related adverse events (TEAEs) were mild/moderate (Table 44). The most common AEs were anemia, neutropenia, and increased ALT levels. One serious adverse event (SAE) not related to treatment (a bone fracture that required surgery) was reported in the NTK group. Table 44 Generalized data on the safety of the drug Proportion of papists with Group ; rshachepne BCD-O85 (η 114) 1 l.iaiieoo (η 114) Any AE/SAE 33.33% (38) 25.44% (29) 0.245 SLNYA 17.54% (20) 14.04% (16) 0.586 Any SAE 0.88% (1) 0 1.00 AE grade 3-4 2.63% (3) 3.51% (4) 1.00 SANE grade 3-4 severity 1.75% (2) 1.75% (2) 1.00 Focal reactions 1.75% (2) 0.88% (1) 1.00 Netakimab, up to a dose of 120 mg (e.g., the dosage proposed herein), is a well-tolerated drug with a favorable safety profile that results in a reduction in AS exacerbation, including improvements in functional status, axial mobility, MRI signs of inflammation, and improving quality of life. CLAIM 1. An aqueous pharmaceutical composition suitable for parenteral administration to a subject to inhibit the activity of the TL17a protein, containing netakimab in an amount of 5 to 150 mg/ml; histidine-based buffering agent; and mannitol in an amount of 25-60 mg/ml as an osmotic agent, where the specified buffering agent consists of L-histidine in an amount from 0.4 to 1.6 mg/ml; and histidine hydrochloride monohydrate in an amount of 0.4 to 1.6 mg/ml. - 80 046015 2. An aqueous pharmaceutical composition according to any one of claims 1, where said netakimab is in an amount of 10 to 100 mg/ml. 3. An aqueous pharmaceutical composition according to claim 1, where said netakimab is present in an amount of 40 mg/ml. 4. An aqueous pharmaceutical composition according to claim 1, where said netakimab is present in an amount of 60 mg/ml. 5. An aqueous pharmaceutical composition according to claim 1, where said netakimab is present in an amount of 70 mg/ml. 6. An aqueous pharmaceutical composition according to claim 1, where said mannitol is present in an amount of 50-60 mg/ml. 7. An aqueous pharmaceutical composition according to any one of claims 1 to 6, wherein a suitable amount of a histidine-based buffering agent is added to adjust the pH to about 5.5 to 6.5. 8. An aqueous pharmaceutical composition according to any one of claims 1 to 7, further containing a suitable solubilizer. 9. An aqueous pharmaceutical composition according to claim 8, wherein said solubilizer is poloxamer 188. 10. The aqueous pharmaceutical composition according to claim 9, wherein said poloxamer 188 is present in an amount that is greater than 0 mg/ml but equal to or less than 1 mg/ml. 11. An aqueous pharmaceutical composition according to claim 10, where a) the specified poloxamer 188 is in an amount of 0.5 mg/ml; or b) the indicated poloxamer 188 is present in an amount of 1 mg/ml. 12. An aqueous pharmaceutical composition suitable for parenteral administration to a subject to inhibit the activity of IL17a protein, containing netakimab in an amount of 40 mg/ml; L-histidine in an amount of 0.4 mg/ml; L-histidine hydrochloride monohydrate in an amount of 0.4 mg/ml; mannitol in the amount of 54.5 mg/ml; poloxamer 188 in an amount of 1 mg/ml; pH 6.0±0.5. 13. An aqueous pharmaceutical composition suitable for parenteral administration to a subject to inhibit the activity of IL17a protein, containing netakimab in an amount of 5 to 150 mg/ml; acetate-based buffering agent; and trehalose dihydrate in an amount of 50 to 120 mg/ml as an osmotic agent, wherein the acetate-based buffering agent consists of sodium acetate trihydrate in an amount of 0.4 to 1.8 mg/ml; and a suitable amount of acetic acid to adjust the pH of said composition to 4.0 to 6.0, inclusive. 14. An aqueous composition according to claim 13, where said netakimab is in an amount of 10 to 120 mg/ml. 15. An aqueous pharmaceutical composition according to claim 13, where said netakimab is present in an amount of 60 mg/ml. 16. An aqueous pharmaceutical composition according to any one of claim 13, where said netakimab is in an amount of 100 mg/ml. 17. An aqueous pharmaceutical composition according to claim 13, where said netakimab is present in an amount of 120 mg/ml. 18. An aqueous pharmaceutical composition according to claim 13, where said trehalose is added to said composition in the form of trehalose dihydrate in an amount of 50 or 80 mg/ml. 19. An aqueous pharmaceutical composition according to any one of claims 13 to 18, further containing a suitable solubilizer. 