Methods for treating ocular diseases

Abstract

To provide methods for reducing the treatment burden for patients who have an intraocular neovascular disorder.SOLUTION: The present invention provides a method for treating neovascular age-related macular degeneration (nAMD) in a mammal, the method comprising: a) administering to the mammal three individual doses of a VEGF antagonist at 4 week intervals; b) assessing the mammal for best corrected visual acuity (BCVA), visual acuity (VA), central subfield thickness (CSFT), and the presence of intraretinal cysts / fluid at week 12; and c) assessing the mammal for BCVA, VA, CSFT, and the presence of intraretinal cysts / fluid at week 16.SELECTED DRAWING: None

Description

[Technical field]

[0001] This application is a continuation of U.S. Provisional Application No. 62 / 076,770, filed November 7, 2014. and priority to U.S. Provisional Application No. 62 / 088,061, filed December 5, 2014. No. 6,313,935, the disclosures of which are specifically incorporated herein by reference.

[0002] FIELD OF THEINVENTION The present invention relates to methods of treating ocular diseases with VEGF antagonists. The invention provides a method for treating ocular neovascular disease (OCD) with less frequent dosing compared to currently approved treatment regimens. The drug is intended to treat chronic neovascular disease (CND). 1. A method for identifying a patient who can be treated with a VEGF antagonist in a patient comprising: The patient underwent a loading phase of three separate doses administered four weeks apart. A method is provided in which [Background technology]

[0003] 2. Background of the Invention Age-related macular degeneration (AMD) affects 10% to 19% of individuals over the age of 65 in North America, Europe, and Australia. It is the leading cause of severe vision loss in the population, affecting 3% of all people (Kawasaki 2010, Rein et al., Arch Ophthalmol. 2009;127:533-40, Smith 2001). In the pathogenesis of this disease, Genetic, environmental and health factors play an important role.

[0004] AMD is classified into two clinical subtypes: non-neovascular (atrophic) or dry, and neovascular. They are classified as ductal (exudative) or wet (Ferris et al., Arch Ophthalmol. 1984;102:1 640-2, Lim et al., Lancet. 2012;379:1728-38, Miller et al., Am J Ophthalmol. 201 3;155:1-35). Neovascular AMD (nAMD) refers to choroidal neovascularization ( Abnormal new blood vessels growing from the subchoroidal layer under the RPE or subretinal space, called CNV, (Ferris et al., Arch Ophthalmol. 1984;102:164 These newly formed blood vessels are more likely to leak blood and serum, causing inflammation. and damage the retina by stimulating scar tissue formation. This damage to the retina , progressive, severe, and irreversible vision loss occurs (Shah et al., Am J Ophthalmol 2007;143:83-89; Shah et al., Am J Ophthalmol. 2009;116:1901-07). Without glaucoma, most affected eyes are expected to experience deterioration in central vision (20 / 200) within 12 months. The neovascular form of the disease is thought to be present in approximately 10% of all AMD cases. However, before the introduction of anti-vascular endothelial growth factor (VEGF) treatment, It accounted for approximately 90% of severe vision loss (Ferris et al., Am J Ophthalmol. 1983;118:1 32-51, Sommer et al., N Engl J Med. 1991;14:1412-17, Wong et al., Ophthalmology. 2008;115:116-26).

[0005] VEGF is known to be elevated in patients with nAMD and is involved in the neovascularization process. It is believed to play an important role in the process (Spilsbury et al., Am J Pathol. 2000; 157:135-44). The use of intravitreal (IVT) drug therapy targeting VEGF has been shown to improve nAM Visual outcomes have been significantly improved in patients with D (Bloch et al., Am J Ophthalmology, 2018). mol. 2012;153:209-13, Campbell et al., Arch Ophthalmol. 2012;130:794-5). Ranibi Zumab (LUCENTIS®) and aflibercept (EYLEA®) Anti-VEGF treatments such as VEGF inhibit the VEGF signaling pathway and slow the growth of neovascular lesions. It has been shown to halt retinal edema and resolve retinal edema.

[0006] Two Phase 3 trials of ranibizumab have demonstrated that patients treated with ranibizumab on a monthly dosing regimen Approximately 95% of subjects placed had stabilized vision (defined as loss of less than 15 ETDRS letters) or improved vision at 12 months, compared with 62% and 67% in the control group. and 64% (Rosenfeld et al., N Engl J Med. 2006;355:1419-31, Brown et al. l., N Engl J Med. 2006;355:1432-44). 25-40% of subjects in the ranibizumab group had 12 ≥15 letters were obtained at month 1 in both groups, compared with 5-6% in the two control groups. Nibizumab-treated subjects gained 7 to 11 letters of vision after 12 months, whereas co The control subjects lost, on average, about 10 letters. was essentially maintained throughout the second year of both Phase 3 trials, whereas the control Visual acuity continued to decline on average in patients with nAMD. This visual acuity benefit is consistent with studies reporting similar efficacy and outcomes by lesion anatomy. The latter was endorsed by the National Eye Institute Visua Functioning Questionnaire-25 (VFQ-25) When measured by the The study showed statistically and clinically meaningful improvements in fic dependency.

