RU2747193C2 - Compositions containing antibodies to il6r for treatment of uveitis and macular edema and methods of their use - Google Patents

Abstract

FIELD: medicine.SUBSTANCE: group of inventions relates to the field of medicine, namely to ophthalmology, and is intended for the treatment of uveitis and macular edema in the subject. For the treatment of these diseases in the subject, a composition containing an effective amount of an antibody that specifically binds IL-6 receptor is used. Said subject has a vitreous haze (VH) level of 2 on the Miami 9-Grade Scale or greater, or said subject has a central retinal thickness (CRT) greater than 300 μm. An antibody that specifically binds to IL-6 receptor contains a sequence of a variable heavy chain site under SEQ ID NO: 2 and a sequence of a variable light chain site under SEQ ID NO: 3. The antibody is administered at a dose of 150 to 200 mg once every two weeks.EFFECT: use of the group of inventions makes it possible to increase the effectiveness of uveitis and macular edema treatment in the subject.18 cl, 16 tbl, 1 ex

Description

RELATED APPLICATIONS

This application claims priority under US Provisional Application Serial No. 62/408391, filed October 14, 2016; European patent application EP16306166.6, filed September 14, 2016; and U.S. Provisional Application Serial No. 62/250269, filed November 3, 2015, each of which is incorporated herein by reference in its entirety.

FIELD OF TECHNOLOGY

The present invention relates to the field of therapeutic treatment of uveitis and / or macular edema. More specifically, the present invention relates to the use of interleukin-6 (IL-6R) receptor antagonists, such as antibodies to IL-6R, for the treatment of uveitis.

LEVEL OF TECHNOLOGY

Interleukin-6 is a key cytokine with a wide range of biological activities, including regulation of immune reactivity, acute phase response, inflammation, tumorigenesis and hematopoiesis (Kishimoto T., The Cytokine Handbook, AW Thomson, Lotze, MT, ed. (London: Academic Press) 2003 pp. 281-304). Over-synthesis of IL-6 has been found to play a pathological role in chronic inflammatory diseases, including rheumatoid arthritis (RA). It has also been repeatedly shown that the level of IL-6 is increased in the vitreous body of patients with non-infectious uveitis (Ongkosuwito et al., Invest Ophthalmol Vis Sci. 1998; 39 (13): 2659-65; Perez et al., Ocul Immunol Inflamm. 2004 ; 12 (3): 193-201; Yoshimura et al., PloS One 2009; 4 (12): e8158; and Valentincic et al., Mol Vis. 2011; 17: 2003-10. Epub 2011 Jul 20).

IL-6 interacts directly with the IL-6Rα subunit, and the IL-6 / IL-6Rα pair forms a high-affinity complex with the glycoprotein 130 (gp130) subunit. IL6Rα also exists in a soluble form that is involved in trans-signaling and causes IL6 to affect cells that do not express IL6Rα, including synovial cells in the joint (Rose-John et al., J Leukoc Biol. 2006; 80 (2 ), 227-36).

Sarilumab (SAR153191), also referred to as REGN88, was developed jointly by Sanofi and Regeneron. Sarilumab is a recombinant anti-IgG1-kappa monoclonal antibody with a fully human sequence directed against the alpha subunit of the IL-6 receptor complex (IL-6Rα). Sarilumab is an effective and specific inhibitor of IL-6 signaling. As a result of IL-6Rα binding with high affinity, sarilumab blocks IL-6 binding and interrupts the cytokine-mediated signaling cascade. Sarilumab is being evaluated in phase 3 clinical trials for the treatment of RA. In addition, a preliminary study of the clinical efficacy of treating patients with non-infectious secondary uveitis, posterior uveitis and panuveitis is under way.

Interleukin-6 is a major element in the etiology of rheumatic conditions, and inhibition of signal transmission through it is an important part of the mechanism of action of sarilumab.

Proinflammatory cytokines associated with RA include tumor necrosis factor alpha (TNF-α), interleukin-1 (IL-1), and IL-6. Interleukin-6 is expressed in a large proportion of cells in the rheumatoid synovium, and elevated levels of IL-6 are found in the serum and synovial fluid of RA patients. Increased levels of soluble IL6R α have also been observed in a number of inflammatory diseases, including RA (Lipsky PE. Interleukin-6 and rheumatic diseases. Arthritis Res Ther. 2006; 8 (Suppl 2): S4). Interaction of IL6 with soluble IL6R α leads to the formation of complexes that are capable of transactivating gp130 present on the surfaces of a number of cells, a potentially major pathogenic mechanism in RA (Rose-John et al., J Leukoc Biol. 2006; 80 (2), 227-36 ). IL6 is located downstream of TNFα and IL-1 in the inflammatory cytokine cascades and thus may represent the final common signaling pathway in a wide range of inflammatory processes. Rheumatoid arthritis is a chronic inflammatory disease characterized by persistent synovitis and progressive destruction of cartilage and bone tissue in many joints. Concomitant symptoms of systemic inflammation include fever, fatigue, anemia, elevated levels of acute phase reactants such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels, and the formation of autoantibodies such as rheumatoid factor (RF) (Kishimoto T., The Cytokine Handbook, AW Thomson, Lotze, MT, ed. (London: Academic Press. 2003 pp. 281-304).

Uveitis is a term used to describe a group of intraocular inflammatory diseases that can occur at any age, but predominantly affect patients in the working age group (Nussenblatt et al., Ophthalmology 1985; 92 (4): 467-471). Non-infectious uveitis (NIU) can result from an underlying inflammatory disease, autoimmune disorder, tumor, or damage to the eye. In most cases, the cause remains unknown (eg, idiopathic uveitis) (Durrani et al., Br J Ophthalmol. 2004; 88 (9): 1159-62).

The goal of NIU treatment is to control inflammation, prevent vision loss, and minimize long-term complications of the disease and treat it.

Systemic corticosteroids are widely used to control posterior segment inflammation that requires treatment, especially when associated with systemic disease or when bilateral ocular disease is present. IL-6 has been shown to increase in the vitreous humor of NIU patients (Ongkosuwito et al., Invest Ophthalmol Vis Sci. 1998; 39 (13): 2659-65; Perez et al., Ocul Immunol Inflamm. 2004; 12 (3): 193-201; Yoshimura et al., PloS One. 2009; 4 (12): e8158; Valentincic et al. Mol Vis. 2011; 17: 2003-10. Epub 2011 Jul 20), blockade of IL signaling -6 via IL-6Ra with sarilumab may be promising as a treatment for this disease.

To enhance the treatment of uveitis following subcutaneous injection of sarilumab in patients, the efficacy of a murine surrogate IL-6Rα antibody (REGN844) was investigated in a murine organ-specific T-lymphocyte-mediated experimental autoimmune uveoretinitis (EAU) model. In this study, intraperitoneal (IP) administration of REGN844 to mice at a dose level of 10 to 100 mg / kg every two days, starting on day 5 after induction of EAU, resulted in dose-dependent inhibition of non-infectious uveitis, as evidenced by a decrease in retinal thickness, morphological abnormalities and infiltration of inflammatory cells confirmed by histological measurements and optical coherence tomography (OCT) measurements. Systemic (intraperitoneal) administration of mouse anti-mouse IL6R antibody (REGN844) stably normalizes the development of vitreoretinal inflammation in a mouse model of experimental autoimmune uveitis (EAU) (Cao, J, et.al: Investigative Ophthalmology & Visual Science June 2013, Vol.54, 5193) ...

Macular edema involves abnormal leakage and accumulation of fluid from damaged macular blood vessels in the nearby retina. Diabetic retinopathy is a common cause of macular edema. See Bresnick 1986 Ophthalmology, 93 (7): pages 989-97. Macular edema can also occur after eye surgery, due to age-related macular degeneration, or as a consequence of inflammatory conditions that affect the eye. Virtually any disease that destroys blood vessels in the retina can cause macular edema.

Sarilumab (SAR153191), also known as REGN88, is being evaluated for the treatment of rheumatoid arthritis (RA) and for the treatment of non-infectious secondary, posterior uveitis, or panuveitis. Sarilumab is a recombinant human monoclonal antibody from the kappa isotype of immunoglobulin G1 (IgG1) directed against the α-subunit of the interleukin-6 receptor (IL6Rα). Sarilumab binds human IL-6Rα and has been shown to block signaling through interleukin-6 (IL-6) and does not induce signaling in the absence of IL-6. In ex vivo assays, sarilumab showed no antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC) for the respective cell types, where sarilumab binding was confirmed by fluorescence-activated cell sorter (FACS) assay.

SHORT DESCRIPTION

One aspect of the present invention provides a method of treating uveitis and / or macular edema in a subject in need thereof, comprising administering an effective amount of an antibody that specifically binds the IL-6 receptor.

In various embodiments, an antibody that specifically binds to an IL-6 receptor comprises a heavy chain variable region sequence SEQ ID NO: 2 and a light chain variable region sequence SEQ ID NO: 3. In various embodiments of the method, the antibody is sarilumab.

In various embodiments of the method, the subject suffers from at least one symptom of macular edema. In various embodiments, at least one symptom is selected from the group consisting of eye inflammation, visual impairment, color recognition impairment, tissue thickening, and ocular vascular leakage. For example, the subject has blurry vision. In various embodiments, the condition of a subject suffering from at least one symptom of macular edema is improved upon administration of the antibody.

In various embodiments of the method, the subject suffers from cystic macular edema. In various embodiments of the method, the subject suffers from diabetic retinopathy.

In various embodiments, the macular edema is macular edema secondary to uveitis. For example, uveitis is selected from the group consisting of moderate uveitis, posterior uveitis, and panuveitis.

In various embodiments of the method, the subject has a central retinal thickness (CRT) greater than 300 microns.

In various embodiments, the condition of a subject suffering from at least one symptom is improved upon administration of the antibody. In various embodiments, the uveitis symptom is selected from the group consisting of: vitreous opacity (VH), maximum corrected visual acuity (BCVA), signs of ocular inflammation, retinal vascular leakage, and inflammation in the anterior chamber of the eye.

In various embodiments, the subject suffers from at least one symptom of macular edema and from at least one symptom of uveitis. In various embodiments, the condition of a subject suffering from both of these symptoms is improved upon administration of the antibody.

In various embodiments of the method, the subject has been previously treated with a corticosteroid for at least three months. For example, the corticosteroid is prednisone. In various embodiments, prednisone is administered at 15 to 80 mg / day.

In various embodiments of the method, methotrexate is administered to the subject. For example, methotrexate was administered at 6 to 25 mg / week.

In various embodiments, the subject is also administered a corticosteroid. For example, the corticosteroid is prednisone. In various embodiments of the method, prednisone is administered in an amount of 15 to 80 mg / day.

In various embodiments of the method, methotrexate is administered to the subject. For example, methotrexate is administered at 6 to 25 mg / week.

In various embodiments, after 16 weeks, the subject achieves a decrease in VH level on the Miami 9-point scale by at least 2 stops, or is allowed to reduce the dose of corticosteroids to less than 10 mg per day.

In various embodiments, after 16 weeks, the subject achieves a decrease in VH level on the Miami 9-point scale of at least 2 stops.

In various embodiments, after 16 weeks, it is possible to reduce the dose of corticosteroids required by the subject to less than 10 mg per day.

In various embodiments, the subject has a greater than 20% reduction in CRT, an improvement in BCVA greater than 10 letters, a reduction in retinal vascular leakage, and / or an improvement in the clinical score of uveitis. For example, an assessment score is calculated using feedback from a subject and / or determined using an assessment and / or procedure by a physician. For example, improvement or decrease is determined with respect to a healthy subject, or a control value or sample from a subject having uveitis and / or macular edema, prior to having an ocular condition.

In various embodiments, the subject achieves an improvement in BCVA after 16 weeks.

In various embodiments, CRT normalization is achieved in the subject after 16 weeks.

In various embodiments, after 16 weeks, the subject has normalized retinal vascular leakage.

In various embodiments, after 16 weeks, the subject achieves an improvement in the clinical score.

In various embodiments of the method, the antibody is administered subcutaneously. In various embodiments, the antibody is administered intravenously.

In various embodiments of the method, the antibody is administered in an amount of about 150 mg to about 200 mg every two weeks. For example, the antibody is administered subcutaneously.

In various embodiments of the method, the antibody is administered in an amount of about 150 mg once every two weeks. In various embodiments of the method, the antibody is administered in an amount of about 200 mg once every two weeks.

In various embodiments of the method, the antibody is tocilizumab. For example, tocilizumab is administered intravenously at about 4 to about 8 mg / kg every four weeks. In various embodiments, tocilizumab is administered subcutaneously at about 162 mg once a week or once every two weeks.

One aspect of the present invention provides an antibody for use in a method of treating uveitis and / or macular edema in a subject, wherein the antibody specifically binds to an IL-6 receptor, optionally wherein the subject has a VH level of 2 on the Miami 9-grade scale or greater, or where the subject has a CRT of more than 300 microns.

In addition, the present disclosure provides a method of treating uveitis in a subject in need thereof, comprising administering an effective amount of an antibody that specifically binds to the IL-6 receptor, wherein the subject has a VH of 2 on the Miami 9-grade scale or greater, or where the subject has a CRT of more than 300 microns. The subject may have a VH of 3, 4, 5, 6, 7, or 8 on the Miami 9-point scale or greater. The subject may have a VH of 4 on the Miami 9-point scale or greater.

In various embodiments, the uveitis can be selected from the group consisting of middle uveitis, posterior uveitis, and panuveitis. In various embodiments, the uveitis can be non-infectious uveitis. In various embodiments, the uveitis can be systemic or idiopathic. Subject may suffer from macular edema. In various embodiments, the subject may have a CRT greater than 300 μm. In various embodiments, the subject has other signs of intraocular inflammation. In certain specific embodiments, the other signs of intraocular inflammation are selected from the group consisting of perivascular retinal vascular hardening and retinal vascular leakage.

In some embodiments, the subject has been suffering from uveitis for at least three months.

In certain embodiments, at least one symptom of uveitis in the subject is normalized. The symptom of uveitis can be selected from the group consisting of VH level, BCVA, macular edema, signs of eye inflammation, retinal vascular leakage, CRT, and inflammation in the anterior chamber of the eye. For example, a symptom of uveitis (eg, VH level) is determined by comparison with a healthy individual without uveitis and / or macular edema, or with a control value or sample from a subject before having uveitis and / or macular edema.

In some specific embodiments, the subject is treated with a corticosteroid for at least three months. In specific embodiments, the corticosteroid is prednisone. In some embodiments, prednisone is administered at 15 to 80 mg / day.

In certain specific embodiments, the subject is also administered methotrexate. In some embodiments, methotrexate is administered in an amount of 6 to 25 mg / week.

In some embodiments, a corticosteroid is administered to the subject. In various embodiments, the corticosteroid may be prednisone. In some specific embodiments, prednisone is administered at 15 to 80 mg / day.

In some specific embodiments, methotrexate is also administered to the subject. In various embodiments, methotrexate can be administered in an amount of 6 to 25 mg / week.

In certain embodiments, after 16 weeks, the subject achieves a decrease in VH level on the Miami 9-point scale by at least 2 stops or is allowed to reduce the dose of corticosteroids to less than 10 mg per day. In certain specific embodiments, after 16 weeks, the subject achieves a decrease in VH level on the Miami 9-point scale of at least 2 stops. In some embodiments, after 16 weeks, it is possible to reduce the dose of corticosteroids required by the subject to less than 10 mg per day.

In some specific embodiments, the subject exhibits a greater than 20% reduction in CRT, an improvement in BCVA greater than 10 letters, a reduction in retinal vascular leakage, and / or an improvement in the clinical score of uveitis. In certain embodiments, after 16 weeks, the subject achieves an improvement in BCVA. In some embodiments, CRT normalization is achieved in the subject after 16 weeks. In certain specific embodiments, after 16 weeks, the subject has normalized retinal vascular leakage. In some specific embodiments, after 16 weeks, the subject achieves an improvement in the clinical score for uveitis.

In any embodiment, the antibody that specifically binds to the IL-6 receptor may be an antibody that contains the amino acid sequence of the heavy chain variable region SEQ ID NO: 2 and the amino acid sequence of the light chain variable region SEQ ID NO: 3. In some embodiments, the antibody is administered in an amount of about 150 mg to about 200 mg every two weeks. In various embodiments, the antibody is administered in an amount of about 150 mg once every two weeks. In various embodiments, the antibody is administered in an amount of about 200 mg once every two weeks. In some specific embodiments, the antibody is sarilumab.

In certain embodiments, the antibody is tocilizumab. In certain embodiments, tocilizumab is administered intravenously at about 4 to about 8 mg / kg every four weeks. In various embodiments, tocilizumab is administered subcutaneously at about 162 mg once a week or once every two weeks.

One aspect of the present invention provides an antibody for use in a method of treating uveitis and / or macular edema in a subject, wherein the antibody comprises a heavy chain variable region sequence SEQ ID NO: 2 and a light chain variable region sequence SEQ ID NO: 3.

In addition, the present disclosure also provides a method of treating uveitis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an antibody, wherein the antibody comprises a heavy chain variable region sequence SEQ ID NO: 2 and a light chain variable region sequence SEQ ID NO: 3. In some embodiments, the antibody is sarilumab.