20. An aqueous pharmaceutical composition according to claim 19, wherein said solubilizer is poloxamer 188. 21. The aqueous pharmaceutical composition according to claim 20, wherein said poloxamer 188 is in an amount of greater than 0 mg/ml to equal to or less than 1 mg/ml. 22. An aqueous pharmaceutical composition suitable for parenteral administration to a subject to inhibit the activity of IL17a protein, containing netakimab in an amount of 60 mg/ml; sodium acetate trihydrate in an amount of 1.74 mg/ml; trehalose dihydrate in an amount of 80 mg/ml; glacial acetic acid - up to pH 5.0; pH 5.0±0.5. 23. An aqueous pharmaceutical composition suitable for parenteral administration to a subject for - 81 046015 inhibition of IL17a protein activity, containing netakimab in an amount of 60 mg/ml; sodium acetate trihydrate in an amount of 1.74 mg/ml; trehalose dihydrate in an amount of 80 mg/ml; poloxamer 188 in an amount of 0-1 mg/ml; glacial acetic acid - up to pH 5.0; pH 5.0±0.5. 24. An aqueous pharmaceutical composition according to claim 23, where a) the specified poloxamer 188 is in an amount of 0.5 mg/ml; or b) the indicated poloxamer 188 is present in an amount of 1 mg/ml. 25. An aqueous pharmaceutical composition suitable for parenteral administration to a subject to inhibit the activity of IL17a protein, containing netakimab in an amount of 120 mg/ml; sodium acetate trihydrate in an amount of 1.74 mg/ml; trehalose dihydrate in an amount of 80 mg/ml; glacial acetic acid - up to pH 5.0; pH 5.0±0.5. 26. An aqueous pharmaceutical composition suitable for parenteral administration to a subject to inhibit the activity of IL17a protein, containing netakimab in an amount of 120 mg/ml; sodium acetate trihydrate in an amount of 1.74 mg/ml; trehalose dihydrate in an amount of 80 mg/ml; poloxamer 188 in an amount of 0-1 mg/ml; glacial acetic acid - up to pH 5.0; pH 5.0±0.5. 27. An aqueous pharmaceutical composition according to claim 26, in which a) the specified poloxamer 188 is in an amount of 0.5 mg/ml; or b) the indicated poloxamer 188 is present in an amount of 1 mg/ml. 28. Use of an aqueous pharmaceutical composition according to any one of claims 1 to 27 for the treatment of IL17 a-mediated disease. 29. The use of claim 28, 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-associated arthritis; enthesitis; spondyloarthropathy, axial spondyloarthritis; Behçet's disease; inflammatory bowel disease, Crohn's disease, ulcerative colitis; asthma, allergic disorders, atopic allergies; ichthyosis; red hairy pityriasis; papulopustular rosacea; gangrenous pyoderma; hidradenitis suppurativa; psoriasis, psoriatic arthropathy, type I psoriasis, type II psoriasis, plaque psoriasis; dermatitis, atopic dermatitis, autoimmune dermatitis, dermatological conditions; systemic sclerosis; transplantation, graft-versus-host disease, graft rejection, acute or chronic immune disease associated with organ transplantation, acute immune disease related to transplantation, chronic immune disease associated with transplantation, small bowel transplant rejection, pancreas transplant rejection, transplant rejection of any organ or tissue graft rejection, cardiac graft rejection, cartilage graft rejection, kidney graft rejection, liver graft rejection, allograft rejection, skin allograft rejection, heterograft rejection of any organ or tissue, bone graft rejection, bone marrow graft (BMT) rejection, parathyroid graft rejection ; bone erosion; sarcoidosis, atherosclerosis, Wegener's disease, microscopic polyangiitis with kidney damage, uveitis, phacogenic uveitis, non-infectious uveitis, cachexia, acute transverse myelitis, primary biliary cirrhosis, autoimmune polyglandular syndrome type I and II, Schmidt's syndrome, acute respiratory distress syndrome; arthropathy, seronegative arthropathy, arthropathy associated with ulcerative colitis, Reiter's syndrome, enteropathic synovitis, atheromatosis/coronary sclerosis, autoimmune bullous disease, pemphigus, pemphigus foliaceus, linear IgA-dependent bullous dermatosis, autoimmune