[0007] In two parallel phase 3 trials of aflibercept, treatment naive ), and subjects with nAMD were treated with two doses (0.5 mg and 2.0 mg). and two regimens (2.0 mg every 4 weeks and every 8 weeks) or a control group (4 Patients were randomized to receive ranibizumab 0.5 mg weekly. At week 52, the dose and regimen were Regardless of the outcome, all aflibercept arms were non-inferior to ranibizumab, and ocular Visual acuity was maintained in 95% of cases (Heier et al., Ophthalmology. 2012;119:2537 -48) Compared with the control group, patients taking 2 mg every four weeks improved by an average of 8.7 letters. The aflibercept group improved BCVA by a mean of 9.3 letters, with a dose of 2 mg every 8 weeks The aflibercept arm improved by 8.4 letters. Switched to a capped pro-renata (PRN) regimen The proportion of subjects who maintained BCVA ranged from 91% to 92% in all groups. BCVA improvement was 7.9 (ranibizumab 0.5 mg every 4 weeks) and 7.6 (ranibizumab 0.5 mg every 4 weeks). and aflibercept 2 mg to 6.6 mg (aflibercept 0.5 mg) every 8 weeks. In all groups, patients were switched from a fixed regimen to a PRN regimen with a cap. After that, there was an average drop of 0.8 to 1.7 characters. The frequency of retreatment was similar between the aflibercept and ranibizumab groups, with In the aflibercept 2 mg group, the number of injections was 4.1, and in the aflibercept 2 mg group, the number of injections was 4.1. In the 2 mg-septocept group, the number of injections was 4.2, whereas the 0.5 mg-ranibizumab group received 0.5 mg of ranibizumab every 4 weeks. and 4.7 injections in the 100 mg group (Schmidt-Erfurth et al., Br J Ophthalmo l 2014;98:1144-1167 2014;98:1144-1167).

[0008] Monthly or bimonthly treatments are generally recommended for older patients as well as their caregivers. This procedure also places a significant burden on the patient and the physician. Each injection is proven to have a beneficial effect on the body, but is not without risks. , subconjunctival hemorrhage, vitreous hemorrhage, retinal tears, retinal detachment, possible iatrogenic cataract and endophthalmitis (Ohr et al., Expert Opin. Pharmacother. 2012;13:585-591), and anti-VEGF agents Continuous injections may also result in a sustained increase in intraocular pressure (IOP) (Tseng et al., J Gl aucoma. 2012;21:241-47). In addition, monthly IVT injections are effective in 60-70% of patients. This will obviously affect more patients than currently available products. The aim of the project is to develop a product that achieves greater visual acuity gains in patients and / or has long-term therapeutic effects. There is a medical need to Summary of the Invention

[0009] Summary of the Invention The present invention relates to a therapeutic VEGF antagonist for treating ocular diseases, particularly ocular neovascular diseases. In certain aspects, the present invention provides improved methods of administering an ophthalmic agent to a patient. A method for treating vascular disease comprising administering VEGF inhibitors at four week intervals (i.e., once a month). administering to the mammal three individual doses of the antagonist; The results of disease activity assessment using predefined visual and anatomical criteria are then reported. Depending on efficacy, additional doses may be administered every 12 weeks (q12) and / or every 8 weeks (q8). The present invention provides a method for detecting a stoichiometric amount of ...

[0010] In certain embodiments, the VEGF antagonist used in the methods of the invention is an anti-VEGF In certain embodiments, the anti-VEGF antibody is a single chain antibody (scFv) or F ab fragment. Specifically, the anti-VEGF antibody is RTH258.

[0011] Certain preferred embodiments of the present invention are described below with reference to certain preferred embodiments. This will become apparent from the detailed description and claims. [Brief description of the drawings]

[0012] [Figure 1] FIG. 1 shows a dosing schedule for treating nAMD with RTH258. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] Detailed Description definition The following definitions and explanations are as follows, unless expressly and unambiguously changed in the following examples: unless application of the meaning would render any interpretation meaningless or essentially meaningless. It is meant and intended to control all future interpretations. If the term is rendered meaningless or essentially meaningless, the definition is: r d Edition or a dictionary known to those skilled in the art (e.g., the Oxford Dictionary of Biochemistry and Mol ecular Biology (Ed. Anthony Smith, Oxford University Press, Oxford, 2004)) This will be done in accordance with the following:

[0014] As used herein, all percentages are by weight unless otherwise specified. This is a page.

[0015] As used herein and unless otherwise indicated, the terms “a” and “one” "An" means "one," "at least one," or "one or more." As used herein, singular terms include plurals unless otherwise required by context. and plural terms include the singular.