In various embodiments, the uveitis can be selected from the group consisting of middle uveitis, posterior uveitis, and panuveitis. In various embodiments, the uveitis can be non-infectious uveitis. Uveitis can be systemic or idiopathic.

In some specific embodiments, the subject has a VH level of 2 on the Miami 9-grade scale or greater. In certain specific embodiments, the subject has a VH of 3, 4, 5, 6, 7, or 8 on the Miami 9-step scale or greater. In some embodiments, the subject has a VH level of 4 on the Miami 9-grade scale or greater.

In certain embodiments, the subject suffers from macular edema. In certain specific embodiments, the subject has a CRT greater than 300 μm. In some embodiments, the subject has other signs of intraocular inflammation. In some embodiments, the other signs of intraocular inflammation are selected from the group consisting of perivascular retinal vascular hardening and retinal vascular leakage. In some specific embodiments, the subject has been suffering from uveitis for at least three months.

In some embodiments, at least one symptom of uveitis in the subject is normalized. In various embodiments, the uveitis symptom can be selected from the group consisting of VH level, BCVA, macular edema, ocular inflammation signs, CRT, and anterior chamber inflammation.

In certain embodiments, the subject is treated with a corticosteroid for at least three months. For example, the corticosteroid can be prednisone. In some embodiments, prednisone is administered at 15 to 80 mg / day. In some specific embodiments, methotrexate was also administered to the subject. In specific embodiments, methotrexate is administered in an amount of 6 to 25 mg / week.

In some embodiments, a corticosteroid is administered to the subject. The corticosteroid may be prednisone. In some specific embodiments, prednisone is administered at 15 to 80 mg / day.

In some specific embodiments, methotrexate is also administered to the subject. In certain embodiments, methotrexate is administered in an amount of 6 to 25 mg / week.

In certain embodiments, after 16 weeks, the subject achieves a decrease in VH on the Miami 9-point scale by at least 2 stops or is allowed to reduce the dose of corticosteroids to less than 10 mg per day. In certain specific embodiments, after 16 weeks, the subject achieves a decrease in VH level on the Miami 9-point scale of at least 2 stops. In some embodiments, after 16 weeks, it is possible to reduce the dose of corticosteroids required by the subject to less than 10 mg per day. In some specific embodiments, the subject exhibits a greater than 20% reduction in CRT, an improvement in BCVA greater than 10 letters, a reduction in retinal vascular leakage, and / or an improvement in the clinical score of uveitis. In certain embodiments, after 16 weeks, the subject achieves an improvement in BCVA. In certain specific embodiments, CRT normalization is achieved in the subject after 16 weeks. In some embodiments, after 16 weeks, the subject has normalized retinal vascular leakage. In some specific embodiments, after 16 weeks, the subject achieves an improvement in the clinical score for uveitis.

One aspect of the present invention provides a composition for use in treating macular edema in a subject in need thereof, the composition comprising an effective amount of an antibody that specifically binds the IL-6 receptor.

In various embodiments, an antibody that specifically binds to an IL-6 receptor comprises a heavy chain variable region sequence SEQ ID NO: 2 and a light chain variable region sequence SEQ ID NO: 3. For example, the antibody is sarilumab.

In various embodiments, the subject suffers from at least one symptom of macular edema selected from the group consisting of eye inflammation, visual impairment, color recognition impairment, tissue thickening, and ocular vascular leakage. For example, macular edema is cystic macular edema. In various embodiments, the subject suffers from diabetic retinopathy. In various embodiments, macular edema is secondary to uveitis. For example, uveitis is selected from the group consisting of moderate uveitis, posterior uveitis, and panuveitis (or panuveitis).

In various embodiments, the subject has a CRT greater than 300 μm.

In various embodiments, at least one symptom of macular edema in the subject is normalized upon administration of the antibody.

In various embodiments, at least one symptom of uveitis in the subject is normalized upon administration of the antibody. In various embodiments, the uveitis symptom is selected from the group consisting of VH, BCVA levels, signs of ocular inflammation, retinal vascular leakage, central retinal thickness, and inflammation in the anterior chamber of the eye.

In various embodiments, the subject has been previously treated for a period of time with corticosteroids. For example, the period is at least one month, two months, or three months of corticosteroid treatment. In various embodiments, the corticosteroid is prednisone. For example, prednisone was administered at 15 to 80 mg / day.

In various embodiments, methotrexate was also administered to the subject. For example, methotrexate was administered at 6 to 25 mg / week.

In various embodiments, a corticosteroid is also administered to the subject. For example, the corticosteroid is prednisone. In various embodiments, prednisone is administered at 15 to 80 mg / day.

In various embodiments, methotrexate is also administered to the subject. For example, methotrexate is administered at 6 to 25 mg / week.

In various embodiments, after 16 weeks, the subject achieves a decrease in VH level on the Miami 9-point scale by at least 2 stops, or is allowed to reduce the dose of corticosteroids to less than 10 mg per day. In various embodiments, after 16 weeks, the subject achieves a decrease in VH level on the Miami 9-point scale of at least 2 stops. In various embodiments, after 16 weeks, it is possible to reduce the dose of corticosteroids required by the subject to less than 10 mg per day. In various embodiments, the subject has a greater than 20% reduction in CRT, an improvement in BCVA greater than 10 letters, a reduction in retinal vascular leakage, and / or an improvement in the clinical score of uveitis.

In various embodiments, the subject achieves an improvement in BCVA after 16 weeks. In various embodiments, CRT normalization is achieved in the subject after 16 weeks. In various embodiments, after 16 weeks, the subject has normalized retinal vascular leakage. In various embodiments, after 16 weeks, the subject achieves an improvement in the clinical score.

In various embodiments, the antibody is administered subcutaneously. In various embodiments, the antibody is administered in an amount of about 150 to about 200 mg every two weeks. In various embodiments, the antibody is administered in an amount of about 150 mg once every two weeks.

In various embodiments, the antibody is tocilizumab. For example, tocilizumab is administered intravenously at about 4 to about 8 mg / kg every four weeks. In various embodiments, tocilizumab is administered subcutaneously at about 162 mg once a week or once every two weeks.

One aspect of the present invention provides a composition for use in the treatment of uveitis, wherein the composition comprises an effective amount of an antibody that specifically binds an IL-6 receptor. In various embodiments, the subject has a VH level of 2 on the Miami 9-grade scale or greater, or wherein the subject has a CRT greater than 300 microns. For example, a subject has a VH of 3, 4, 5, 6, 7, or 8 on the Miami 9-point scale or greater. In various embodiments, the subject has a VH level of 4 on the Miami 9-grade scale or greater.

In various embodiments, the uveitis is selected from the group consisting of middle uveitis, posterior uveitis, and panuveitis. In various embodiments, the uveitis is non-infectious uveitis. In various embodiments, the uveitis is systemic or idiopathic.

In various embodiments, the subject suffers from macular edema.

In various embodiments, the subject has a CRT greater than 300 μm. For example, the CRT is approximately 350 microns, 400 microns, 450 microns, 500 microns, 550 microns, 600 microns, 650 microns 700 microns, 750 microns, 800 microns, or more than 800 microns.

In various embodiments, the subject has a different sign or other symptom of intraocular inflammation. For example, other signs of intraocular inflammation are selected from the group consisting of perivascular retinal vascular hardening and retinal vascular leakage.

In various embodiments, the subject has been suffering from uveitis for at least three months. For example, at least one symptom of uveitis in a subject is normalized after application of the composition. In various embodiments, the uveitis symptom is selected from the group consisting of VH level, BCVA, macular edema, signs of ocular inflammation, retinal vascular leakage, CRT, and anterior chamber inflammation.

In various embodiments, the subject is treated with a corticosteroid for at least three months. For example, the corticosteroid is prednisone. In various embodiments, prednisone is administered at 15 to 80 mg / day.

In various embodiments, methotrexate was also administered to the subject. For example, methotrexate was administered at 6 to 25 mg / week.

In various embodiments, a corticosteroid is administered to the subject. For example, the corticosteroid is prednisone. In various embodiments, prednisone is administered at 15 to 80 mg / day.

In various embodiments, methotrexate is also administered to the subject. For example, methotrexate is administered at 6 to 25 mg / week.

In various embodiments, after 16 weeks, the subject achieves at least a 2-stop decrease in VH on the Miami 9-point scale or is allowed to reduce the dose of corticosteroids to less than 10 mg per day.

In various embodiments, after 16 weeks, the subject achieves a decrease in VH level on the Miami 9-point scale of at least 2 stops.

In various embodiments, after 16 weeks, it is possible to reduce the dose of corticosteroids required by the subject to less than 10 mg per day.

In various embodiments, the subject exhibits a decrease (eg, more than 20%) CRT, an increase in the number of BCVA letters (eg, more than 10 BCVA letters), shows a decrease in retinal vascular leakage, and / or an improvement in the clinical score of uveitis. In various embodiments, the subject achieves an improvement in BCVA after 16 weeks. In various embodiments, CRT normalization is achieved in the subject after 16 weeks. In various embodiments, after 16 weeks, the subject has normalized retinal vascular leakage.

In various embodiments, after 16 weeks, the subject achieves an improvement in the clinical score for uveitis.

In various embodiments, an antibody that specifically binds to an IL-6 receptor comprises a heavy chain variable region sequence SEQ ID NO: 2 and a light chain variable region sequence SEQ ID NO: 3.

In various embodiments, the antibody is administered in an amount of about 150 mg to about 200 mg every two weeks. In various embodiments, the antibody is administered in an amount of about 150 mg once every two weeks. In various embodiments, the antibody is administered in an amount of about 200 mg once every two weeks.

In various embodiments, the antibody is sarilumab. In various embodiments, the antibody is tocilizumab. For example, tocilizumab is administered intravenously at about 4 to about 8 mg / kg every four weeks.

One aspect of the present invention provides a composition for use in treating uveitis in a subject in need thereof, the composition comprising a therapeutically effective amount of an antibody, wherein the antibody comprises a heavy chain variable region sequence SEQ ID NO: 2 and a light chain variable region sequence SEQ ID NO: 3.

In various embodiments, the antibody is sarilumab.

In various embodiments, the uveitis is selected from the group consisting of middle uveitis, posterior uveitis, and panuveitis.

In various embodiments, the uveitis is non-infectious uveitis. In various embodiments, the uveitis is systemic or idiopathic.

In various embodiments, the subject has a VH level of 2 on the Miami 9-grade scale or greater. In various embodiments, the subject has a VH of 3, 4, 5, 6, 7, or 8 on the Miami 9-step scale or greater. In various embodiments, the subject has a VH level of 4 on the Miami 9-grade scale or greater. In various embodiments, the subject suffers from macular edema. In various embodiments, the subject has a CRT greater than 300 μm.

In various embodiments, the subject has other signs of intraocular inflammation.

For example, other signs of intraocular inflammation are selected from the group consisting of perivascular retinal vascular hardening and retinal vascular leakage.

In various embodiments, the subject has been suffering from uveitis for at least three months.

In various embodiments, at least one symptom of uveitis in the subject is normalized following application of the composition. In various embodiments, the uveitis symptom is selected from the group consisting of VH level, BCVA, macular edema, ocular inflammation signs, CRT, and anterior chamber inflammation.

In various embodiments, the subject is treated with a corticosteroid for at least three months. For example, the corticosteroid is prednisone. In various embodiments, prednisone is administered at 15 to 80 mg / day.

In various embodiments, methotrexate was also administered to the subject.

For example, methotrexate was administered at 6 to 25 mg / week.

In various embodiments, a corticosteroid is administered to the subject. For example, the corticosteroid is prednisone. In various embodiments, prednisone is administered at 15 to 80 mg / day.

In various embodiments, methotrexate is also administered to the subject. For example, methotrexate is administered at 6 to 25 mg / week.

In various embodiments, after 16 weeks, the subject achieves a decrease in VH level on the Miami 9-point scale by at least 2 stops, or is allowed to reduce the dose of corticosteroids to less than 10 mg per day.

In various embodiments, after 16 weeks, the subject achieves a decrease in VH level on the Miami 9-point scale of at least 2 stops.

In various embodiments, after 16 weeks, it is possible to reduce the dose of corticosteroids required by the subject to less than 10 mg per day.

In various embodiments, the subject has a greater than 20% reduction in CRT, an improvement in BCVA greater than 10 letters, a reduction in retinal vascular leakage, and / or an improvement in the clinical score of uveitis.

In various embodiments, the subject achieves an improvement in BCVA after 16 weeks. In various embodiments, CRT normalization is achieved in the subject after 16 weeks. In various embodiments, after 16 weeks, the subject has normalized retinal vascular leakage. In various embodiments, after 16 weeks, the subject achieves an improvement in the clinical score for uveitis.

One aspect of the present invention provides for the use of a composition for the manufacture of a medicament for the treatment of macular edema in a subject in need thereof, the composition comprising an effective amount of an antibody that specifically binds the IL-6 receptor.

In various embodiments, an antibody that specifically binds to an IL-6 receptor comprises a heavy chain variable region sequence SEQ ID NO: 2 and a light chain variable region sequence SEQ ID NO: 3. For example, the antibody is sarilumab.

In various embodiments, the subject suffers from at least one symptom of macular edema selected from the group consisting of eye inflammation, visual impairment, color recognition impairment, tissue thickening, and ocular vascular leakage. In various embodiments, at least one symptom of macular edema in the subject is normalized upon administration of the antibody.

In various embodiments, the subject suffers from cystic macular edema. In various embodiments, the subject suffers from diabetic retinopathy. In various embodiments, the macular edema is macular edema secondary to uveitis. For example, uveitis is selected from the group consisting of moderate uveitis, posterior uveitis, and panuveitis.

In various embodiments, the subject has a CRT greater than 300 μm.

In various embodiments, at least one symptom of uveitis in the subject is normalized upon administration of the antibody. In various embodiments, the uveitis symptom is selected from the group consisting of VH, BCVA levels, signs of ocular inflammation, retinal vascular leakage, central retinal thickness, and inflammation in the anterior chamber of the eye.

In various embodiments, at least one symptom of macular edema and at least one symptom of uveitis in the subject is normalized upon administration of the antibody.

In various embodiments, the subject has been previously treated with a corticosteroid for at least three months. For example, the corticosteroid is prednisone.

In various embodiments, prednisone is administered at 15 to 80 mg / day.

In various embodiments, methotrexate was also administered to the subject. For example, methotrexate was administered at 6 to 25 mg / week.

In various embodiments, a corticosteroid is also administered to the subject. For example, the corticosteroid is prednisone. In various embodiments, prednisone is administered in an amount of 15 to 80 mg / day.

In various embodiments, methotrexate is also administered to the subject. For example, methotrexate is administered at 6 to 25 mg / week.

In various embodiments, after 16 weeks, the subject achieves a decrease in VH level on the Miami 9-point scale by at least 2 stops, or is allowed to reduce the dose of corticosteroids to less than 10 mg per day.

In various embodiments, after 16 weeks, the subject achieves a decrease in VH level on the Miami 9-point scale of at least 2 stops.

In various embodiments, after 16 weeks, it is possible to reduce the dose of corticosteroids required by the subject to less than 10 mg per day.

In various embodiments, the subject has a greater than 20% reduction in CRT, an improvement in BCVA greater than 10 letters, a reduction in retinal vascular leakage, and / or an improvement in the clinical score of uveitis.

In various embodiments, the subject achieves an improvement in BCVA after 16 weeks.

In various embodiments, CRT normalization is achieved in the subject after 16 weeks.

In various embodiments, after 16 weeks, the subject has normalized retinal vascular leakage.

In various embodiments, after 16 weeks, the subject achieves an improvement in the clinical score.

In various embodiments, the antibody is administered subcutaneously.

In various embodiments, the antibody is administered in an amount of about 150 to about 200 mg every two weeks. For example, the antibody is administered in an amount of about 150 mg once every two weeks. In various embodiments, the antibody is administered in an amount of about 200 mg once every two weeks.

In various embodiments, the antibody is tocilizumab. For example, tocilizumab is administered intravenously at about 4 to about 8 mg / kg every four weeks. In various embodiments, tocilizumab is administered subcutaneously at about 162 mg once a week or once every two weeks.

One aspect of the present invention provides for the use of an antibody for the manufacture of a medicament for the treatment of uveitis and / or macular edema in a subject, wherein the antibody specifically binds an IL-6 receptor, optionally wherein the subject has a VH level of 2 on the Miami 9-grade scale or greater, or where the subject has a CRT greater than 300 μm.

One aspect of the present invention provides for the use of a composition for the manufacture of a medicament for the treatment of uveitis in a subject, wherein the composition comprises an effective amount of an antibody that specifically binds an IL-6 receptor, wherein the subject has a VH level of 2 on the Miami 9-grade scale or greater, or where the subject has a CRT greater than 300 μm.

In various embodiments, the subject has a VH of 3, 4, 5, 6, 7, or 8 on the Miami 9-step scale or greater.

In various embodiments, the subject has a VH level of 4 on the Miami 9-grade scale or greater.