hemolytic anemia, giant cell arteritis, primary th 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 pulmonary disease, dermatomyositis/polymyositis associated with pulmonary disease, Sjögren's syndrome associated with pulmonary disease, ankylosing spondylitis associated with pulmonary disease, vasculitis, diffuse pulmonary vasculitis, primary vasculitis - 82 046015 ta, fibrosis, lung disease with lymphocyte infiltration, autoimmune hepatitis, autoimmune hepatitis type I (classical autoimmune or lupoid hepatitis), autoimmune hepatitis type II (associated with antibody to LKM), autoimmune hypoglycemia, osteoarthritis, primary sclerosing cholangitis, erythematosis ; systemic lupus erythematosus, discoid lupus erythematosus, lupus nephritis; multiple sclerosis (all types), sympathetic ophthalmia, pulmonary hypertension secondary to connective tissue disease, Goodpasture's syndrome, pulmonary manifestations of polyarteritis nodosa, acute rheumatic attack, rheumatoid spondylitis, Still's disease, systemic scleroderma, scleroderma disease, scleroderma, Takayasu's disease/arteritis; autoimmune thrombocytopenia, idiopathic thrombocytopenia; autoimmune thyroiditis, hyperthyroidism, autoimmune hypothyroidism (Hashimoto's disease), autoimmune atrophic hypothyroidism; vitiligo, acute liver diseases, chronic liver diseases, cholestasis, diseases mediated by Th2 type and Th1 type, malignant tumors such as lung cancer, breast cancer, stomach cancer, bladder cancer, colorectal cancer, pancreatic cancer, pancreatic carcinoma , ovarian cancer, prostate cancer and malignancies of the hematopoietic system (leukemia and lymphomas), acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, adenocarcinoma, B-cell lymphoma, Burkitt's lymphoma, inflammatory responses to cardiopulmonary bypass, chronic myelocytic leukemia (CML) ), chronic inflammatory pathologies, chronic lymphocytic leukemia (CLL), colorectal carcinoma (rectocolytic carcinoma), cystic fibrosis, malignant lymphoma, malignant histiocytosis, malignant melanoma, multiple myeloma, non-Hodgkin's lymphomas, nasopharyngeal cancer, solid tumors, hairy cell leukemia, Hodgkin's disease, sarcoma, myelodysplastic syndrome, cytokine therapy-related disorders, demyelinating diseases, inflammatory demyelinating disease, pulmonary fibrosis, idiopathic pulmonary fibrosis, usual interstitial pneumonia, iridocyclitis/uveitis/optic neuritis, lymphedema, mixed connective tissue disease, monoclonal gammopathy, chronic neonatal lung diseases, nephritis, nephrotic, neurodegenerative disorders, osteoporosis, paraneoplastic syndrome/hypercalcemia associated with malignancy, phenomenon and Raynaud's disease, systemic inflammatory response syndrome, thrombocytopenia, toxic effects, urticaria, acute coronary syndrome, Still's disease developed in adults, aplastic anemia, coronary sclerosis, atopic eczema; autoimmune disorder associated with streptococcal 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 risk of multiple sclerosis, erythema multiforme, severe erythema multiforme, pemphigoid, bullous pemphigoid, cicatricial pemphigoid, mucosal pemphigoid, gestational pemphigoid, iritis, keratitis, motor neuron disease, non-A hepatitis, none B, optic neuritis, oligoarticular JIA, polyarteritis nodosa, polychondritis, poliosis, polymyositis, recurrent neuromyelitis optica, rheumatic heart disease, SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, osteitis), secondary amyloidosis, ankylosing spondylitis, systemic inflammatory response syndrome , cranial arteritis and arthropathy associated with Yersinia or Salmonella. 30. A method of preparing an aqueous pharmaceutical composition suitable for parenteral administration to a subject to inhibit the activity of the IL17a protein, comprising combining a pharmaceutically effective amount of netakimab with a histidine-based buffering agent; and an effective amount of mannitol as an osmotic agent. 31. A method of preparing an aqueous pharmaceutical composition suitable for parenteral administration to a subject to inhibit the activity of the IL17a protein, comprising combining a pharmaceutically effective amount of netakimab with an acetate-based buffering agent; and an effective amount of trehalose as an osmotic agent. -