[0016] The contents of all patents, patent applications and references cited throughout this specification are the property of their respective owners. is incorporated herein by reference in its entirety.

[0017] The term "VEGF" is used in conjunction with the methods described in Leung et al., Science 246:1306 (1989) and Houck et al., M As described by Ol. Endocrin. 5:1806 (1991), the 165 amino acid endothelial Vascular endothelial cell proliferation and cell growth factors and related 121, 189 and 206 amino acids The term "proliferative growth factors" refers to the naturally occurring allelic and processed forms of these growth factors. means.

[0018] The term "VEGF receptor" or "VEGFr" refers to a receptor that is normally found on vascular endothelial cells. A cell surface receptor for VEGF and the binding of this cell receptor to hVEGF An example of a VEGF receptor is a tyrosine kinase. The fms-like tyrosine kinase (flt) is a member of the mitochondrial kinase family of transmembrane receptors. et al., Science 255:989 (1992); Shibuya et al., Oncogene 5:519 (1990). This fl The t receptor is a cellular component that has an extracellular domain, a transmembrane domain, and tyrosine kinase activity. The extracellular domain is involved in VEGF binding, and the intracellular domain Another example of a VEGF receptor is the flk-1 receptor (also known as KDR). Matthews et al., Proc. Nat. Acad. Sci. 88:9026 (1991), Terman et al., Oncogene 6:1677 (1991), Terman et al., Biochem. Biophys. Res. Commun. 18 7:1579 (1992). Binding of VEGF to the flt receptor results in the formation of 205,000 dalton and and at least two high molecular weight complexes having apparent molecular weights of 300,000 daltons. The 300,000 dalton complex binds to a single molecule of VEGF. It is thought to be a dimer containing two receptor molecules.

[0019] As used herein, a "VEGF antagonist" refers to an agent that inhibits VEGF in vivo. By "VEGF" is meant a compound capable of reducing or inhibiting the activity of VEGF. The antagonist is capable of binding to a VEGF receptor or a VEGF protein. The VEGF antagonist can block the binding of VEGF to the VEGF receptor. , one or more VEGF proteins or one or more VEGF receptors a small molecule capable of specifically binding to VEGF, an anti-VEGF antibody or antigen-binding fragment thereof, a fusion Proteins (e.g. aflibercept), aptamers, antisense nucleic acid molecules, interfering RNA A, receptor proteins and the like. Some VEGF antagonists Gonists are described in WO 2006 / 047325.

[0020] In a preferred embodiment, the VEGF antagonist is an anti-VEGF antibody.

[0021] The term "antibody," as used herein, includes whole antibodies and any antigen-binding fragments (i.e., "antigen-binding portion," "antigen-binding peptide" or "immunobinder") or An "antibody" is a single chain of at least two amino acids interconnected by disulfide bonds. It contains a glycoprotein that contains a heavy (H) chain and two light (L) chains or antigen-binding portions thereof. Each heavy chain comprises a heavy chain variable region (V Hand the heavy chain constant region. The heavy chain constant region is composed of three domains: CH1, CH2, and CH3. Each light chain comprises a light chain variable region (V L and the light chain constant region The light chain constant region is composed of one domain, CL. H territory Area and V L The more conserved regions are called framework regions (FR). These can be further divided into regions of hypervariability called complementarity determining regions (CDRs), which are interspersed with Each V H and V L is in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4, and three CDRs arranged from the amino terminus to the carboxy terminus. The variable regions of the heavy and light chains are composed of binding domains that interact with antigens. The constant region of an antibody contains a domain that binds to various cells of the immune system (e.g., effector cells and and the first component of the classical complement system (Clq). It can mediate the binding of

[0022] The term "antigen-binding portion" of an antibody (or simply "antibody portion") refers to an antibody that binds to an antigen (e.g., VEGF). The term "antibody fragment" refers to one or more fragments of an antibody that retain the ability to specifically bind to a target protein. It has been shown that the antigen-binding function can be performed by fragments of a full-length antibody. Examples of binding fragments encompassed by the term "antigen-binding portion" include: L Domain, V H Domain (ii) a Fab fragment, which is a monovalent fragment consisting of the IgG1 domain, the CL domain and the CH1 domain; A bivalent fragment containing two Fab fragments linked by a disulfide bridge at the hinge region (iii) a F(ab')2 fragment having a structure of V H Fd domain and CH1 domain (iv) a V fragment of a single arm of an antibody L Domains and V H Fv fragment consisting of domains, (v) V H Single domains or dAb fragments consisting of domains (Ward et al., (1989) Nature re 341:544-546), and (vi) an isolated complementarity determining region (CDR), or (vii) a synthetic The present invention also includes combinations of multiple isolated CDRs, which may optionally be linked by a synthetic linker. The two domains V of the Fv fragment L and V H are encoded by separate genes , with a synthetic linker that allows these domains to be assembled into a single protein chain. Using recombinant methods, these domains can be linked together in a protein chain. , V L Area and V H The domains pair to form monovalent molecules (single-chain Fv (scFv) See, e.g., Bird et al. (1988) Science 242:423-426 and Huston et al. (see, for example, et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883). Single chain antibodies are also intended to be encompassed within the term "antigen-binding portion" of an antibody. The antibody fragments may be obtained using conventional techniques known to those skilled in the art, and these fragments may be prepared by any method known to those skilled in the art. The antigen-binding portions are screened for utility in the same manner as for the humanized polypeptides. They can be produced by surgery or by enzymatic or chemical cleavage of intact immunoglobulins. The antibodies can be of various isotypes, for example, IgG (e.g., IgG 1 subtype, IgG2 subtype, IgG3 subtype or IgG4 subtype) IgA1 antibody, IgA2 antibody, IgD antibody, IgE antibody, or IgM antibody. can be done.