In various embodiments, the uveitis is selected from the group consisting of middle uveitis, posterior uveitis, and panuveitis. In various embodiments, the uveitis is non-infectious uveitis. In various embodiments, the uveitis is systemic or idiopathic.

In various embodiments, the subject suffers from macular edema, eg, cystic macular edema.

In various embodiments, the subject has a CRT greater than 300 μm.

In various embodiments, the subject has other signs of intraocular inflammation. For example, other signs of intraocular inflammation are selected from the group consisting of perivascular retinal vascular hardening and retinal vascular leakage.

In various embodiments, the subject has been suffering from uveitis for at least three months.

In various embodiments, at least one symptom of uveitis in the subject is normalized. For example, a symptom of uveitis is selected from the group consisting of VH, BCVA, macular edema, signs of ocular inflammation, retinal vascular leakage, CRT, and anterior chamber inflammation.

In various embodiments, the subject is treated with a corticosteroid for at least three months. For example, the corticosteroid is prednisone. In various embodiments, prednisone is administered at 15 to 80 mg / day.

In various embodiments, methotrexate was also administered to the subject. For example, methotrexate was administered at 6 to 25 mg / week.

In various embodiments, a corticosteroid is administered to the subject. For example, the corticosteroid is prednisone. In various embodiments, prednisone is administered at 15 to 80 mg / day.

In various embodiments, methotrexate is also administered to the subject. For example, methotrexate is administered at 6 to 25 mg / week.

In various embodiments, after 16 weeks, the subject achieves a decrease in VH level on the Miami 9-point scale by at least 2 stops, or is allowed to reduce the dose of corticosteroids to less than 10 mg per day.

In various embodiments, after 16 weeks, the subject achieves a decrease in VH level on the Miami 9-point scale of at least 2 stops. In various embodiments, after 16 weeks, it is possible to reduce the dose of corticosteroids required by the subject to less than 10 mg per day. In various embodiments, the subject has a greater than 20% reduction in CRT, an improvement in BCVA greater than 10 letters, a reduction in retinal vascular leakage, and / or an improvement in the clinical score of uveitis.

In various embodiments, the subject achieves an improvement in BCVA after 16 weeks. In various embodiments, CRT normalization is achieved in the subject after 16 weeks. In various embodiments, after 16 weeks, the subject has normalized retinal vascular leakage. In various embodiments, after 16 weeks, the subject achieves an improvement in the clinical score for uveitis.

In various embodiments, an antibody that specifically binds to an IL-6 receptor comprises a heavy chain variable region sequence SEQ ID NO: 2 and a light chain variable region sequence SEQ ID NO: 3.

In various embodiments, the antibody is administered in an amount of about 150 to about 200 mg every two weeks. For example, the antibody is administered in an amount of about 150 mg once every two weeks. In various embodiments, the antibody is administered in an amount of about 200 mg once every two weeks.

In various embodiments, the antibody is sarilumab.

In various embodiments, the antibody is tocilizumab. For example, tocilizumab is administered intravenously at about 4 to about 8 mg / kg every four weeks. In various embodiments, tocilizumab is administered subcutaneously at about 162 mg once a week or once every two weeks.

One aspect of the present invention provides for the use of an antibody for the manufacture of a medicament for the treatment of uveitis and / or macular edema in a subject, wherein the antibody comprises a heavy chain variable region sequence SEQ ID NO: 2 and a light chain variable region sequence SEQ ID NO: 3.

One aspect of the present invention provides for the use of a composition for the manufacture of a medicament for the treatment of uveitis in a subject in need thereof, wherein the composition comprises a therapeutically effective amount of an antibody, wherein the antibody comprises a heavy chain variable region sequence under SEQ ID NO: 2 and a light chain variable region sequence under SEQ ID NO: 3. In various embodiments, the antibody is sarilumab.

In various embodiments, the uveitis is selected from the group consisting of middle uveitis, posterior uveitis, and panuveitis. In various embodiments, the uveitis is non-infectious uveitis. In various embodiments, the uveitis is systemic or idiopathic.

In various embodiments, the subject has a VH level of 2 on the Miami 9-grade scale or greater.

In various embodiments, the subject has a VH of 3, 4, 5, 6, 7, or 8 on the Miami 9-step scale or greater. In various embodiments, the subject has a VH level of 4 on the Miami 9-grade scale or greater.

In various embodiments, the subject suffers from macular edema.

In various embodiments, the subject has a CRT greater than 300 μm.

In various embodiments, the subject has other signs of intraocular inflammation. For example, other signs of intraocular inflammation are selected from the group consisting of perivascular retinal vascular hardening and retinal vascular leakage.

In various embodiments, the subject has been suffering from uveitis for at least three months.

In various embodiments, at least one symptom of uveitis in the subject is normalized. In various embodiments, the uveitis symptom is selected from the group consisting of VH level, BCVA, macular edema, ocular inflammation signs, CRT, and anterior chamber inflammation.

In various embodiments, the subject is treated with a corticosteroid for at least three months. For example, the corticosteroid is prednisone.

In various embodiments, prednisone is administered at 15 to 80 mg / day.

In various embodiments, methotrexate was also administered to the subject. For example, methotrexate was administered at 6 to 25 mg / week.

In various embodiments, a corticosteroid is administered to the subject. For example, the corticosteroid is prednisone. In various embodiments, prednisone is administered at 15 to 80 mg / day.

In various embodiments, methotrexate is also administered to the subject. For example, methotrexate is administered at 6 to 25 mg / week.

In various embodiments, after 16 weeks, the subject achieves a decrease in VH level on the Miami 9-point scale by at least 2 stops, or is allowed to reduce the dose of corticosteroids to less than 10 mg per day.

In various embodiments, after 16 weeks, the subject achieves a decrease in VH level on the Miami 9-point scale of at least 2 stops.

In various embodiments, after 16 weeks, it is possible to reduce the dose of corticosteroids required by the subject to less than 10 mg per day.

In various embodiments, the subject has a greater than 20% reduction in CRT, an improvement in BCVA greater than 10 letters, a reduction in retinal vascular leakage, and / or an improvement in the clinical score of uveitis.

In various embodiments, the subject achieves an improvement in BCVA after 16 weeks.

In various embodiments, CRT normalization is achieved in the subject after 16 weeks.

In various embodiments, after 16 weeks, the subject has normalized retinal vascular leakage.

In various embodiments, after 16 weeks, the subject achieves an improvement in the clinical score for uveitis.

Examples of embodiments of the present invention are shown below.

Embodiment 1. A method of treating uveitis and / or macular edema in a subject in need thereof, comprising administering an effective amount of an antibody that specifically binds the IL-6 receptor.

Embodiment 2. The method of Embodiment 1, wherein the subject has a vitreous opacity (VH level) of 2 on the Miami 9-grade scale or greater.

Embodiment 3. The method of embodiment 1 or 2, wherein the subject has a central retinal thickness (CRT) greater than 300 microns.

Embodiment 4. A method as in any preceding embodiment, wherein the subject has a VH level of 3, 4, 5, 6, 7, or 8 on the Miami 9-step scale or greater.

Embodiment 5. A method as in any preceding embodiment, wherein the subject has a VH level of 4 on the Miami 9-step scale or greater.

Embodiment 6. A method according to any of the preceding embodiments, wherein the uveitis is selected from the group consisting of middle uveitis, posterior uveitis, and panuveitis.

Embodiment 7. A method according to any of the preceding embodiments, wherein the uveitis is non-infectious uveitis.

Embodiment 8. A method according to any of the preceding embodiments, wherein the uveitis is systemic or idiopathic.

Embodiment 9. A method according to any of the previous embodiments, wherein the subject suffers from macular edema.

Embodiment 10. A method according to any of the previous embodiments, wherein the subject has a CRT greater than 300 microns.

Embodiment 11. A method according to any of the preceding embodiments, wherein the subject has other signs of intraocular inflammation.

Embodiment 12. The method of Embodiment 11, wherein the other signs of intraocular inflammation are selected from the group consisting of perivascular retinal vascular hardening and retinal vascular leakage.

Embodiment 13. A method according to any of the preceding embodiments, wherein the subject has been suffering from uveitis for at least three months.

Embodiment 14. The method of Embodiment 13, wherein at least one symptom of uveitis and / or macular edema in the subject is normalized.

Embodiment 15. The method of Embodiment 14, wherein the uveitis symptom is selected from the group consisting of increased VH, decreased maximum corrected visual acuity (BCVA), macular edema, signs of ocular inflammation, retinal vascular leakage, CRT, and anterior chamber inflammation ...

Embodiment 16. A method according to any of the preceding embodiments, wherein the subject has been treated with a corticosteroid for at least three months.

Embodiment 17 The method of Embodiment 16, wherein the corticosteroid is prednisone.

Embodiment 18. The method of Embodiment 17 wherein prednisone is administered in an amount of 15 to 80 mg / day.

Embodiment 19. A method according to any of the preceding embodiments, wherein the subject is also administered methotrexate.

Embodiment 20. The method of Embodiment 19, wherein methotrexate is administered in an amount of 6 to 25 mg / week.

Embodiment 21. A method according to any of the preceding embodiments, wherein a corticosteroid is administered to the subject.

Embodiment 22. The method of Embodiment 21, wherein the corticosteroid is prednisone.

Embodiment 23. The method of Embodiment 22 wherein prednisone is administered in an amount of 15 to 80 mg / day.

Embodiment 24. A method according to any of the preceding embodiments, wherein methotrexate is also administered to the subject.

Embodiment 25. The method of Embodiment 24 wherein methotrexate is administered in an amount of 6 to 25 mg / week.

Embodiment 26. The method of any one of Embodiments 16-18 or 21-23, wherein after 16 weeks, the subject achieves:

- a decrease in VH level on the Miami 9-point scale by at least 2 notches, or

- reducing the dose of corticosteroids to less than 10 mg per day.

Embodiment 27. The method of any preceding embodiment, wherein after 16 weeks, the subject achieves a decrease in VH level on the Miami 9-point scale of at least 2 stops.

Embodiment 28. The method of any one of Embodiments 16-18 or 21-23, wherein after 16 weeks it is possible to reduce the dosage of corticosteroids required by the subject to less than 10 mg per day.

Embodiment 29. A method according to any of the preceding embodiments, wherein the subject exhibits:

- decrease in CRT by more than 20%,

- improvement of BCVA by more than 10 letters,

- reduction of retinal vascular leakage and / or

- improvement in the clinical assessment score of uveitis.

Embodiment 30. The method of embodiment 29, wherein after 16 weeks, the subject has improved BCVA.

Embodiment 31. The method of Embodiment 29, wherein after 16 weeks, the subject achieves CRT normalization.

Embodiment 32. The method of Embodiment 29, wherein after 16 weeks, the subject has normalized retinal vascular leakage.

Embodiment 33. The method of Embodiment 29, wherein after 16 weeks, the subject achieves an improvement in clinical score.

Embodiment 34. A method according to any of the preceding embodiments, wherein the antibody that specifically binds to the IL-6 receptor comprises a heavy chain variable region sequence SEQ ID NO: 2 and a light chain variable region sequence SEQ ID NO: 3.

Embodiment 35. The method of Embodiment 34, wherein the antibody is administered in an amount of about 200 mg every two weeks.

Embodiment 36. A method according to any of the preceding embodiments, wherein the antibody is sarilumab.

Embodiment 37. The method of any one of Embodiments 1-33, wherein the antibody is tocilizumab.

Embodiment 38. The method of Embodiment 37, wherein tocilizumab is administered in an amount of 4 to 8 mg / kg.

Embodiment 39. A method of treating uveitis and / or macular edema in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an antibody, wherein the antibody comprises a heavy chain variable region sequence under SEQ ID NO: 2 and a light chain variable region sequence under SEQ ID NO: 3.

Embodiment 40. The method of Embodiment 39, wherein the antibody is sarilumab.

Embodiment 41. A method as in any one of Embodiments 39 or 40, wherein the uveitis is selected from the group consisting of middle uveitis, posterior uveitis, and panuveitis.

Embodiment 42. The method of any one of Embodiments 39-41, wherein the uveitis is non-infectious uveitis.

Embodiment 43. The method of any one of Embodiments 39-42, wherein the uveitis is systemic or idiopathic.

Embodiment 44. The method of any one of Embodiments 39-43, wherein the subject has a VH level of 2 on the Miami 9 Grade Scale or greater.

Embodiment 45. The method of Embodiment 44, wherein the subject has a vitreous haze (VH) level of 3, 4, 5, 6, 7, or 8 on the Miami 9 Grade Scale or greater.

Embodiment 46. The method of Embodiment 44, wherein the subject has a vitreous (VH) opacity level of 4 on the Miami 9 Grade Scale or greater.

Embodiment 47. The method of any one of Embodiments 39-46, wherein the subject suffers from macular edema.

Embodiment 48. The method of any one of Embodiments 39-47, wherein the subject has a CRT greater than 300 microns.

Embodiment 49. The method of any one of Embodiments 39-48, wherein the subject has other signs of intraocular inflammation.

Embodiment 50. The method of Embodiment 49, wherein the other signs of intraocular inflammation are selected from the group consisting of perivascular retinal vascular hardening and retinal vascular leakage.

Embodiment 51. The method of any one of Embodiments 39-50, wherein the subject has been suffering from uveitis for at least three months.

Embodiment 52. The method of any one of Embodiments 39-51, wherein at least one symptom of uveitis in the subject is normalized.

Embodiment 53. The method of embodiment 52, wherein the uveitis symptom is selected from the group consisting of increased VH, decreased BCVA, macular edema, signs of ocular inflammation, CRT, and anterior chamber inflammation.

Embodiment 54. The method of any one of Embodiments 39-53, wherein the subject has been treated with a corticosteroid for at least three months.

Embodiment 55. The method of embodiment 54, wherein the corticosteroid is prednisone.

Embodiment 56. The method of Embodiment 55 wherein prednisone is administered in an amount of 15 to 80 mg / day.

Embodiment 57. The method of any one of Embodiments 39-56, wherein the subject has also been administered methotrexate.

Embodiment 58. The method of Embodiment 58, wherein methotrexate is administered in an amount of 6 to 25 mg / week.

Embodiment 59. The method of any one of Embodiments 39-58, wherein a corticosteroid is administered to the subject.

Embodiment 60. The method of Embodiment 59, wherein the corticosteroid is prednisone.

Embodiment 61. The method of Embodiment 60 wherein prednisone is administered in an amount of 15 to 80 mg / day.

Embodiment 62. The method of any one of Embodiments 39-61, wherein methotrexate is also administered to the subject.

Embodiment 63. The method of Embodiment 62 wherein methotrexate is administered in an amount of 6 to 25 mg / week.

Embodiment 64. The method of any one of Embodiments 54-56 or 59-60, wherein after 16 weeks, the subject achieves:

- a decrease in the VH level on the 9-point Miami scale by at least 2 steps; or

- reducing the dose of corticosteroids to less than 10 mg per day.

Embodiment 65. The method of any one of Embodiments 39-64, wherein after 16 weeks, the subject achieves a decrease in VH level on the Miami 9-point scale of at least 2 stops.

Embodiment 66. The method of any one of Embodiments 54-56 or 59-60, wherein after 16 weeks it is possible to reduce the dosage of corticosteroids required by the subject to less than 10 mg per day.

Embodiment 67. The method of any one of Embodiments 39-66, wherein the subject exhibits:

- decrease in CRT by more than 20%,

- improvement of BCVA by more than 10 letters,

- reduction of retinal vascular leakage and / or

- improvement in the clinical assessment score of uveitis.

Embodiment 68. The method of embodiment 67, wherein after 16 weeks, the subject has improved BCVA.

Embodiment 69. The method of Embodiment 67, wherein after 16 weeks, the subject achieves CRT normalization.

Embodiment 70. The method of Embodiment 67, wherein after 16 weeks, the subject achieves a reduction in retinal vascular leakage.

Embodiment 71. The method of Embodiment 66, wherein after 16 weeks, the subject achieves an improvement in clinical score.

DETAILED DESCRIPTION

The present disclosure provides pharmaceutical compositions and methods of using these compositions for treating uveitis and / or macular edema and normalizing at least one symptom of one or both of these disorders. These compositions provide at least one antibody that specifically binds the human interleukin-6 receptor (hIL-6R), and optionally at least one additional therapeutic agent such as methotrexate or a corticosteroid.

Antibodies to hIL-6R

The present disclosure provides methods that involve administering to a patient a human antibody or antigen binding fragment thereof that binds specifically to hIL-6R. As used herein, the term "hIL-6R" means a human cytokine receptor that specifically binds human interleukin-6 (IL-6). In certain embodiments, an antibody that is administered to a patient specifically binds to the extracellular domain of hIL-6R.