[0023] As used herein, "mammal" includes any animal classified as a mammal. Mammals include humans, domestic animals, livestock and companion animals. Not limited to these.

[0024] As used herein, the term "subject" or "patient" refers to human and non-human mammals. Non-human animals include primates, rabbits, pigs, horses, dogs, cats, sheep, etc. Preferably, the subject or patient is a human. do.

[0025] "Ocular diseases" or "neovascular ocular diseases" that can be treated using the methods of the present invention Examples of such conditions, diseases, and disorders include those involving ocular neovascularization. and disorders include abnormal angiogenesis, choroidal neovascularization (CNV), retinal vascular permeability, and retinal Edema, diabetic retinopathy (especially proliferative diabetic retinopathy), diabetic macular edema, neovascularization (exudation) Age-related macular degeneration (AMD), such as CNV associated with neovascular AMD (nAMD), retinal ischemia The associated sequelae include central retinal vein occlusion (CRVO) and posterior segment neovascularization. The present invention is not limited to these.

[0026] Selection of treatment regimen The present invention relates to a method for treating patients with ocular disease with a VEGF antagonist, the method comprising the steps of: The present invention provides a method for determining whether a patient can receive treatment every 12 weeks or every 12 weeks.

[0027] The present invention relates to a method for treating neovascular diseases of the eye in a mammal, such as neovascular age-related macular degeneration (nAMD). The method comprises administering VEGF inhibitors to a mammal at various intervals over a period of at least two years. The method includes administering multiple doses of the antagonist. In certain embodiments, these doses are administered four weeks apart for a total of three doses. , followed by 8-week intervals, 12-week intervals, or a combination of 8-week and 12-week intervals. The present invention provides guidance as to when to use the 8 week interval and when to use the 12 week interval. The authors based their assessment of disease activity to determine when intervals should be used. The present invention further provides specific criteria established for determining when to switch from one treatment interval to another. For example, the first three steps described in this specification provide a method for determining whether to change the If one chooses to administer doses to a patient at 12 week intervals (after the dose loading phase), the method of the present invention Using the method, patients were advised to continue on the 12-week interval regimen or to switch to the 8-week interval regimen. Using the methods of the present invention, it can be determined whether a patient should be switched to an 8 week interval regimen. Decisions can be made as to whether to continue taking Zymen or switch to a 12-week interval regimen. In some cases, patients are on a 12 week interval regimen for a while, then 8 week intervals. may be switched to a weekly interval and then back to a 12-week interval. Therefore, patients do not need to continue on one interval regimen and can receive the same treatment as described herein. They can move back and forth depending on the evaluation according to the standards.

[0028] In one embodiment, the present invention is a method for treating an ocular disease, particularly an ocular neovascular disease. So, here is the schedule: A "loading phase" of three doses administered four weeks apart (e.g., weeks 0, 4, and 8); Rabi 8 weeks (q8) and / or 12 weeks (q12) depending on the selection criteria further described herein. 12) additional doses at intervals administering to a mammal in need thereof a VEGF antagonist according to A method is provided.

[0029] In certain embodiments, disease activity assessment is performed, for example, after initial administration of a VEGF antagonist. at weeks 16, 20, 32, and 44 after the first injection, and at the end of the first year of treatment. By the end of the study (week 48), subjects with q12 could be reassigned to q8 treatment at four time points. Early identification of subjects more suitable for the q8 dosing regimen at week 16 may allow for later reassignment is required at week 20, week 32, or week 44 (reassignment is also possible at week 20, week 32, or week 44) It is expected that this will minimize the percentage of q12 subjects who will need Analysis from the PIER and EXCITE studies revealed that the Visual and anatomical responses immediately following the treatment phase were correlated with visual acuity outcomes over the remainder of the first year of treatment. Recent analysis from the EXCITE study has shown that Subjects with declining vision during the treatment period had better visual outcomes with frequent treatment compared to q12 treatment. Recent studies from CATT and EXCITE have also shown that it can be effective. Analysis revealed new intra-retinal fluid / cysts and smaller Small increases in CSFT have been shown to be associated with decreased visual acuity. These dynamic criteria , supporting their use in the 16-week disease activity assessment.