The extracellular domain of hIL-6R is shown in the amino acid sequence under SEQ ID NO: 1. Sequence under SEQ ID NO: 1 represents MVAVGCALLAALLAAPGAALAPRRCPAQEVARGVLTSLPGDSVTLTCPGVEPEDNATVHWVLRKPAAGSHPSRWAGMGRRLLLRSVQLHDSGNYSCYRAGRPAGTVHLLVDVPPEEPQLSCFRKSPLSNVVCEWGPRSTPSLTTKAVLLVRKFQNSPAEDFQEPCQYSQESQKFSCQLAVPEGDSSFYIVSMCVASSVGSKFSKTQTFQGCGILQPDPPANITVTAVARNPRWLSVTWQDPHSWNSSFYRLRFELRYRAERSKTFTTWMVKDLQHHCVIHDAWSGLRHVVQLRAQEEFGQGEWSEWSPEAMGTPWTESRSPPAENEVSTPMQALTTNKDDDNILFRDSANATSLPVQD.

Unless specifically indicated otherwise, the term "antibody" as used herein should be understood to encompass antibody molecules that contain two heavy chains of immunoglobulins and two light chains of immunoglobulins (i.e. "complete antibody molecules"), as well as antigen-binding fragments thereof. The terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, and the like, as used herein, include any naturally occurring, enzymatically, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex ... Antigen-binding antibody fragments can be obtained by for example, from complete antibody molecules using any suitable standard techniques, such as proteolytic cleavage or recombination techniques in genetic engineering, involving the manipulation and expression of DNA encoding the variable and optionally constant domains of antibodies. Such DNA is known and / or readily available, for example, from commercial sources, DNA libraries (including, for example, phage-antibody libraries), or it can be synthesized. DNA can be sequenced and chemically manipulated or manipulated using molecular biology techniques, for example, to position one or more variable and / or constant domains in a suitable configuration or to introduce codons, create cysteine residues, modify, add or remove amino acids and etc.

Non-limiting examples of antigen binding fragments include: (i) Fab fragments; (ii) F (ab ') 2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single chain Fv molecules (scFv); (vi) dAb fragments; and (vii) minimal recognition units, consisting of amino acid residues that mimic the hypervariable region of an antibody (eg, an isolated complementarity determining region (CDR)). Other engineered molecules such as diabodies, tribodies, tetrabodies, and miniantibodies are also encompassed by the expression "antigen binding moiety" as used herein.

Antigennegative fragment of an antibody, as a rule, will contain at least one variable domain. The variable domain can be of any size or amino acid composition and will typically contain at least one CDR that is adjacent to or within the reading frame of one or more framework sequences. In antigen-binding fragments having a V _H domain linked to a V _L domain, the V _H and V _L domains can be located relative to each other in any suitable order. For example, the variable region may be dimeric and contain V _H -V _H , V _H -V _L, or V _L -V _L dimers. Alternatively, the antigen-binding fragment of an antibody may contain a monomeric VH or VL domain.

In certain embodiments, an antigen-binding antibody fragment may comprise at least one variable domain covalently linked to at least one constant domain. Non-limiting illustrative variable and constant domain configurations that can be found in an antigen-binding fragment of an antibody of the present invention include: (i) V_H-C_H1; (ii) V_H-C_H2; (iii) V_H-C_H3; (iv) V_H-C_H1-C_H2; (v) V_H-C_H1-C_H2-C_H3; (vi) V_H-C_H2-C_H3; (vii) V_H-C_L; (viii) V_L-C_H1; (ix) V_L-C_H2; (x) V_L-C_H3; (xi) V_L-C_H1-C_H2; (xii) V_L-C_H1-C_H2-C_H3; (xiii) V_L-C_H2-C_H3 and (xiv) V_L-C_L... In any variable and constant domain configuration, including any of the illustrative configurations listed above, the variable and constant domains can either be directly linked to each other, or can be linked through an entire or partial hinge or linker region. The hinge section can consist of at least 2 (for example, 5, 10, 15, 20, 40, 60 or more) amino acids that result in the formation of a flexible or semi-flexible bond between adjacent variable and / or constant domains in one polypeptide molecule. In addition, an antigen-binding fragment of an antibody of the present invention may contain a homodimer or heterodimer (or other multimer) from any of the variable and constant domain configurations set forth above in non-covalent association with each other and / or with one or more monomeric V domains._H or V_L (eg, using disulfide (disulfide) bonds (bonds)).

The term "specifically binds" means that an antibody or antigen-binding fragment thereof forms a complex with an antigen that is relatively stable under physiological conditions. Specific binding can be characterized by a dissociation constant of at least about 1 x 10 ^-6 M or less. In other embodiments, the dissociation constant is at least about 1 x 10 ^-7 M, 1 x 10 ^-8 M, or 1 x 10 ^-9 M. Methods for determining whether two molecules bind specifically are well known in the art and include, e.g. equilibrium dialysis, surface plasmon resonance, etc.

As with whole antibody molecules, antigen-binding fragments can be monospecific or multispecific (for example, bispecific). A multispecific antigen binding fragment of an antibody will typically contain at least two different variable domains, where each variable domain is capable of specifically binding to a separate antigen or to a different epitope of the same antigen. Any multispecific antibody format, including the formats of the exemplary bispecific antibodies disclosed herein, can be adapted for use in the context of an antigen binding fragment of an antibody of the present invention using standard techniques available in the art.

In specific embodiments, an antibody or antibody fragment for use in a method of the present invention may be a multispecific antibody that may be specific for different epitopes of one target polypeptide, or may contain antigen binding domains specific for epitopes of more than one target polypeptide. An illustrative antibody in a bispecific format that can be used in the context of the present invention comprises the use of a C _H3 domain of a first immunoglobulin (Ig) and a C _H3 domain of a second Ig immunoglobulin, wherein the C _H3 domains of the first and second Ig differ from each other at least one amino acid, and wherein a difference of at least one amino acid reduces the binding of the bispecific antibody to Protein A as compared to a bispecific antibody in which there is no amino acid difference. In one embodiment, the C _H3 domain of the first Ig binds protein A, and the C _H3 domain of the second Ig contains a mutation that reduces or eliminates protein A binding, such as the H95R modification (IMGT exon numbering; EU H435R numbering). The second C _H3 may additionally contain modification Y96F (according to IMGT; Y436F according to EU). Additional modifications that can be found within the second C _H3 include: D16E, L18M, N44S, K52N, V57M and V82I (by IMGT; D356E, L358M, N384S, K392N, V397M and V422I by EU) in the case of IgG1 antibodies; N44S, K52N and V82I (IMGT; N384S, K392N and V422I according to EU) in the case of antibodies IgG2 and Q15R, N44S, K52N, V57M, R69K, E79Q and V82I (according to IMGT; Q355R, N384S, K392N, V399K4M, R and V422I by EU) in the case of IgG4 antibodies. The bispecific antibody format options described above are contemplated within the scope of the present invention.

In other specific embodiments, the antibody is sarilumab (SAR153191). The variable region of the heavy chain of sarilumab contains the sequence under SEQ ID NO: 2.

The variable region of the light chain of sarilumab contains the sequence under SEQ ID NO: 3.

"Neutralizing" or "blocking" antibody, as used herein, means an antibody that binds to hIL-6R and inhibits the biological activity of hIL-6. Such inhibition of the biological activity of hIL-6 can be assessed by measuring one or more indicators of the biological activity of hIL-6 known in the art, such as hIL-6-induced cellular activity and hIL-6 binding to hIL-6R (see examples below) ...

Fully human monoclonal antibodies to IL-6R can contain one or more amino acid substitutions, insertions and / or deletions in the framework regions and / or CDR regions of the variable domains of the heavy and light chains compared to the corresponding sequences of the germline. Such mutations can be easily identified by comparing the amino acid sequences disclosed herein with germline sequences available, for example, from public antibody sequence databases. The present invention provides antibodies and antigen-binding fragments thereof derived from any amino acid sequences disclosed herein, wherein one or more amino acids within one or more frameworks and / or CDRs are mutated back to the corresponding germline residue (s) or a conservative amino acid substitution (natural or unnatural) of the corresponding germline residue (s) (such sequence changes are referred to herein as "germline reverse mutations"). A person skilled in the art, from the sequences of the variable regions of the heavy and light chains disclosed herein, can readily obtain a variety of antibodies and antigen-binding fragments that contain one or more individual germline reverse mutations or combinations thereof. In certain embodiments, all framework and / or CDR residues in the VH and / or VL domains are mutated back to the germline sequence. In other embodiments, only certain residues are mutated back to the germline sequence, for example, only residues located in the first 8 amino acids of FR1 or in the last 8 amino acids of FR4 are mutated, or only residues located in CDR1, CDR2 or CDR3 are mutated. In addition, the antibodies of the present invention may contain any combination of two or more germline reverse mutations within frameworks and / or CDRs, that is, where certain individual residues are mutated back to the germline sequence, while certain other residues that differ from the germline sequence are retained. Once obtained, antibodies and antigen binding fragments that contain one or more germline reverse mutations can be easily tested for one or more desired properties, such as improved binding specificity, increased binding affinity, improved or enhanced biological antagonist or agonist properties (in if necessary), reduced immunogenicity and etc. Antibodies and antigennegative fragments obtained using this general method are encompassed by the present invention.

The term "epitope" refers to an antigenic determinant that interacts with a specific antigen-binding site in a variable region of an antibody molecule known as a paratope. One antigen can have more than one epitope. Epitopes can be conformational or linear. A conformational epitope is formed by spatially close amino acids from different segments of a linear polypeptide chain. A linear epitope is formed by contiguous amino acid residues in the polypeptide chain. Under certain conditions, the epitope may include fragments of saccharides, phosphoryl groups, or sulfonyl groups of the antigen.

The anti-hIL-6R antibody can be sarilumab (SAR153191). In one embodiment, sarilumab is defined as an antibody comprising a heavy chain variable region SEQ ID NO: 2 and a light chain variable region SEQ ID NO: 3.

The amino acid sequence SEQ ID NO: 2 is EVQLVESGGGLVQPGRSLRLSCAASRFTFDDYAMHWVRQAPGKGLEWVSGISWNSGRIGYADSVKGRFTISRDNAENSLFLQMNGLRAEDTALYYCAKGRDSFDIWGQGTMV

The amino acid sequence SEQ ID NO: 3 is DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYGASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFASYYCQQANSFPYTFGQGTKLEIK.

In other embodiments, sarilumab is defined as an antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 4 and a light chain comprising the amino acid sequence of SEQ ID NO: 5.

The amino acid sequence under SEQ ID NO: 4 is

EVQLVESGGGLVQPGRSLRLSCAAS RFTFDDYA MHWVRQAPGKGLEWVSG ISWNSGRI GYADSVKGRFTISRDNAENSLFLQMNGLRAEDTALYYC AKGRDSFDI WGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

The amino acid sequence under SEQ ID NO: 5 is

DIQMTQSPSSVSASVGDRVTITCRAS QGISSW LAWYQQKPGKAPKLLIY GAS SLESGVPSRFSGSGSGTDFTLTISSLQPEDFASYYC QQANSFPYT FGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC. The anti-hIL6R antibody can also be tocilizumab. Tocilizumab is also known as "humanized anti-PM-1 antibody" or "hMP1" and was obtained by grafting the complementarity determining regions (CDRs) into the murine PM-1 antibody (Hirata et al., J. Immunology (1989) 143, 2900 -2906) to a human antibody (international patent application WO 92/19759). WO96 / 11020 shows that a humanized anti-PM1 antibody is effective in an animal model of rheumatoid arthritis. Tocilizumab is sold under the trade name Actemra®.

Dosage ranges

As used herein, "administered from about X to about Y mg" means that the specified substance is administered at any value within the specified range, including the end points of the range. For example, “the dose of anti-hIL-6R antibody administered to a patient is between 10 mg and 500 mg” includes 10 mg of anti-hIL-6R antibody, 500 mg of anti-hIL-6R antibody, and all doses in between.

Corticosteroids

Corticosteroids include prednisone, hydrocortisone, hydrocortisone acetate, cortisone acetate, thixocortol pivalate, prednisolone, and methylprednisolone. In accordance with the compositions and methods of the present disclosure, corticosteroids can be administered as follows. The corticosteroid can be administered in an amount of 15 to 80 mg orally daily. In certain embodiments, the corticosteroid can be administered in an amount of 15 to 20, 20 to 50, and 35 to 80 mg per day. In other embodiments, the corticosteroid is administered at 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80 mg per day. In certain embodiments, the corticosteroid is prednisone.

In accordance with other embodiments, the corticosteroid can also be selected from triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, galcinonide, betamethasone, betamethasone sodium phosphate, damehexamethasone sodium hydrocortone, dexamethasone phosphate 17 valerate, halomethasone, alcomethasone dipropionate, betamethasone valerate, betamethasone dipropionate, predicarbate, clobetasone-17-butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate, fluprednidrizidene-hydroxydene acetate-17 17-buteprate, ciclesonide, and prednicarbate.

Methotrexate

Methotrexate can be administered in an amount of 6 to 25 mg per week orally or intramuscularly. In another embodiment, methotrexate is administered in an amount of 6 to 25 mg / week orally or intramuscularly to patients from the Asia Pacific region or those originating from individuals from the Asia Pacific region. The Asia Pacific region includes Taiwan, South Korea, Malaysia, the Philippines, Thailand, and India. In certain embodiments, methotrexate is administered in an amount of 6 to 12, 10 to 15, 15 to 20, and 20 to 25 mg per week. In other embodiments, methotrexate is administered at 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 mg per week.

Uveitis

Uveitis, as used herein, refers to any intraocular inflammatory disease or disorder. See. "Taber's Cyclopedic Medical Dictionary" , 1997 (18 ^th edition), edited by Clayton L. Thomas, MD, M.PH., published by FA Davis Company, Philadelphia, Pennsylvania. The different types of uveitis are described below. Structures of the uveal tract (eg, the iris, ciliary body, and choroid) and parts outside the uveal tract of the eye (eg, the retina and cornea) can be implicated in uveitis. Uveitis can include iritis (i.e., inflammation of the iris), cyclitis (i.e., inflammation of the ciliary body), panuveitis (i.e., inflammation of the entire uveo-vascular layer of the eye), posterior uveitis, and anterior uveitis. Medium uveitis, also called peripheral uveitis, concentrates in the area immediately behind the iris and lens in the ciliary body and flat part of the ciliary body and is also called "cyclin" and "parsplanitis". See also U.S. Patent No. 9139646; U.S. Patent No. 8895521 and U.S. Patent Publication No. 20090082288 A1, each of which is incorporated herein in its entirety. Uveitis can be acute (i.e., signs and symptoms come on suddenly and last for a short period of time, such as days or weeks) or it can be chronic (i.e., onset is gradual and lasts longer than acute uveitis e.g. over several weeks, months or years).

"Posterior uveitis" is often called chorioretinitis, which is a form of uveitis involving inflammation of the choroid and retina. See also Suttorp-Schulten et al., 1996 Ocul Immunol Inflamm. 4 (4): pp. 207-217. "Anterior uveitis" as used herein means ididocyclitis, which is a disorder characterized by inflammation of the iris and ciliary body and / or iritis. Anterior uveitis usually results in symptoms such as pain, redness, photophobia, and decreased vision. Signs of anterior uveitis include pupillary miosis and injection of the conjunctiva adjacent to the cornea, called perilimbal erythema. See also Gordon et al., 1998 J Clin Immunol. 18 (4): pages 264-271. "Diffuse" uveitis means a type of uveitis characterized by inflammation involving all parts of the eye, including the anterior, middle and posterior structures. See Huang et al., "Ocular Inflammatory Disease and Uveitis Manual: Diagnosis and Treatment."

Inflammatory products (eg, cells, fibrin, excess proteins) in ocular inflammation in various embodiments may be present in the fluid spaces of the eye. For example, products of inflammation can be found in the anterior chamber, posterior chamber, and vitreous space.

Uveitis can occur after a surgical or traumatic injury to the eye; as a component of an autoimmune disorder (for example, such as rheumatoid arthritis, Behcet's disease, sarcoidosis, etc.), a separate immune-mediated eye disorder (such as parsplanitis or iridocyclitis), as a disease not associated with known etiologies, and after certain systemic diseases that cause the deposition of antibody-antigen complexes in uveal tissues. Uveitis includes eye inflammation associated with Behcet's disease, sarcoidosis, Vogt-Koyanagi-Harada syndrome, and others. In various embodiments, non-infectious uveitis occurs in the absence of an infectious agent.

Macular edema

“ Macular edema,” as used herein, means the accumulation of fluid within a portion of the macular retina. The fluid interferes with the blood supply to the macular and / or retina, resulting in a negative effect on vision. Symptoms of macular edema include decreased visual acuity, micropsia, metamorphopsia, decreased color perception, and central or paracentral scotoma. See US Patent No. 6,046,223. There are various types of macular edema, including cystic macular edema, which is a disorder that affects the central retina or macular macula. Cystic macular edema is often diagnosed by the presence of multiple cystic (cystic) areas of fluid appearing in the macula that cause swelling or edema. In various embodiments, the subject suffers from diabetic retinopathy, which can cause macular edema.

Administration for the purpose of therapy and therapeutic formulations

The methods described herein comprise administering a therapeutically effective amount of an anti-hIL-6R antibody to a subject. As used herein, the phrase "therapeutically effective amount" means a dose of a therapeutic agent that results in treatment of uveitis and / or macular edema. Used in this document, the term "treatment" means bringing to the normalization of one or more symptoms associated with uveitis and / or macular edema, or leading to a biological effect (for example, a decrease in the level of a specific biomarker) that is associated with an underlying pathological (pathological) mechanism (s) leading to the condition or symptom (s). For example, the following symptoms or conditions are associated with uveitis and macular edema: increased levels of vitreous opacity (VH), decreased maximum corrected visual acuity (BCVA), increased amounts of fluid in the macula, signs of eye inflammation, retinal vascular leakage, increased central thickness retinal (CRT) and eye inflammation in the anterior chamber. More specifically, symptoms that are associated with macular edema include blurry or erratic vision near the center of the visual field, eye inflammation, blurred vision, impaired color recognition, tissue thickening, and ocular vascular leakage. In certain embodiments, the macular edema symptoms are normalized by reducing the amount of excess fluid in the macula.

Vitreous opacity (VH)

Vitreous opacity will be graded on the Miami 9-point scale (grade 0 to 8) (see Davis JL, et al. Am J Ophthalmol. 2010; 150 (5): 637-41). Vitreous opacity is a darkening of the fundus features by vitreous cells and protein exudate. It affects vision more significantly than inflammation of the anterior chamber and is thus widely used as an efficacy criterion for clinical trials, including middle, posterior uveitis or panuveitis.

BCVA (ETDRS Letter Grade)

Visual acuity (VA) can be assessed using the BCVA index, as measured by the standardized early treatment for diabetic retinopathy study (ETDRS) protocol. Maximum corrected visual acuity can be measured at each visit.

Central Retinal Thickness (CRT)

Central retinal thickness (CRT) can be measured using spectral domain optical coherence tomography (SD-OCT). Spectral domain optical coherence tomography can be performed using standardized techniques.

Clinical Assessment Score

A patient can be identified as "active" based on one of the following criteria at an initial time point (index variable) and assessed by this parameter after treatment to determine if the patient has reached an "inactive" state after treatment: VH, CRT and BCVA. Secondary Variables: Clinical Assessment Score (CAS) [regardless of the parameter for activity] -improved: I, no change: N, worsened: W.

Improved: A score I (Improved) is assigned for what is considered clinically significant improvement. A score of N (no change) is assigned if there is no change or if the change is not considered clinically important. A W (worsened) score is assigned if the change results in a short-term risk of vision loss for the study participant and requires completion of his participation in the study.

Index Variable Active Inactive Clinical assessment of VH > 4 0 Clinical CRT Evaluation > = 300 <300 BCVA score <70 > = 70

If several variables are available for a particular type of uveitis, then the variable with the worst status at the baseline (clinical score) can be selected as the index.

Definition of success Clinical assessment of VH 2-step reduction in eye examination according to the change from the starting point in time Clinical CRT Evaluation Reduction of CRT in eye examination by> = 20% compared to baseline for patients with macular edema Front camera 2 points BCVA score BCVA on eye examination - change in direction of magnification from the starting point in time by> = 10 letters

All signs of inflammation other than the index variable for a particular patient can be considered as a secondary variable for the patient. Primary signs of inflammation, not selected as an index variable, can be considered secondary variables. Gradation is used primarily in the rules for discontinuing treatment; improvement in the secondary variable is not considered improvement even if the secondary variable is the primary sign of inflammation (but not selected as an index variable for this patient).

In certain embodiments, the VH level is reduced by 2 on the Miami 9-point scale. In accordance with certain embodiments, the VH level is reduced by 1, 2, 3, 4, 5, 6, 7, 8, or 9 on the Miami 9-point scale. In accordance with certain embodiments, the VH level is reduced by 1-2, 1-3, 1-4, 2-4, or 3-5 points on the Miami 9-point scale.

In certain embodiments, the BCVA is increased by 10 letters on the EDTRS card. In accordance with other embodiments, BCVA is increased by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 letters per the EDTRS map. In accordance with other embodiments, the BCVA is increased by 5-15, 7-13, or 8-12 letters on the EDTRS card.

In other embodiments, the therapeutically effective amount reduces the dose of corticosteroids administered to the patient. In certain embodiments, such a dose of corticosteroid is reduced to less than 100, 90, 80, 70, 60, 50, 40, 30, 20, 10, 5, or 1 mg per day. In certain embodiments, the corticosteroid is prednisone.

In accordance with the methods of the present invention, the therapeutically effective amount of anti-hIL-6R antibody that is administered to a patient will vary with age and size (e.g. body weight or body surface area) of the patient, as well as the route of administration and other factors well known to those skilled in the art. In certain embodiments, the dose of anti-hIL-6R antibody administered to a patient is from about 10 mg to about 500 mg. For example, the present invention provides methods where about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, approximately 190 mg, approximately 195 mg, approximately 200 mg, approximately 205 mg, approximately 210 mg, approximately 215 mg, approximately 220 mg, approximately 225 mg, approximately 230 mg, approximately 235 mg, approximately 240 mg, approximately 245 mg, approximately 250 mg, approximately 255 mg, approximately 260 mg, approximately 265 mg, approximately 270 mg, approximately 275 mg , about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg or more anti-hIL-6R antibody is administered to a patient per week.

In various embodiments, the anti-hIL-6R antibody is administered in an amount of 100 to 200 mg once a week. In one embodiment, the anti-hIL-6R antibody is administered at 100 mg once a week. In one embodiment, the anti-hIL-6R antibody is administered at 150 mg once a week. In one embodiment, the anti-hIL-6R antibody is administered at 200 mg once a week. In one embodiment, the anti-hIL-6R antibody is administered in an amount of 100 to 150 mg once a week. In another embodiment, the anti-hIL-6R antibody is administered in an amount of 100 to 200 mg once every two weeks. In another embodiment, the anti-hIL-6R antibody is administered in an amount of 150 to 200 mg once every two weeks. In other embodiments, the anti-hIL-6R antibody is administered in an amount of about 100 to about 150 mg once a week. In other embodiments, the anti-hIL-6R antibody is administered at about 100, 150, or 200 mg every two weeks. In one embodiment, the anti-hIL-6R antibody is administered at 100 mg once every two weeks. In one embodiment, the anti-hIL-6R antibody is administered at 150 mg once every two weeks. In one embodiment, the anti-hIL-6R antibody is administered at 200 mg once every two weeks. In some of these embodiments, the anti-hIL-6R antibody is administered subcutaneously. In some of these embodiments, the anti-hIL-6R antibody is sarilumab.

In one embodiment, the anti-hIL-6R antibody is administered in an amount of about 100 to about 150 mg once a week. In another embodiment, the anti-hIL-6R antibody is administered in an amount of about 100 to about 200 mg once every two weeks. In another embodiment, the anti-hIL-6R antibody is administered in an amount of about 150 to about 200 mg once every two weeks. In some of these embodiments, the anti-hIL-6R antibody is administered subcutaneously. In some of these embodiments, the anti-hIL-6R antibody is sarilumab.

In one embodiment, the anti-hIL-6R antibody is administered at about 162 mg once a week. In another embodiment, the anti-hIL-6R antibody is administered at about 162 mg once every two weeks. In another embodiment, the anti-hIL-6R antibody is administered at 162 mg once a week. In another embodiment, the anti-hIL-6R antibody is administered at 162 mg once every two weeks. In some of these embodiments, the anti-hIL-6R antibody is administered subcutaneously. In accordance with some of these embodiments, the anti-hIL-6R antibody is tocilizumab.

The amount of anti-hIL-6R antibody that is administered to a patient can be expressed in milligrams of antibody per kilogram of the patient's body weight (i.e. mg / kg). For example, the methods of the present invention comprise administering an anti-hIL-6R antibody to a patient at a daily dose of about 0.01 to about 100 mg / kg, about 0.1 to about 50 mg / kg, or about 1 to about 10 mg / kg. the patient's body weight. In certain embodiments, the anti-hIL6R antibody is tocilizumab and is administered in an amount of about 4 mg / kg to about 8 mg / kg. In other embodiments, the anti-hIL6R antibody is tocilizumab and is administered in an amount of 4 mg / kg to 8 mg / kg. In some of these embodiments, tocilizumab is administered intravenously.

The methods of the present invention involve administering multiple doses of anti-hIL-6R antibody to a patient over a period of time. For example, an anti-hIL-6R antibody can be administered about 1-5 times a day, about 1-5 times a week, about 1-5 times a month, or about 1-5 times a year. In certain embodiments, the methods of the present invention comprise administering a first dose of anti-hIL-6R antibody to a patient at a first time point, followed by administering at least a second dose of anti-hIL-6R antibody to a patient at a second time point. In certain embodiments, the first and second doses may contain the same amount of anti-hIL-6R antibody. For example, each of the first and second doses may contain from about 10 mg to about 500 mg, from about 20 mg to about 300 mg, from about 100 mg to about 200 mg, or from about 100 mg to about 150 mg of antibody. The interval between the first and second doses can be from about a few hours to several weeks. For example, the second time point (i.e. the time at which the second dose is administered) may range from about 1 hour to about 7 weeks after the first time point (i.e. time when the first dose is administered). In accordance with certain illustrative embodiments of the present invention, the second time point may be at about 1 hour, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 2 days, about 3 days , approximately 4 days, approximately 5 days, approximately 6 days, approximately 7 days, approximately 2 weeks, approximately 4 weeks, approximately 6 weeks, approximately 8 weeks, approximately 10 weeks, approximately 12 weeks, approximately 14 weeks or more after the first time point ... In certain embodiments, the second time point is about 1 week or about 2 weeks later. The second and subsequent doses can be administered to the patient in a similar manner during the course of treatment.

As used herein, "about" means at least 5% more or less of the value. For example, about 100 mg would mean a range of 95 to 105 mg.

The present invention provides methods of using therapeutic compositions comprising antibodies to IL-6R or antigen binding fragments thereof, and optionally one or more additional therapeutic agents. Therapeutic compositions of the present invention will be administered with suitable carriers, excipients, and other agents that are formulated to provide improved transfer, delivery, tolerance, and the like. Many suitable formulations can be found in the reference book known to pharmaceutical chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, vesicles containing (cationic or anionic) lipids (such as LIPOFECTIN ™), DNA conjugates, anhydrous absorption pastes, oil-in-water emulsions and water-in-oil, carbovax emulsions (polyethylene glycols of various molecular weights), semi-liquid gels and semi-liquid mixtures containing carbovax. See also Powell et al . "Compendium of excipients for parenteral formulations" PDA (1998) J Pharm Sci Technol 52: 238-311.

The dose may vary depending on the weight of the subject to be administered, the target disease, conditions, route of administration, and the like. Various delivery systems are known and can be used to administer the pharmaceutical composition of the present invention, for example, encapsulation in liposomes, microparticles, microcapsules, receptor-mediated endocytosis (see e.g. Wuet al., 1987, J. Biol. Chem. 262: 4429-4432). The routes of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The composition can be administered by any convenient route, for example, by infusion or bolus injection, absorption through epithelial or mucocutaneous membranes (for example, oral mucosa, rectal and intestinal mucosa and etc.) and can be administered in conjunction with other biologically active agents. The introduction can be systemic or local. Anti-hIL-6R antibody can be administered subcutaneously.

The pharmaceutical composition can also be delivered in a vial, in particular in a liposome (see Langer (1990) Science 249: 1527-1533). In certain situations, the pharmaceutical composition can be delivered in a controlled release system, for example, using a pump or polymeric materials. In another embodiment, the controlled release system can be placed close to the composition target, requiring only a fraction of the systemic dose.

Injectable preparations can include dosage forms for intravenous, subcutaneous, intradermal and intramuscular injection, for local administration, drip administration, etc. These injectables can be prepared using well known methods. For example, injection forms can be obtained, for example, dissolving, suspending or emulsifying the antibody or a salt thereof described above in a sterile aqueous medium or oily medium commonly used for injection. The aqueous medium for injection is, for example, physiological saline solution, isotonic solution containing glucose and other adjuvants, and the like, which can be used in combination with a suitable solvent such as alcohol (for example, ethanol), polyhydric alcohol (for example, propylene glycol, polyethylene glycol), nonionic surfactant [e.g. polysorbate 80, HCO-50 (polyoxyethylene (50 mol) hydrogenated castor oil adduct)], etc. As an oil medium, for example, sesame oil, peanut butter and the like, which can be used in combination with a solvent such as benzyl benzoate, benzyl alcohol and etc. The injectable composition prepared in this way can be filled into a suitable ampoule.

Advantageously, the pharmaceutical compositions for oral or parenteral administration described above are prepared in dosage forms in a dosage unit suitable for adjusting the dosage of the active ingredients. Such unit dosage forms include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc. The amount of anti-hIL-6R antibody contained is typically from about 100 to about 200 mg per subcutaneous dosage form.

In accordance with the methods disclosed herein, an anti-hIL-6R antibody (or a pharmaceutical formulation containing the antibody) can be administered to a patient using any suitable device or mechanism. For example, administration can be performed with a syringe and needle, or with a reusable syringe pen and / or autoinjector delivery device. The methods of the present invention involve the use of multiple reusable syringes and / or autoinjector delivery devices to administer anti-hIL-6R antibody (or a pharmaceutical formulation containing the antibody). Examples of such devices include, but are not limited to AUTOPEN ™ (Owen Mumford, Inc., Woodstock, UK), DISETRONIC ™ pen (Disetronic Medical Systems, Burgdorf, Switzerland), HUMALOG MIX 75/25 ™ pen, HUMALOG ™ pen , pen HUMALIN 70/30 ™ (Eli Lilly and Co., Indianapolis, Indiana), NOVOPEN ™ I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR ™ (Novo Nordisk, Copenhagen, Denmark), syringe a BD ™ pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN ™, OPTIPEN PRO ™, OPTIPEN STARLET ™ and OPTICLIK ™ (Sanofi-Aventis, Frankfurt, Germany), to name a few. Examples of reusable pen delivery devices and / or autoinjector delivery devices useful for subcutaneous administration of a pharmaceutical composition of the present invention include, but are not limited to, SOLOSTAR ™ (Sanofi-Aventis), FLEXPEN ™ (Novo Nordisk), and KWIKPEN. ™ (Eli Lilly), SURECLICK ™ Auto-Injector (Amgen, Thousand Oaks, CA), PENLET ™ (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP) and HUMIRA ™ Injector (Abbott Labs, North Chicago, IL ), while only a few of them are mentioned.

The use of a microinfusor to deliver an anti-hIL-6R antibody (or a pharmaceutical composition containing the antibody) to a patient is also contemplated herein. As used herein, the term "microinfuser" means a subcutaneous delivery device designed for slow administration of large volumes (e.g. up to about 2.5 ml or more) of the therapeutic composition for an extended period of time (for example, approximately 10, 15, 20, 25, 30 or more minutes). See, for example, U.S. 6629949; US 6659982; and Meehanet al., J. Controlled Release 46: 107-116 (1996). Microinfusers are particularly useful for delivering large doses of therapeutic proteins contained in high concentration solutions (e.g. approximately 100, 125, 150, 175, 200 or more mg / ml) and / or viscous solutions.

Patient group

In certain embodiments, the methods and compositions described herein are provided for specific patient populations. These groups include subjects who have a vitreous opacity (VH) level of 2 on the Miami 9-point scale or greater. In other embodiments, subjects in this group have a VH of more than 3, 4, 5, 6, 7, or 8. In other embodiments, subjects in this group have a VH of more than 4 on the Miami 9-step scale.

In other embodiments, the implementation of the subjects in this group have macular edema. In certain embodiments, the subject with macular edema has a CRT greater than 300 microns.

In other embodiments, the subjects in this group have other signs of intraocular inflammation, such as perivascular retinal vascular hardening and retinal vascular leakage.

In accordance with certain embodiments, the methods of the present invention comprise selecting a patient that exhibits any of the aforementioned characteristics and administering an anti-IL-6R antibody to the patient, as described elsewhere in this document.

Combination therapies

The present invention provides methods of treating uveitis and / or macular edema, which include administering to a patient in need thereof such treatment with an anti-hIL-6R antibody. In certain embodiments, the anti-hIL-6 antibody is administered as "monotherapy" or as a single therapeutic agent. In alternative embodiments, the anti-hIL-6 antibody is administered in combination with at least one additional therapeutic agent. Examples of additional therapeutic agents that can be administered in combination with an anti-hIL-6R antibody in the practice of the methods of the present invention include, but are not limited to, corticosteroids and any other compound known to treat, prevent, or normalize uveitis and / or macular edema in a human subject. Specific non-limiting examples of additional therapeutic agents that can be administered in combination with an anti-hIL-6R antibody in the context of the method of the present invention include, but are not limited to, methotrexate and prednisone. In the methods of the present invention, additional (additional) therapeutic (s) agent (s) can be administered simultaneously or sequentially with the antibody to hIL-6R. For example, in the case of simultaneous administration, a pharmaceutical composition can be prepared that contains both an anti-hIL-6R antibody and at least one additional therapeutic agent. The amount of additional therapeutic agent that is administered in combination with an anti-hIL-6R antibody in the practice of the methods of the present invention can be readily determined using standard methods known and readily available in the art.

The disclosure of the present invention provides pharmaceutical compositions comprising any of the following.

A composition containing 100 to 200 mg of sarilumab (SAR153191) to be administered every two weeks and 15 to 80 mg of prednisone to be administered every day.