[0030] In one embodiment, patients treated with the first three doses of a VEGF antagonist are This patient will be evaluated at weeks 1, 16, 20, 32, and 44 to receive additional doses. Determine whether the doses should be administered at 8-week or 12-week intervals.

[0031] In another embodiment, patients treated with the first three doses of a VEGF antagonist are This patient was followed up in the second year of treatment at weeks 8, 56, 68, and 80. The patient is then tested for efficacy and safety in a controlled trial to determine whether the different doses should be administered at 8 week intervals or 12 week intervals.

[0032] On the week of evaluation, patients could be currently on an 8-week or 12-week interval regimen. This assessment therefore allows the patient to decide whether to continue on the current interval or switch to another interval. The decision can be made as to whether to

[0033] As used herein, best-corrected visual acuity (BCA) is used. CVA, visual acuity (VA), and central subfield thickness measured by SD / OCT ld thickness (CSFT), and / or new or worsening intraretinal cysts / Determine the presence of intraretinal cysts / intraretinal fluid (IRC / IRF) The following are some of the things that can be done:

[0034] Means for determining and monitoring VA, BCVA, CSFT and IRC / IRF Means for determining whether a baseline is acceptable are well understood and commonly used by those skilled in the art. The number of letters of the patient's mean change in BCVA from the desired time Monitor the patient's visual performance by assessing changes. This baseline can be, for example, the VA at the start of therapeutic treatment or after treatment has begun. may be the VA at a particular point in time.

[0035] In certain embodiments, the methods of the present invention provide a method for measuring the concentration of a compound in a sample from baseline to a particular time (e.g., 12 hours). To determine the mean change in BCVA from week 1 to week 16 and to determine whether subjects had a mean change in BCVA from baseline There is a particular difference in visual acuity at a particular time (e.g., from 12 weeks to 16 weeks) compared to the baseline. This involves evaluating whether the character loss is less than a certain number of characters.

[0036] In certain embodiments, after the first three doses administered four weeks apart, the patient is The selection criteria for determining whether to treat weekly or every 12 weeks were as follows: This is: 0 weeks to 48 weeks If met, patients will be treated with VEGF antagonists every 8 weeks (q8) for up to 48 weeks. The patient will be assigned to receive an injection of Week 16: - Neovascular AMD (nAMD) disease activity at 16 weeks compared to baseline Attributable loss of BCVA of ≥5 letters. ≥ 5-letter BC due to nAMD disease activity at Week 16 compared with Week 12 Decreased VA. ≥3 letter decline in VA and ≥75 μm CSFT at Week 16 compared to Week 12 increase. New or worsening intraretinal cysts (IRCs) at week 16 compared to week 12 / Intraretinal fluid (IRF). Weeks 20, 32 and 44: - ≥ 5 letter loss in BCVA due to nAMD disease activity compared to Week 12.

[0037] In another embodiment, the method of the present invention includes an additional 48 weeks after the initiation of treatment as described below. Rating includes: 48 weeks to 96 weeks Patients assigned to q8 treatment at weeks 16 and 20 met any of the following criteria: If not, in the second year of treatment, reassign the patient to the q12 treatment regimen: Week 48: ≥ 5-letter BC due to nAMD disease activity at Week 48 compared with Week 32 Decreased VA. New or worsening IRC / IRF at Week 48 compared with Week 32.

[0038] Subjects entering the second year of treatment on the q12 treatment regimen were randomized to receive 100 mg / kg / day of treatment at any of the following visits: Patients are maintained on a q12 regimen unless the following criteria are met: Weeks 56, 68, and 80: ≥ 5 letter loss in BCVA due to nAMD disease activity compared to Week 48.

[0039] Anti-VEGF antibody In certain embodiments, the VEGF antagonist used in the methods of the invention is an anti-VEGF F antibody, specifically as described in WO 2009 / 155724. and is an anti-VEGF antibody which is incorporated herein by reference in its entirety. It is used.

[0040] In one embodiment, the anti-VEGF antibody of the invention has the sequence set forth in SEQ ID NO:1. and a variable light chain having the sequence set forth in SEQ ID NO:2.

number

[0041] In another embodiment, the anti-VEGF antibody used in the methods of the invention is set forth in SEQ ID NO:3. Contains the array.

number

[0042] In a preferred embodiment, the anti-VEGF antibody used in the methods of the invention is RTH258 (sequence RTH258 is a humanized version of VEGF with a molecular weight of approximately 26 kDa. RTH258 is a single-chain Fv (scFv) antibody fragment inhibitor that inhibits VEGF-A. It acts by binding to the receptor binding site of the VEGF-A molecule, This allows VEGF-A to bind to its receptor VEGFR1 on the surface of endothelial cells. and VEGFR2. Increased levels of VEGF are associated with pathological ocular neovascularization and retinal edema. This has been shown to inhibit the growth of neovascular lesions and reduce retinal edema in patients with nAMD. I know it will disperse.

[0043] Pharmaceutical preparations In one embodiment, the methods of the invention involve the use of a pharmaceutical formulation comprising an anti-VEGF antibody. A pharmaceutical preparation is a drug that demonstrates the biological activity of an antibody or antibody derivative. This means a formulation in a form that effectively treats the disease, and this formulation has the effect of Contains no additional ingredients that are toxic to humans or animals. "Pharmaceutically acceptable" excipients (vehicles, additives) can be reasonably administered to the target mammal to provide an effective dose of the active ingredient used. be.

[0044] A "stable" formulation means that the antibody or antibody derivative therein has sufficient physical stability and and / or formulations that essentially retain chemical stability and / or biological activity. A variety of analytical techniques are available in the art for measuring protein stability, e.g. Peptide and Protein Drug Delivery, 247-301, Vincent Lee Ed., Marcel Dekker, Inc. , New York, NY, Pubs. (1991) and Jones, A. Adv. Drug Delivery Rev. 10: 29-90 (1993). Stability can be measured at a selected temperature for a selected period of time. Preferably, the formulation is stored at room temperature (about 30° C.) or Stable at 40°C and / or stable at approximately 2-8°C for at least 3 months to 2 years Furthermore, the formulation is preferably freezing (e.g., to -70°C) and It is stable after thawing and defrosting.

[0045] The antibody or antibody derivative may be detected upon visual inspection for color and / or transparency or by UV light scattering. Random or size exclusion chromatography or other suitable art recognized methods. The pharmaceutical formulation is free of aggregation, degradation, precipitation and / or denaturation as measured by a method If the release specifications set forth in the above are met, the pharmaceutical formulation will be deemed to have "maintained physical stability." "

[0046] The antibody or antibody derivative has a chemical stability over a given time period that is in accordance with the protein as defined below. In pharmaceutical preparations, the compound is deemed to retain its biological activity. "Retains chemical stability" by detecting chemically modified forms of the protein. Chemical stability can be assessed by measuring and quantifying the chemical modification. For example, size exclusion chromatography, SDS-PAGE and / or matrix Using magnetic resonance assisted laser desorption / ionization / time-of-flight mass spectrometry (MALDI / TOF MS), Examples of such changes include resizing (e.g. clipping) that can be evaluated using the Other types of chemical modifications can be assessed, for example, by ion exchange chromatography. and charge changes that can occur, for example as a result of deamidation.

[0047] An antibody or antibody derivative has a specific binding activity at a given time, e.g., as measured by an antigen binding assay. The biological activity of the antibody is within about 10% of the biological activity exhibited at the time of preparation of the pharmaceutical formulation ( An antibody "retains biological activity" in this pharmaceutical formulation if it is within the error of the assay. Other "biological activity" assays for are detailed herein below.

[0048] "Isotonic" means that the subject formulation has essentially the same osmotic pressure as human blood. The tonicity formulation may typically have an osmotic pressure of about 250 to 350 mOsm. Isotonicity can be measured using a pressure or ice-freezing osmometer. Cut.

[0049] "Polyols" are substances that have multiple hydroxyl groups and are sugars (reducing and non-reducing sugars). The preferred polyols herein include polyols having a molecular weight of Less than about 600 kDa (e.g., in the range of about 120 to about 400 kDa). " is capable of reducing metal ions or lysine groups in proteins and other It contains a hemiacetal group that can covalently react with an amino group and is A "reducing sugar" is one that does not have these properties of a reducing sugar. An example of a reducing sugar is fructose. , mannose, maltose, lactose, arabinose, xylose, ribose, rhamno The non-reducing sugars are sucrose, trehalose, and glucose. Examples of sugar alcohols include: Mannitol, xylitol, erythritol, threitol, sorbitol and glycol The sugar acids include L-gluconates and metal salts of these. If it is desired that the agent be freeze-thaw stable, the polyol may be selected from polyols that can withstand freezing temperatures (e.g., −20 It is preferable that the antibody in the formulation does not become unstable by crystallizing at temperatures of 100° C. or less. Sugars (e.g., sucrose and trehalose) are preferred polyols, with trehalose being preferred. Trehalose is preferred over sucrose due to its superior solution stability.

[0050] As used herein, a "buffer" refers to a substance that is resistant to changes in pH due to the action of acid-base conjugate components. The buffer solution of the present invention has a pH range of about 4.5 to about 8.0. The pH of the buffer solution can be adjusted within this range, preferably from about 5.5 to about 7. Examples include acetates (e.g. sodium acetate) and succinates (e.g. sodium succinate). , gluconate, histidine, citrate and other organic acid buffers. If a freeze-thaw stable formulation is desired, the buffer is preferably not phosphate.