A composition containing approximately 200 mg of sarilumab (SAR153191) to be administered every two weeks and 15 to 80 mg of prednisone to be administered every day.

A composition containing 100 to 150 mg of sarilumab (SAR153191) administered once every two weeks, 15 to 80 mg of prednisone to be administered every day, and 6 to 25 mg of methotrexate to be administered once a week.

A composition containing 100 to 200 mg of sarilumab (SAR153191) administered once every two weeks, 15 to 80 mg of prednisone to be administered every day, and 6 to 25 mg of methotrexate to be administered once a week.

The disclosure of the present invention provides methods for normalizing symptoms associated with uveitis comprising any of the following.

A method comprising administering 100 to 200 mg of sarilumab (SAR153191) once every two weeks and 15 to 80 mg per day to a subject in need thereof.

A method comprising administering approximately 200 mg of sarilumab (SAR153191) once every two weeks and 15 to 80 mg per day of prednisone to a subject in need thereof.

EXAMPLES

Example 1. Anti-IL6R antibody is effective in the treatment of uveitis and / or macular edema in humans

A study was performed to evaluate the efficacy and safety of sarilumab administered subcutaneously every two weeks (q2w) in patients with non-infectious mean, posterior uveitis, and panuveitis.

The study was a randomized, double-blind, placebo-controlled, parallel-group study. The randomization was 2: 1 (sarilumab: placebo) and patients were divided according to screening for vitreous opacity (VH) (VH = 4 and from VH <4), macular edema (yes, no), and etiology of uveitis (systemic and idiopathic).

The primary goals were to evaluate the efficacy of 200 mg sarilumab q2w at week 16 in patients with non-infectious uveitis (NIU); changes in maximum corrected visual acuity (BCVA); the safety of subcutaneous sarilumab in patients with NIU; changes in macular edema; changes in other signs of eye inflammation; influence on retinal vascular leakage; the effect of sarilumab on the reduction of concomitant immunosuppressive therapy at week 16; changes in inflammation in the anterior chamber of the eye; pharmacokinetics (PK) of sarilumab in patients with NIU and antidrug antibody (ADA) immunogenicity. Also evaluated the effect of serum biomarkers of inflammation, such as highly sensitive C-reactive protein (hs-CRP) and serum amyloid A (SAA); the effect of an underlying systemic disease, as appropriate; the effect of sarilumab on eye disease at week 52; the effect of sarilumab on the reduction of concomitant immunosuppressive therapy at week 52 and the characteristics of uveitis when symptoms worsen.

The study included 2 periods.

• The main treatment period (part A). At inclusion, the patient must have already been on prednisone or an equivalent steroid (as monotherapy or in combination with methotrexate); sarilumab or placebo was added to current therapy. After 2 injections of the study drug (visit 4), with confirmation of improvement during at least 2 consecutive evaluations, a gradual relaxation of the background therapy was started following predetermined rules. Clinical evaluations (efficacy and safety) were performed every two weeks for 16 weeks;

• Additional treatment period (part B). If the patient completed Part A and was identified as a Responder, then he or she continued the same double-blind study until the completion of 1 year (last injection at week 50). Clinical evaluations (efficacy and safety) were performed every 4 weeks.

In addition, there were 2 additional features.

• Periods of open treatment (part C). At any time during Part A, patients experiencing worsening symptoms, or those identified as non-responders at week 16, could, at the discretion of the investigator, and in participating countries where the procedure was acceptable, continue with open regimen sarilumab in Part C. Patients were treated for up to 34 additional weeks (up to 18 additional injections). Efficacy and safety assessments were performed.

• Optional genomic supplemental research to organize a DNA and RNA bank to offer exploratory research to patients.

Approximately 57 patients were planned to randomize (80% power acceptance versus 59% expected response with sarilumab versus 20% expected response with placebo).

Patients with non-infectious secondary, posterior uveitis or panuveitis with acute illness or recent acute (active in the previous 3 months) illness. The patients planned to receive a corticosteroid as monoimmunosuppressive therapy or in combination with methotrexate. No other immunosuppressive therapy was allowed. Patients should have received oral prednisone (≥15 mg and <80 mg / day [or equivalent oral corticosteroid]) as monoimmunosuppressive therapy or in combination with methotrexate (MTX) (≤ 25 mg / week) by mouth or equivalent intravenously, intramuscularly or subcutaneously.

The primary endpoint was the proportion of patients at week 16 with (1) at least a 2-step decrease in confirmed VH (Miami 9-point scale) in the study eye or (2) oral prednisone or equivalent corticosteroid dose <10 mg / day at week 16. Other efficacy points at week 16 included changes from baseline in central retinal thickness (CRT), maximal corrected visual acuity, corticosteroid dose, retinal vascular leakage (FA) (research), and clinical efficacy score (research).

Study patients

A total of 58 patients were randomized: 38 patients in the sarilumab group and 20 patients in the placebo group. All 58 patients were exposed to IMP (study drug) and included in the mITT group (modified for treatment). For purposes of clarity, the mITT group includes all randomized patients who received at least one IMP injection. A total of 28 (73.7%) patients in the sarilumab group and 13 (65.0%) in the placebo group completed the main treatment period (part A); one patient in the placebo group was excluded from the treatment group as a result of an unmeasurable primary efficacy endpoint (VH score) at week 16.

Patient demographics and characteristics at baseline were balanced across treatment groups (Table 1). It should be noted that the number of patients with macular edema (defined as CRT = 300 µm) was lower in the sarilumab group compared to the placebo group (21 [55.3%] versus 13 [65.0%], respectively).

Table 1. Description of stratification factors (as documented in the IVRS database) - VH level stratum in the randomized group based on the confirmed screening value

Placebo
(N = 20) SAR153191, 200mg, q2w
(N = 38) Total
(N = 58) Vitreous opacity (J Davis / Miami 9-point scale) [n (%)] Number twenty 38 58 VH <4 17 (85.0%) 32 (84.2%) 49 (84.5%) VH> = 4 3 (15.0%) 6 (15.8%) 9 (15.5%) Etiology of uveitis [n (%)] Number twenty 38 58 Idiopathic 13 (65.0%) 25 (65.8%) 38 (65.5%) Systemic 7 (35.0%) 13 (34.2%) 20 (34.5%) Macular edema [n (%)] Number twenty 38 58 Yes 13 (65.0%) 21 (55.3%) 34 (58.6%) Not 7 (35.0%) 17 (44.7%) 24 (41.4%)

The macular edema stratum is based on the median of the confirmed CRT value, automatically measured by the computer program of the device at screening.

The median corticosteroid dose at baseline was 20 mg / day. Of 58 patients, one (1.7%) had an initial dose of corticosteroids less than 15 mg / day, 45 (77.6%) had an initial dose of corticosteroids of 15 or 20 mg / day, 12 (20, 7%) had a corticosteroid dose at baseline of 20 or 40 mg / day, and 0 patients had a corticosteroid dose greater than 40 mg / day. In addition, the majority, 55 (94.8%) patients, had active disease at baseline, and 29 (50%) patients had panuveitis.

The median time from first diagnosis was 17.92 months (1.49 years) and was higher in the placebo group (24.02 months) compared with the sarilumab group (17.58 months).

At baseline, the number of patients with a confirmed VH <4 was higher in the sarilumab group (49 patients [86.0%]) compared with the placebo group (17 patients [85.0%]). The median confirmed CRT at baseline was lower in the sarilumab group (298.0 µm) compared to the placebo group (308.0 µm). Also, the percentage of patients with macular edema (defined as CRT ≥300 μm) was lower in the sarilumab group compared to the placebo group (i.e. 18 patients [48.6%] in the sarilumab group versus 14 patients [70.0 %] in the case of the placebo group, respectively). See table 2.

Table 2. Confirmed eye score at baseline for the study eye - randomized group

Placebo
(N = 20) SAR153191, 200mg, q2w
(N = 38) Total
(N = 58) Vitreous opacity (J Davis / Miami 9-stop) Number twenty 37 57 0 6 (30.0%) 13 (35.1%) 19 (33.3%) one 9 (45.0%) 14 (37.8%) 23 (40.4%) 2 2 (10.0%) 2 (5.4%) 4 (7.0%) 3 0 3 (8.1%) 3 (5.3%) four 1 (5.0%) 2 (5.4%) 3 (5.3%) five 1 (5.0%) 2 (5.4%) 3 (5.3%) 6 0 1 (2.7%) 1 (1.8%) 7 0 0 0 eight 1 (5.0%) 0 1 (1.8%) VH <4 17 (85.0%) 32 (86.5%) 49 (86.0%) VH≥4 3 (15.0%) 5 (13.5%) 8 (14.0%) Vitreous opacity (J Davis / Miami 7-stop) Number twenty 37 57 0 6 (30.0%) 13 (35.1%) 19 (33.3%) one 9 (45.0%) 14 (37.8%) 23 (40.4%) 2 2 (10.0%) 5 (13.5%) 7 (12.3%) 3 1 (5.0%) 2 (5.4%) 3 (5.3%) four 1 (5.0%) 2 (5.4%) 3 (5.3%) five 0 1 (2.7%) 1 (1.8%) 6 1 (5.0%) 0 1 (1.8%) VH <3 17 (85.0%) 32 (86.5%) 49 (86.0%) VH≥3 3 (15.0%) 5 (13.5%) 8 (14.0%) Central retinal thickness (automatic measurement based on SD-OCT) (μm) Number twenty 37 57 Average (SD) 308.9 (53.1) 341.6 (149.6) 330.2 (124.9) Median value 308.0 298.0 303.0 Q1: Q3. 271.0: 338.0 273.0: 340.0 273.0: 339.0 Minimum: maximum 223: 432 148: 992 148: 992 CRT <300 6 (30.0%) 19 (51.4%) 25 (43.9%) CRT≥300 14 (70.0%) 18 (48.6%) 32 (56.1%) Center area thickness
retinal (CRT) (manual measurement
way) (μm) Number twenty 37 57 Average (SD) 217.2 (64.8) 248.4 (165.1) 237.4 (138.5) Median value 195.3 194.0 194.0 Q1: Q3 170.5: 255.8 173.5: 226.0 171.5: 248.5 Minimum: maximum 125: 380 94: 927 94: 927 CRT <300 18 (90.0%) 30 (81.1%) 48 (84.2%) CRT≥300 2 (10.0%) 7 (18.9%) 9 (15.8%)

(SD: standard deviation)

Investigator eye scores with VH <4 and VH <3 at baseline are described in the following Table 3. A total of 14 (24.1%) patients had VH = 4; 9 patients ([23.7%]) were identified in the sarilumab group and 5 patients ([25.0%]) were identified in the placebo group). The number of patients with BCVA = 70 letters at baseline was lower in the sarilumab group than in the placebo group (i.e., 23 patients [60.5%] in the sarilumab group versus 16 patients [80.0%] in the placebo group, respectively). The majority of patients (55 patients; 94.8%) had abnormal fluorescence angiography (FA) at baseline. See table 3.

Table 3. Investigator's eye assessment at baseline for the test eye - randomized group

Placebo
(N = 20) SAR153191, 200mg, q2w
(N = 38) Total
(N = 58) Vitreous opacity (J Davis / Miami 9-stop) Number twenty 38 58 0 4 (20.0%) 7 (18.4%) 11 (19.0%) one 3 (15.0%) 10 (26.3%) 13 (22.4%) 2 5 (25.0%) 6 (15.8%) 11 (19.0%) 3 3 (15.0%) 6 (15.8%) 9 (15.5%) four 3 (15.0%) 5 (13.2%) 8 (13.8%) five 2 (10.0%) 1 (2.6%) 3 (5.2%) 6 0 2 (5.3%) 2 (3.4%) 7 0 1 (2.6%) 1 (1.7%) eight 0 0 0 VH <4 15 (75.0%) 29 (76.3%) 44 (75.9%) VH≥4 5 (25.0%) 9 (23.7%) 14 (24.1%) Vitreous opacity (J Davis / Miami 7-stop) Number twenty 38 58 0 4 (20.0%) 7 (18.4%) 11 (19.0%) one 3 (15.0%) 10 (26.3%) 13 (22.4%) 2 8 (40.0%) 12 (31.6%) 20 (34.5%) 3 3 (15.0%) 5 (13.2%) 8 (13.8%) four 2 (10.0%) 1 (2.6%) 3 (5.2%) five 0 3 (7.9%) 3 (5.2%) 6 0 0 0 VH <3 15 (75.0%) 29 (76.3%) 44 (75.9%) VH≥3 5 (25.0%) 9 (23.7%) 14 (24.1%) Central retinal thickness (CRT) measured with SD-OCT (μm) Number twenty 38 58 Average (SD) 302.3 (60.1) 329.8 (154.1) 320.3 (129.6) Median value 299.5 288.0 296.5 Q1: Q3. 262.5: 333.5 254.0: 337.0 255.0: 335.0 Minimum: maximum 205: 432 153: 1048 153: 1048 CRT <300 10 (50.0%) 21 (55.3%) 31 (53.4%) CRT≥300 10 (50.0%) 17 (44.7%) 27 (46.6%) Maximum corrected visual acuity (ETDRS letter grade) Number twenty 38 58 Average (SD) 74.5 (13.4) 70.4 (14.6) 71.8 (14.2) Median value 79.0 73.5 75.0 Q1: Q3. 74.0: 83.0 63.0: 80.0 64.0: 81.0 Minimum: maximum 35: 88 24: 93 24: 93 BCVA <70 letters 4 (20.0%) 15 (39.5%) 19 (32.8%) BCVA ≥70 letters 16 (80.0%) 23 (60.5%) 39 (67.2%) Fluorescence Angiography (FA) Number twenty 38 58 Normal 1 (5.0%) 2 (5.3%) 3 (5.2%) Pathological 19 (95.0%) 36 (94.7%) 55 (94.8%) Anterior chamber (cells) Number twenty 38 58 0 15 (75.0%) 28 (73.7%) 43 (74.1%) +0.5 3 (15.0%) 4 (10.5%) 7 (12.1%) +1 2 (10.0%) 5 (13.2%) 7 (12.1%) +2 0 1 (2.6%) 1 (1.7%) +3 0 0 0 Iris / pupil pathology (redness) Number twenty 38 58 Normal 16 (80.0%) 33 (86.8%) 49 (84.5%) Pathological 4 (20.0%) 5 (13.2%) 9 (15.5%) Vitreous humor (cells) Number twenty 38 58 0 2 (10.0%) 7 (18.4%) 9 (15.5%) +0.5 3 (15.0%) 7 (18.4%) 10 (17.2%) +1 7 (35.0%) 14 (36.8%) 21 (36.2%) +2 8 (40.0%) 8 (21.1%) 16 (27.6%) +3 0 2 (5.3%) 2 (3.4%) Intraocular pressure (IOP) in mmHg Art. Number twenty 38 58 Average (SD) 16.3 (4.3) 15.0 (3.4) 15.4 (3.7) Median value 16.5 15.0 16.0 Q1: Q3. 13.0: 18.5 13.0: 17.0 13.0: 18.0 Minimum: maximum 9:26 8:24 8:26 Erythema of the eyelids Number twenty 38 58 0 20 (100%) 38 (100%) 58 (100%) +0.5 0 0 0 +1 0 0 0 +2 0 0 0 +3 0 0 0 Erythema of the eyelids Number twenty 38 58 0 20 (100%) 38 (100%) 58 (100%) +0.5 0 0 0 +1 0 0 0 +2 0 0 0 +3 0 0 0 Conjunctival hyperemia Number twenty 38 58 0 20 (100%) 37 (97.4%) 57 (98.3%) +0.5 0 0 0 +1 0 1 (2.6%) 1 (1.7%) +2 0 0 0 +3 0 0 0 Conjunctival edema Number twenty 38 58 0 20 (100%) 38 (100%) 58 (100%) +0.5 0 0 0 +1 0 0 0 +2 0 0 0 +3 0 0 0 Subconjunctival hemorrhage Number twenty 38 58 0 20 (100%) 37 (97.4%) 57 (98.3%) +0.5 0 0 0 +1 0 1 (2.6%) 1 (1.7%) +2 0 0 0 +3 0 0 0 Corneal edema Number twenty 38 58 0 20 (100%) 38 (100%) 58 (100%) +0.5 0 0 0 +1 0 0 0 +2 0 0 0 +3 0 0 0 Corneal staining / erosion Number twenty 38 58 0 20 (100%) 38 (100%) 58 (100%) +0.5 0 0 0 +1 0 0 0 +2 0 0 0 +3 0 0 0 Redness of the anterior chamber Number twenty 36 56 0 15 (75.0%) 30 (83.3%) 45 (80.4%) +0.5 0 0 0 +1 2 (10.0%) 6 (16.7%) 8 (14.3%) +2 3 (15.0%) 0 3 (5.4%) +3 0 0 0 +4 0 0 0 Lens status Number twenty 38 58 Phakic 17 (85.0%) 29 (76.3%) 46 (79.3%) Pseudophakic 3 (15.0%) 9 (23.7%) 12 (20.7%) Afakichny 0 0 0 Lens clouding for phakic eyes Number 17 29 46 one 12 (70.6%) 25 (86.2%) 37 (80.4%) 2 5 (29.4%) 4 (13.8%) 9 (19.6%) 3 0 0 0 Optic nerve (cup / disc ratio) Number twenty 38 58 Average (SD) 0.190 (0.121) 0.208 (0.142) 0.202 (0.134) Median value 0.200 0.200 0.200 Q1: Q3. 0.100: 0.300 0.100: 0.300 0.100: 0.300 Minimum: maximum 0.00: 0.30 0.00: 0.80 0.00: 0.80

The 9-point scale is changed to a 7-point scale by combining slides 2 and 3 as one stage and slides 6 and 7 as one stage according to FDA guidelines.