[0051] In the pharmaceutical sense, in the context of the present invention, a "therapeutically effective amount" of an antibody or antibody derivative. is administered in an amount effective for the prevention or treatment of a disorder for which the antibody or antibody derivative is effective. "Disease / disorder" means a disease or disorder that would benefit from treatment with an antibody or antibody derivative. This includes any condition that predisposes a mammal to the disorder in question. This includes chronic and acute disorders or diseases such as conditions.

[0052] "Preservatives" refer to agents that essentially reduce bacterial activity in a formulation, thereby making it more versatile, e.g. A compound that can be included in a formulation to facilitate its manufacture. Potential preservatives Examples of the ammonium chloride include octadecyldimethylbenzylammonium chloride, hexamethonium chloride, Benzalkonium chloride (alkylbenzyldimethyl chloride, a compound in which the alkyl group is a long chain compound) Other types of preservatives include benzethonium chloride (mixture of ammonium chloride) and benzethonium chloride. As examples, aromatic alcohols, such as phenol alcohol, butyl alcohol and benzene alcohol, Alkyl alcohol, alkylparabens, such as methylparaben or propylparaben, catecholamines, Coal, resorcinol, cyclohexanol, 3-pentanol and m-cresol The most preferred preservative herein is benzyl alcohol.

[0053] The pharmaceutical composition used in the present invention contains a VEGF antagonist (preferably an anti-VEGF antibody). ) together with at least one physiologically acceptable carrier or excipient. The medium may be, for example, water, a buffer solution (e.g., neutral buffered saline or phosphate buffered saline), ethanol, mineral oil, vegetable oil, dimethyl sulfoxide, carbohydrates (e.g. glucose, mannoacetate, sucrose or dextran), mannitol, protein, adjuvant, Polypeptides or amino acids such as glycine, antioxidants, EDTA or glutathione, etc. The composition may include one or more of the chelating agents and / or preservatives described above. As noted above, the pharmaceutical compositions provided herein may, but do not necessarily, include other active ingredients. does not need to be included.

[0054] A carrier is a substance that is administered to a patient, often with the aim of controlling the stability or bioavailability of a compound. In such a formulation, the agent may be associated with an antibody or antibody derivative prior to administration to the subject. Carriers intended for use in the present invention are generally biocompatible and may also be biodegradable. As an antibody, for example, a monovalent or polyvalent molecule, such as serum albumin (e.g., human or mouse serum albumin), C), egg albumin, peptides, polylysine, and polysaccharides such as aminodextran, and polyamidoamines. Carriers include, for example, polylactate, polyglycol, Poly(lactide-co-glycosides), polyacrylates, latexes, starches , solid supports (e.g., beads and microparticles) including cellulose or dextran The support can support the compound in various ways, including (directly) These include covalent bonding (directly or via a linker group), non-covalent interactions or mixing. can be done.

[0055] The pharmaceutical compositions can be administered by any suitable mode of administration, e.g., topically, ocularly, orally, nasally, In certain embodiments, the composition may be formulated for oral administration, rectal administration, or parenteral administration. Preferably, the composition is in a form suitable for intraocular injection, such as intravitreal injection. For example, pills, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or or granules, emulsions, hard or soft capsules, or syrups or elixirs In yet other embodiments, the compositions provided herein are administered as a lyophilizate. The term parenteral as used herein includes subcutaneous injection, intradermal injection, and the like. injection, intravascular (e.g., intravenous) injection, intramuscular injection, spinal injection, intracranial injection, intrathecal injection, and and intraperitoneal injection, and any similar injection or infusion technique.

[0056] The pharmaceutical composition is prepared by mixing the active agent (i.e., VEGF antagonist) with the vehicle and Sterile injectable aqueous or Such compositions can be formulated as oily suspensions. The composition may be formulated according to the known art using suitable dispersing, wetting and / or suspending agents. Acceptable vehicles and solvents that may be employed include water, 1,3-butanediol, In addition, sterile fixed oils, As a solvent or suspending medium, any sterile solvent may be employed. Any fixed oil may be employed, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectable compositions and as an adjuvant. For example, a local anesthetic, a preservative and / or a buffering agent can be dissolved in the vehicle. do.

[0057] Dosage The dosages used in the methods of the present invention are based on the particular disease or condition being treated. A "therapeutically effective dose" is defined as a dose sufficient to achieve or at least partially achieve a desired effect. A sufficient amount is defined as an amount sufficient to produce even a slight change in symptoms or condition associated with the disease. Preferably, a therapeutically effective dose is sufficient. A therapeutically effective dose is sufficient to completely cure a disease. It is not necessary to completely eliminate symptoms. Preferably, a therapeutically effective dose is , at least partially inhibiting the disease and complications of the disease in patients already suffering from the disease. Amounts effective for this use will depend on the severity of the disorder being treated and the patient's own immune system. It is expected to depend on the overall state of the system.