It should be noted that discrepancies were observed between the investigator's estimates and the confirmed estimates in the case of VH. The validated score for VH was less severe than the investigator score in over 52.6% of the patient group. In addition, there was the percentage of patients who had a difference of two points or more between both ratings. Thus, an additional sensitivity analysis for the primary endpoint was included using the VH values assessed by the investigator. There was no difference between the investigator's scores and the validated scores for CRT in 55.2% of patients, and the confirmed score for CRT was less severe than the investigator's score for 12 (20.7%) patients.

Dosage and duration

Injection exposure was equivalent in both groups, with a mean of 14.1 weeks of IMP injection exposure over 16 weeks of Part A. Overall compliance was also equivalent in both groups; all 58 patients received at least 80% of the theoretical dose.

EFFICIENCY

Primary efficacy endpoint

The primary endpoint analysis (proportion of patients with a 2-step VH reduction or corticosteroid dose <10 mg / day at week 16) was based on the prone VH value. The results of the analysis of the primary endpoint are presented in Table 4.

The proportion of patients with a 2-step decrease in VH or a corticosteroid dose <10 mg / day was higher in the sarilumab group (46.1%) compared with the placebo group (30.0%), but the difference was not statistically significant (p = 0, 2354).

The primary efficacy endpoint was chosen to evaluate the efficacy of sarilumab in reducing uveitis-associated ocular inflammation. We assumed the inclusion of patients with a significant VH index, for whom a decrease in VH value was necessary. Ultimately, the recruited group had lower VH values because patients with high VH were treated with concomitant immunosuppressive drugs, which were not allowed in the present study.

Additional endpoints (such as BCVA) were scored when evaluating the efficacy of sarilumab in terms of functional parameters.

Comparison of the proportions of responders between the 2 treatment groups was performed for each complete dataset using the Cochran-Mantel-Hensel (CMH) test at a 2-tailed alpha level of 0.10.

Table 4. Primary Efficacy Analysis - mITT Group

Placebo SAR153191

(N = 20) 200 mg, q2w

(N = 38)

Patients with a decrease in VH> 2 or a dose of corticosteroid <10 mg / day at week 16

Combined score for the proportion of respondents (%) 30.0

46.1

Comparison with placebo

Pooled score for an odds ratio of 2.1

90% CI (0.8 to 5.6)

p-value 0.2354

Note: The multiple recovery method was used to indicate missing values in the mITT group (initial values = 13480, 26960; number of substitutions = 100).

A pooled estimate of the proportion of responders was obtained by averaging the entire proportion of responders from the various recovered datasets. The pooled odds ratio score was obtained by combining the log transformation of the odds ratio from the CMH analyzes of the various reconstructed datasets using Rubin's formula and then re-transforming the combined score.

The CMH analysis was adjusted for the VH level of the randomization stratification factor (VH> = 4 and VH <4).

Responder status was determined using confirmed VH and corticosteroid values over a time window of week 16.

Table 5. Components of primary efficacy endpoints by responder status - mITT group

Placebo
(N = 20) SAR153191
200 mg, q2w
(N = 38) Responders 6 (30.0%) 17 (44.7%) Decreased VH ≥2 at week 16 2 (10.0%) 6 (15.8%) Corticosteroid dose <10 mg / day at week 16 five (25.0%) sixteen (42.1%) Nonresponders 13 (65.0%) twenty (52.6%) Did not complete the main treatment period (part A) due to lack of efficacy 6 (30.0%) 6 (15.8%) No decline in VH ≥2 and corticosteroid dose ≥10 mg / day at week 16 6 (30.0%) eleven (28.9%) No decline in VH ≥2 and no corticosteroid dose at week 16 0 3 (7.9%) Nonresponder according to medical clearance one (5.0%) 0

VH values are confirmed VH values over a week 16 time window. Corticosteroid values are based on a week 16 time window.

The results of a sensitivity analysis of a 2-step reduction in VH or a corticosteroid dose <10 mg / day, taking into account the absence of responder status as a non-responder, was similar to the primary analysis (see Table 6).

Components were also calculated for the proportion of patients with a 2-step or greater decrease in VH or an oral prednisone or equivalent corticosteroid dose <10 mg / day at week 16, taking into account the absence of the responder's non-responder status.

Table 6. Sensitivity analysis: Proportion of patients with at least 2-step reductions in confirmed VH or oral prednisone or equivalent corticosteroid dose <10 mg / day at week 16 based on missing non-responder status - mITT

Placebo
(N = 20) SAR153191, 200mg, q2w
(N = 38) Patients with a decrease in VH> 2 or a dose of corticosteroid <10 mg / day at week 16 Responders [n (%)] 6 (30.0%) 17 (44.7%) Comparison with placebo Ordinary odds ratio 2 90% accurate CI (0.6 to 6.2) Exact p-value 0.3893

Note: Typical odds ratios are derived from CMH analysis adjusted for VH level of randomization stratification factor (VH> = 4 and VH <4). Two-sided confidence interval (CI) and p-values based on an exact stratified test (Gart 1971).

Responder status was determined using confirmed VH and corticosteroid values over a time window of week 16.

Patients with absent responder status at week 16 were considered non-responders.

Other key performance endpoints

In the investigator's assessment, the proportion of patients with a 2-step decrease in VH or a corticosteroid dose <10 mg / day was nominally significantly higher (p = 0.0372) in the sarilumab group (64.0%) compared with placebo (35.0%). See Table 7. Components were also calculated for the proportion of patients with a 2-step or greater decrease in VH or an oral dose of prednisone or an equivalent corticosteroid <10 mg / day at week 16 based on the values of the investigator's assessment. See table 8.

Table 7. Sensitivity Analysis: Proportion of Patients with 2-Step or Greater VH Decrease Based on Investigator Assessment or Dose of Oral Prednisone or Equivalent Corticosteroid <10 mg / day at Week 16 - mITT Group

SAR153191,

Placebo 200 mg, q2w

(N = 20) (N = 38)

Patients with a decrease in VH> 2 or a dose of corticosteroid <10 mg / day at week 16

Combined score for the proportion of respondents (%) 35.0

64.0

Comparison with placebo

Pooled score for odds ratio 3.7

90% CI (1.3 to 10.4)

95% CI (1.1 to 12.6)

p-value

0.0372

Note: The multiple recovery method was used to indicate missing values in the mITT group (initial values = 13480, 26960; number of substitutions = 100).

A pooled estimate of the proportion of responders was obtained by averaging the entire proportion of responders from the various recovered datasets. The pooled odds ratio score was obtained by combining the log transformation of the odds ratio from the CMH analyzes of the various reconstructed datasets using Rubin's formula and then re-transforming the combined score.

The CMH analysis was adjusted for the VH level of the randomization stratification factor (VH> = 4 and VH <4).

Responder status was determined by VH based on the investigator's assessment and corticosteroid values over a time window of week 16.

Table 8. Sensitivity Analysis Components: Proportion of Patients with 2-Step or Greater VH Decrease Based on Investigator Assessment or Dose of Oral Prednisone or Equivalent Corticosteroid <10 mg / day at Week 16 - mITT Group

Placebo
(N = 20) SAR153191
200 mg, q2w
(N = 38) Responders 7 (35.0%) 23 (60.5%) Decreased VH ≥2 at week 16 four (20.0%) sixteen (42.1%) Corticosteroid dose <10 mg / day at week 16 five (25.0%) sixteen (42.1%) Nonresponders 13 (65.0%) 13 (34.2%) Did not complete the main treatment period (part A) due to lack of efficacy 6 (30.0%) 6 (15.8%) No decline in VH ≥2 and corticosteroid dose ≥10 mg / day at week 16 6 (30.0%) five (13.2%) No decline in VH ≥2 and no corticosteroid dose at week 16 0 2 (5.3%) Nonresponder according to medical clearance one (5.0%) 0

VH values are based on an investigator's estimate over a time window of week 16.

Corticosteroid values are based on a weekly time window of 16.

Key secondary performance endpoints

Change in confirmed VH from start time

A statistically significant difference in the change in confirmed VH from baseline was observed between the sarilumab and placebo groups. The change in LS mean, confirmed VH from baseline to week 16 was greater in the sarilumab group (-0.87) compared to the placebo group (-0.13) with a difference in LS mean. versus placebo -0.74 (90% CI: -1.223 to -0.262); p = 0.0127. See table 9.

Table 9. Secondary efficacy endpoints - change in confirmed VH from baseline - mITT group

Vitreous opacity (J Davis / Miami 9-stop) Placebo
(N = 20) SAR153191, 200mg, q2w
(N = 38) Initial moment in time Number twenty 38 Average (SD) 1.7 (2.0) 1.4 (1.6) Median value 1.0 1.0 Minimum: maximum 0: 7 0: 7 Week 16 Number 13 28 Average (SD) 1.4 (1.6) 0.7 (0.9) Median value 1.0 0.0 Minimum: maximum 0: 6 0: 4 Change from the starting point in time Number 13 28 Average (SD) -0.1 (1.5) -0.9 (1.4) Median value 0.0 -1.0 Minimum: maximum -4: 1 -5: 1 Mean value determined using the LS (SE) method ^a -0.1 (0.23) -0.9 (0.16) 90% CI (-0.519 to 0.267) (-1.146 to -0.592) Difference in mean values determined using LS (SE) method compared with placebo ^a -0.7 (0.29) 90% CI (-1.223 to -0.262) 95% CI (-1.319 to -0.166) p-value 0.0127 CI: confidence interval; MMRM: mixed model for repeated measurements; LS mean: Least squares mean using a mixed model.
Note: Only patients who had a confirmed VH at baseline and after baseline were included in the analysis for changes from baseline.
^a MMRM model with treatment groups, visits, and interaction of visits by treatment group as fixed categorical effects, as well as a fixed continuous covariate of confirmed VH at baseline.
A non-structural correlation matrix was used to model errors at the same patient level.

Preliminary findings on vitreous opacification

Only 7 patients in this group had VH> = 4 at baseline. It was generally more difficult to enroll critically ill patients in this study because the standard of care for critically ill patients included several concomitant immunosuppressive therapies that were prohibited in this study. In addition, inconsistencies in the definition of VH based on pretreatment estimates between the investigator and the independent expert were noted. At week 16, the proportion of patients with a 2-step decrease in VH as judged by the investigator or with a corticosteroid dose <10 mg / day was

significantly higher in the sarilumab group (64.0%) compared with the placebo group (35.0%) (OR: 3.7 (90% CI: 1.3 to 10.4, p = 0.0372). In addition, the changes in VH according to the validated assessment were statistically significantly higher compared to the placebo group) (difference in mean values determined with LS compared with placebo -0.74 (90% CI: -1.223 to -0.262, p = 0 , 0127).

Oral dose of prednisone or corticosteroid

At week 12, after 5 injections of sarilumab, there was a marked difference in the dose of oral corticosteroids compared to the placebo group.

The change in mean values determined by the LS method in the dose of prednisone or corticosteroid for oral administration, from baseline to week 16, was higher in the sarilumab group (-11.20 mg / day) compared to the placebo group (-7, 85 mg / day), but no statistically significant difference.

Confirmed central retinal thickness

The change in mean values determined by the LS method, confirmed by CRT from baseline to week 16 decreased more in the sarilumab group (-35.4 μm) compared to the placebo group (-8.9 μm) with a difference in mean values. determined by the LS method for placebo -26.5 (90% CI: -50.41 to -2.68) (p = 0.0683). Since 8 patients in this study had very high CRT values at baseline, which had a higher ability to normalize (Table 10), the MMRM model that SAP planned for mITT groups was not suitable to match the change in confirmed CRT (as confirmed by graphs based on studentized residues). An analysis evaluating the change from baseline in confirmed CRT in the mITT group, excluding patients with high CRT at baseline, was also performed and detailed in Table 10. Except for patients with high CRT at baseline, the change in mean values determined with LS method, confirmed by CRT from baseline to week 16 was smaller in the sarilumab group (-5.27 μm) and was greater in the placebo group (1.79 μm) with the difference in mean values determined by LS method by compared with placebo -7.06 (90% CI: -22.022 to 7.904) (p = 0.4328). The change in LS mean, confirmed by CRT from baseline to week 16 was reduced in the sarilumab group (-6.4%) compared with no change in the placebo group with the difference in LS mean in placebo -6.4% (90% CI: -12.374 to -0.350) (p = 0.0825) (Table 10).

Таблица 10. Изменение от начального момента времени подтвержденной CRT - группа mITT за исключением пациентов с высоким значением CRT в начальный момент времени

Table 10. Change from baseline confirmed CRT - mITT group excluding patients with high baseline CRT

Central Retinal Thickness (CRT) (automatic measurement based on SD-OCT) (μm) Placebo (N = 20) SAR153191, 200 mg,
q38) Initial moment in time Number twenty 38 Average (SD) 306.1 (58.9) 338.4 (155.5) Median value 306.5 293.0 Minimum: maximum 214: 432 153: 1048 Week 16 Number fourteen 24 Average (SD) 299.2 (60.4) 292.7 (74.1) Median value 294.5 291.00 Minimum: maximum 211: 429 153: 576 Change from initial
moment in time Number fourteen 24 Average (SD) 1.54 (14.36) -7.27 (17.97 Median value -1.72 -4.15 Minimum: maximum -12.0: 41.6 -48.3: 21.9 Mean value determined using the LS (SE) method a 0.0 (2.90) -6.4 (2.15) 90% CI (-4.923 to 4.934) (-10.008 to -2.705) Difference in mean values determined using LS (SE) method compared with placebo ^a -6.4 (3.55) 90% CI (-12.374 to -0.350) p-value 0.0825

CI: confidence interval; MMRM: mixed model for repeated measurements; LS mean: Least squares mean calculated using the mixed model. Note: Only patients who have confirmed CRT (automatic measurement from SD-OCT) scored at baseline and after baseline were included.

a MMRM model with treatment groups, VH level randomization strata (<4,> = 4), visits and interaction of visits depending on treatment group as fixed

categorical effects as well as continuous CRT covariates at baseline (automatic measurement based on SD-OCT).

A non-structural correlation matrix was used to model errors at the same patient level.

Within-group means, determined using the LS method, and standard errors (SE) were calculated using weights equal to the observed proportion of patients in the levels of variable strata: VH level (<4,> = 4) in the study group.

The high CRT value at the start time is determined as the CRT at the start time> = 432 based on the description of the CRT distribution at the start time.

Maximum corrected visual acuity

BCVA remains the most clinically relevant functional parameter in the treatment of uveitis. Other important variables (VH, CRT, FA results) remain critical markers of inflammation to demonstrate the effectiveness of new treatments. At week 10, after 4 injections of sarilumab, a statistically significant improvement in BCVA was observed (Table 11).

There was a statistically significant difference in BCVA change from baseline to week 16. The change in mean BCVA values determined by the LS method from baseline to week 16 was significantly greater in the sarilumab group (8.51) compared to the placebo group (3 , 87) with a difference of mean values determined using the LS method compared with placebo 4.65 (90% CI: 1.091 to 8.201); p = 0.0333. The average increase in the sarilumab group was 8.93 letters (almost 2 lines on the ETDRS map) compared to 3.60 letters in the placebo group.

Table 11. Secondary efficacy endpoints - change from baseline BCVA - mITT group

Maximum corrected visual acuity (ETDRS letter grade) Placebo
(N = 20) SAR153191, 200 mg,
q2w.
(N = 38) Initial moment in time Number twenty 38 Average (SD) 74.50 (13.4) 70.37 (14.6) Median value 79.0 73.5 Minimum: maximum 35: 88 24: 93 Week 16 Number fifteen 29 Average (SD) 75.8 (12.0) 79.5 (10.6) Median value 79.0 80.0 Minimum: maximum 55: 95 52: 100 Change from the starting point in time Number fifteen 29 Average (SD) 3.60 (6.5) 8.93 (9.9) Median value 4.0 7.0 Minimum: maximum -9.0: 20.0 -5.0: 45.0 Mean value determined using the LS (SE) method a 3.5 (1.84) 9.3 (1.36) 90% CI (0.32 to 6.59) (6.97 to 11.61) Difference in mean values determined using LS (SE) method compared with placebo ^a 5.8 (2.26) 90% CI (1.99 to 9.67) 95% CI (1.21 to 10.46) p-value 0.0153

CI: confidence interval; MMRM: mixed model for repeated measurements; LS mean: Least squares mean calculated using the mixed model. Note: Only patients who have confirmed BCVA scored at baseline and after baseline were included.

a MMRM model with treatment groups, VH level randomization strata (<4,> = 4), visits and interaction of visits depending on treatment group as fixed

categorical effects as well as continuous BCVA covariates at baseline.

A non-structural correlation matrix was used to model errors at the same patient level.

Within-group means, determined using the LS method, and standard errors (SE) were calculated using weights equal to the observed proportion of patients in the levels of variable strata: VH level (<4,> = 4) in the study group.

Preliminary findings on BCVA and CRT

At week 16, patients in the sarilumab group showed a statistically significant improvement in BCVA versus placebo (mean difference between LS versus placebo 5.8 (90% CI: 1.99-9.67, p = 0 , 0153) The mean decrease in confirmed CRT (eg, for macular edema) was nominally higher in the sarilumab group compared to the placebo group (difference in mean values determined by LS method versus placebo 5.8 (90% CI: from 1.99 to 9.67); p = 0.0153).

Anterior chamber cell score

Inflammatory activity in the anterior chamber was qualitatively determined by quantitative determination of cells and proteins in aqueous humor (Tyndall effect or SUN classification). The percentage of patients with anterior chamber cell score = 0 or at least a 2-step decline was similar for both the sarilumab and placebo groups, 86.2% and 86.7%, respectively. The results of the sensitivity analysis, counting patients with missing data at week 16 as non-responders, were similar to the original analysis.

Percentage of patients with prednisone dose ≤5 mg / day (or equivalent corticosteroid) at week 16

The proportion of patients with prednisone ≤5 mg / day (or equivalent corticosteroid) at week 16 was similar in the sarilumab and placebo arm, 41.4% and 40.0%, respectively. The results of the sensitivity analysis, counting patients with missing data at week 16 as non-responders, were similar to the original analysis.

The mean change in oral prednisone or corticosteroid dose from baseline in visit windows during the main treatment period was also analyzed.

Percentage of Patients with 2-Step Reduction of Vitreous Opacity Based on the Miami 7-Point Scale at Week 16

The proportion of patients with a 2-step decrease in VH based on the 7-point Miami scale was higher in the sarilumab group (21.4%) compared with the placebo group (7.7%), but the difference was not statistically significant (p = 0.3164 ). The results of the sensitivity analysis, counting patients with missing data at week 16 as non-responders, were similar to the original analysis.

Research endpoints for effectiveness

At the end of the extended treatment period (week 52), the percentage of responders (2-step or greater reductions in confirmed vitreous opacity or prednisone dose <10 mg / day [or an equivalent oral corticosteroid]), non-responders, and patients for whom a response could not be determined was similar for both treatment groups (Table 12). A 2-step or greater reduction was observed for 7.9% of patients in the sarilumab group compared to the placebo group.

Patients who experienced deterioration, or those defined as non-responders at week 16, could continue with sarilumab during the open mode period, part C. Of the 21 patients who entered the open phase, 8 (38.1%) had a corticosteroid dose <10 mg / day at week +36 and were considered responders.

Table 12. Components of the proportion of patients with a 2-step or greater reduction in VH or oral prednisone or equivalent corticosteroid dose <10 mg / day at week 52 (end of extended treatment period) -mITT group

Placebo
(N = 20) SAR153191, 200mg, q2w
(N = 38) Responders 6 (30.0%) 11 (28.9%) Decreased VH ≥2 at week 52 and
corticosteroid dose <10 mg / day at week 52 0 3 (7.9%) Corticosteroid dose <10 mg / day at week 52 6 (30.0%) 8 (21.1%) Nonresponders 8 (40.0%) 16 (42.1%) Did not complete the main treatment period (part A) due to lack of efficacy 6 (30.0%) 6 (15.8%) Did not complete the total treatment period as a result of lack of efficacy 0 5 (13.2%) No decline in VH ≥2 and corticosteroid dose ≥10 mg / day at week 52 1 (5.0%) 1 (2.6%) No decline in VH ≥2 and no corticosteroid dose at week 52 0 2 (5.3%) Nonresponder according to medical clearance 1 (5.0%) 2 (5.3%) Responder status cannot be determined 6 (30.0%) 11 (28.9%) Completed the main treatment period (part A), but did not enter part C 5 (25.0%) 6 (15.8%) Did not complete the main treatment period (part A) due to a cause other than lack of efficacy 1 (5.0%) 4 (10.5%) Did not complete the total treatment period due to a cause other than lack of efficacy 0 1 (2.6%)

The total study period in this document consists of the main and additional treatment period (part A + part B)

Part C is the open treatment period.

The analysis was performed using the values in the week 52 time window.

Change from baseline vitreous opacity at week 52 (week +36 for part C)

The difference in the change in confirmed VH from the baseline, which was observed at week 16, persisted until week 52 in the case of patients who entered the extended treatment period. The change in confirmed VH (according to the Miami 9-point scale) at week 52 was -1.1 in the sarilumab group and -0.4 in the placebo group.

Patients in the open period were characterized by a smaller decrease in VH than those who received sarilumab in the extended period. No change in confirmed VH (according to Miami 9-point scale) from baseline was observed at week +36 and maximum change (-0.4) was observed at week 28 or subsequent weeks.

Percentage of patients with prednisone dose ≤5 mg / day or <10 mg / day (or equivalent oral corticosteroid) at week 52 (week +36 for Part C)

Most patients in the extended treatment period had a prednisone dose of ≤5 mg / day, and it was similar for the sarilumab and placebo groups, 85.7% and 87.5%, respectively. In the open period, the percentage of patients with prednisone dose <10 mg / day was 61.5%, and that with ≤5 mg / day was 53.8%.

Percentage of Patients with Anterior Chamber Scores = 0 or 2-Stage Decreases at Week 52 (Week +36 for Part C)

At week 52, the percentage of patients who were responders (anterior chamber score = 0 or at least a 2-step decrease in the index) were lower for the sarilumab group than for the placebo group. Of the 21 patients who received sarilumab in the open period, 12 (57.1%) were responders. Descriptive statistics of anterior chamber cell scores distributed across visit windows were analyzed for the main and extended periods and for the open period.

Change from baseline in maximum corrected visual acuity at week 52 (week +36 for part C)

The difference in BCVA change from baseline to week 16 persisted through week 52 for patients who entered the extended treatment period. The data show that the change in BCVA at week 52 was larger in the sarilumab group compared to the placebo group.

Patients in the open period were characterized by an increase in BCVA, with the change in BCVA from baseline being 4.5 letters ETDRS at week +36 and the maximum change (5.9 letters ETDRS) was observed at week +28.

Change from the initial point in time of the central region of the retina (automatically generated by the computer program of the device, based on the centralized spectral domain optical coherence tomography at week 52 (week +36 for part C)

The normalization of confirmed CRT that was observed in patients in the sarilumab group at week 16 persisted through week 52. The mean change from baseline confirmed CRT at week 52 was -71.1 µm in the sarilumab group versus -3.4 µm. However, it should be noted that patients who continued to participate in the study in the extended period were considered responders at the end of the main treatment period.

The normalization of confirmed CRT was also observed in the case of patients in the open period. The data show that the mean change from baseline confirmed CRT at week +36 was -37.5 μm.

Analysis of performance data

At week 16, the proportion of patients with a 2-step decrease in VH by validated estimate or corticosteroid dose <10 mg / day was higher in the sarilumab group (46.1%) than in the placebo group (30.0%), but the difference was not statistically significant. significant (p = 0.2354).

At week 16, the proportion of patients with a 2-step decrease in VH as judged by the investigator or with a corticosteroid dose <10 mg / day was higher in the sarilumab group (64.0%) than in the placebo group (35.0%; nominal p = 0, 0372). Other sensitivity analyzes using the observed case and taking into account the absent status of the responder as non-responder yielded similar results as the primary analysis.

The results of the secondary efficacy endpoints showed statistically significant differences in confirmed VH, BCVA, confirmed CRT, and CRT change from baseline at week 16.

• The change in LS mean, confirmed by VH from baseline to week 16 was greater in the sarilumab group (-0.9) compared to the placebo group (-0.1) with a difference in LS mean , for placebo, -0.7 (90% CI: -1.223 to -0.262); p = 0.0127.

• The change in LS mean BCVA from baseline to week 16 was significantly greater in the sarilumab group (9.3) compared to the placebo group (3.5) with a difference in LS mean , for placebo 5.8 (90% CI: 1.99 to 9.67); p = 0.0153.

• Change in mean values determined by LS method, confirmed by CRT from baseline to week 16 decreased more in the sarilumab group (-35.4 μm) compared with placebo group (-8.9 μm) with a difference in mean values determined by the LS method for placebo -26.5 (90% CI: -50.41 to -2.68); p = 0.0683.

• Change in mean values determined by LS method, confirmed by CRT from baseline to week 16 was reduced in the sarilumab group (-6.4%) compared with no change in the placebo group (0.0%) with a difference in mean values. determined by the LS method for placebo -6.4% (90% CI: -12.374 to -0.350); p = 0.0825.

With the exception of patients with high baseline CRT levels, confirmed CRT decreased at week 16 in the sarilumab group and confirmed CRT increased in the placebo group. These data resulted in a difference of -7.06 in the LS mean of sarilumab versus placebo (90% CI: -2.022 to 7.904; p = 0.4328). As observed, analysis of the secondary endpoints of the anterior chamber cell score and the proportion of patients with prednisone ≤5 mg / day (or equivalent corticosteroid) at week 16 did not result in a statistically significant difference between the sarilumab and placebo treatment groups.

Exploratory endpoint analysis showed that differences in confirmed VH from baseline, BCVA from baseline, and CRT from baseline, observed at week 16, persisted at week 52. Secondary pharmacodynamic analysis showed that levels as hs -CRP and SAA decreased from week 4 in the sarilumab group compared to the placebo group and that suppression persisted until week 52.

Primary and secondary analyzes of patients after 52 weeks

Tables 13-16 show the distribution of patients, the underlying etiology of the patients analyzed in this study, and the characteristics of the disease at baseline.

Table 13. Distribution of patients

Placebo Sarilumab All randomized Randomized and treated 20 (100%) 38 (100%) 58 (100%) Completed treatment at week 16 13 (65.0%) 28 (73.7%) 41 (70.7%) Completed treatment at week 52 7 (35.0%) 12 (31.6%) 19 (32.8%) We entered an open study 11 (55.0%) 10 (26.3%) 21 (36.2%) Dropped out of research 2 (10.0%) 16 (68.4%) 18 (31.0%) Undesirable phenomenon 1 (5.0%) 5 (13.2%) 6 (9.67%) Lack of efficiency 1 (5.0%) 7 (18.4%) 8 (13.8%) Other reasons 0 4 (2.6%) four

Table 14. Characteristics of diseases at the initial moment of time

Placebo, q2 wks
(n = 20) Sarilumab, q2 wks
(n = 20) All randomized
(n = 58) Recently active disease, n (%) 1 (5.0%) 2 (5.3%) 3 (5.2%) Active disease, n (%) 19 (95.0%) 36 (94.7%) 55 (94.8%) Anatomical localization Average uveitis 5 (25.0%) 7 (18.4%) 12 (20.7%) Posterior uveitis 2 (10.0%) 12 (31.6%) 14 (24.1%) Panuweit 12 (60.0%) 17 (44.7%) 29 (50.0%) Time since the beginning of the first diagnosis Months (SD) 55.5 (71.9) 39.1 (58.1) 44.7 (62.9) Minimum: maximum 0.6: 300.3 0.0: 286.7 0.0: 300.3

Table 15. Disease characteristics - underlying etiology

Placebo, q2 wks
(n = 20) Sarilumab, q2 wks
(n = 20) All randomized
(n = 58) Idiopathic, n (%) 13 (65%) 25 (65.8%) 38 (65.5%) Behcet's disease 4 (20%) 6 (15.8%) 10 (17.2%) Sarcoidosis 2 (10%) 2 (5.3%) 4 (6.9%) Psoriasis 0 1 (2.5%) 1 (1.7%) Rheumatoid arthritis 0 1 (2.6%) 1 (1.7%) Vogt-Koyanagi-Harada syndrome 1 (5.0%) 1 (2.6%) 1 (1.7%) Vasculitis of unknown etiology 0 2 (5.0%) 2 (3.4%)

Table 16. Characteristics of diseases at the initial moment of time

Placebo, q2 wks
(n = 20) Sarilumab, q2 wks
(n = 20) All randomized
(n = 58) Vitreous opacity as assessed by the investigator Average (SD) 2.2 (1.6) 2.2 (1.9) 2.2 (1.8) Minimum: maximum 0: 5 0: 7 0: 7 VH ≥ 2, n (%) 13 (65%) 21 (55.3%) 34 (58.6%) Average (SD) 3.2 (1.1) 3.5 (1.5) 3.2 (1.1) CRT (μm) (reading center) Average (SD) 306 (58.9) 338 (155.5) 327 (130.8) Minimum: maximum 214: 432 153: 1048 153.0: 1048 CRT ≥300 μm, n (%) 11 (55.0%) 18 (47.4%) 29 (50.0%) Average (SD) 346 (42.3) 432 (181.5) 400 (149.7) BCVA (letters ETDRS) Average (SD) 74.5 (13.5) 70.4 (14.6) 71.8 (14.2) Minimum: maximum 35.0: 88.0 24.0: 93.0 24.0: 93.0

The data show that all of VH, BCVA, and CRT returned to normal in patients treated with sarilumab for 16 weeks compared with patients treated with placebo. At week 52, the sarilumab group continued to show an advantage over the placebo group; especially in relation to CRT normalization in patients with overt macular edema at baseline. The data described in this document indicate that sarilumab was effective in increasing BCVA and reversing macular edema in patients with severe uveitis.

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LIST OF SEQUENCES

<110> SANOFI BIOTECHNOLOGY

REGENERON PHARMACEUTICALS, INC.

<120> COMPOSITIONS CONTAINING ANTIBODIES TO IL6R FOR TREATMENT OF UVEITA AND

MACULAR EDEMA, AND METHODS OF THEIR APPLICATION

<130> 585328: SA9-185PC

<140>

<141>

<150> 62 / 408.391

<151> 2016-10-14

<150> EP 16306166.6

<151> 2016-09-14

<150> 62 / 250.269

<151> 2015-11-03

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<170> PatentIn version 3.5

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<---

Claims (24)

1. The use of a composition containing an effective amount of an antibody that specifically binds the IL-6 receptor for the treatment of uveitis in a subject in need thereof, where the subject has a vitreous opacity (VH) level of 2 on the Miami 9-point scale or greater, or where the subject has a central retinal thickness (CRT) greater than 300 μm, wherein the antibody that specifically binds to the IL-6 receptor comprises a heavy chain variable region sequence under SEQ ID NO: 2 and a light chain variable region sequence under SEQ ID NO: 3, where the antibody is administered at a dose of 150 to 200 mg once every two weeks. 2. Use according to claim 1, wherein the dose of the antibody is 150 or 200 mg once every two weeks. 3. Use according to claim 1 or 2, wherein the uveitis is selected from the group consisting of secondary uveitis, posterior uveitis, panuveitis, non-infectious uveitis, systemic uveitis, and idiopathic uveitis. 4. Application according to any one of paragraphs. 1-3, where the subject was treated with a corticosteroid for at least three months. 5. Use according to claim 4, wherein the corticosteroid is prednisone. 6. Use according to claim 5, wherein the dose of prednisone is 15 to 80 mg / day. 7. The use according to any one of paragraphs. 4-6, where the subject was also treated with methotrexate. 8. Application according to any one of paragraphs. 1-7, where after 16 weeks the subject achieves a decrease in VH level on the Miami 9-point scale of at least 2 stops or is allowed to reduce the dose of corticosteroids to less than 10 mg per day. 9. Application according to any one of paragraphs. 1-8, where the antibody is sarilumab. 10. The use of a composition containing an effective amount of an antibody that specifically binds the IL-6 receptor for the treatment of macular edema in a subject in need thereof, where the antibody, which specifically binds to the receptor for IL-6, contains the sequence of the variable region of the heavy chain under SEQ ID NO: 2 and the sequence of the variable region of the light chain under SEQ ID NO: 3; where the dose of antibody is 150 to 200 mg once every two weeks. 11. Use according to claim 10, wherein the dose of the antibody is 150 or 200 mg every two weeks. 12. Use according to claim 10 or 11, where the subject suffers from at least one symptom of macular edema selected from the group consisting of eye inflammation, visual impairment, color recognition impairment, tissue thickening and ocular vascular leakage; or where macular edema is secondary to uveitis, macular edema. 13. The use according to any one of paragraphs. 10-12, where the subject has previously been treated with a corticosteroid for at least three months. 14. The use of claim 13, wherein the corticosteroid is prednisone. 15. Use according to claim 14, wherein the dose of prednisone is 15 to 80 mg / day. 16. The use according to any one of paragraphs. 10-15, where the subject was also treated with methotrexate. 17. The use according to any one of paragraphs. 10-16, where after 16 weeks the subject achieves a decrease in VH level on the Miami 9-point scale by at least 2 stops or is allowed to reduce the dose of corticosteroids to less than 10 mg per day. 18. The use according to any one of paragraphs. 10-17, where the antibody is sarilumab.