[0058] A physician of ordinary skill in the treatment of a disease or condition may use known dosage adjustment techniques. By doing so, the dose amount can be easily determined. The therapeutic dose of the VEGF antagonist used in the method of the invention should be determined taking into consideration the dosage volume and mode of administration. A therapeutically effective amount is determined. Typically, a therapeutically effective composition is administered in an amount of 0.05 mg / dose. The dosage ranges from about 0.1 mg / ml to about 200 mg / ml. The dosage used in the method is from about 60 mg / ml to about 120 mg / ml (i.e., about 60, 70 , 80, 90, 100, 110 or 120 mg / ml). The dosage of the anti-VEGF antibody used in the method of the present invention is 60 mg / ml or 120 mg / ml. / ml.

[0059] The aqueous formulation of the anti-VEGF antibody used in the method of the present invention has a buffered pH Preferably, such aqueous formulations are buffered to a pH of about 4. It is in the range of 5 to about 8.0, preferably in the range of about 5.5 to about 7.0, and most preferably is approximately 6.75. An example of a buffer that can control the pH within this range is acetate. Salts (e.g. sodium acetate), succinates (e.g. sodium succinate), gluconates , histidine, citrate and other organic acid buffers. The concentration can range from about 1 mM to about 5 mM, depending, for example, on the buffer and on the desired tonicity of the formulation. The concentration may be 0 mM, and preferably about 5 mM to about 30 mM.

[0060] Polyols, which act as tonicifiers, are used to stabilize antibodies in aqueous formulations. In a preferred embodiment, the polyol is a non-reducing sugar, e.g. For example, sucrose or trehalose. Optionally, the polyol may be added to the formulation. The aqueous formulation is preferably isotonic and has a pH of 10. In this case, a suitable concentration of the polyol in the formulation is, for example, about 1% by weight / volume to about 15% by weight / volume. / volume %, preferably in the range of about 2 wt / vol % to about 10 wt / vol %. However, hypertonic or hypotonic preparations may be appropriate. The amount of polyol can also be varied relative to the molecular weight of the polyol. A small amount of a monosaccharide (eg, mannitol) can be added relative to the amount of trehalose.

[0061] Surfactants are also added to aqueous antibody formulations. Typical surfactants include non-ionic Surfactants such as polysorbates (e.g., polysorbate 20, 80, etc.) or poloxamers The surfactants added are: such as to reduce aggregation of the formulated antibody / antibody derivative and / or in the formulation; In an amount that minimizes particle formation and / or reduces adsorption. For example, the surfactant may be present in an amount of about 0.001% to about 0.5%, preferably about 0.005%. % to about 0.2%, and most preferably from about 0.01% to about 0.1%. It is possible.

[0062] In one embodiment, the aqueous antibody formulation used in the methods of the invention contains one or more preservatives. Benzyl alcohol, phenol, m-cresol, chlorobutanol and benzyl alcohol. In another embodiment, the formulation is essentially free of azethonium Cl, particularly when the formulation is a multi-dose formulation. In this case, a preservative may be included in the formulation. The concentration of the preservative is about 0.1% to about 2%. and most preferably in the range of about 0.5% to about 1%. One or more other pharma- ceutically acceptable carriers, excipients or stabilizers, such as Re As explained in Mington's Pharmaceutical Sciences 21st edition, Osol, A. Ed. (2006) may be included in this formulation, provided that they do not adversely affect the desired properties of the formulation. Acceptable carriers, excipients, or stabilizers may be used in accordance with the recipe at the dosages and concentrations used. These include additional buffers, co-solvents, antioxidants, e.g. aspartame. Corbic acid and methionine, chelating agents such as EDTA, metal complexes (e.g. Zn- protein complexes), biodegradable polymers, e.g. polyesters, and / or salt-forming counterions , for example sodium.

[0063] Formulations to be used for in vivo administration must be sterile. This can be readily accomplished by filtration through sterile filtration membranes, prior to or following preparation of the compound.

[0064] In one embodiment, the subject is a mammal in need of treatment, according to known methods for intraocular delivery. The VEGF antagonist is administered to the eye. Preferably, the mammal is a human and the VEGF antagonist is administered to the eye. VEGF antagonists are anti-VEGF antibodies that are administered directly to the eye. Administration can be accomplished, for example, by intravitreal injection.

[0065] In the methods of the invention, a VEGF antagonist is used as the sole treatment or to treat the condition in question. The therapeutic agent may be administered in combination with other agents or therapies useful in the treatment of

[0066] Preferred formulations of RTH258 for intravitreal injection are shown in the table below. The recommended concentrations are 6mg / 50μL and 3mg / 50μL.

[0067] [Table 1]

[0068] The following examples are included to demonstrate preferred embodiments of the invention. The techniques disclosed in the above publication have been discovered by the inventors to work well in the practice of the present invention. These techniques represent well-established techniques and, as such, may be considered to constitute preferred modes of practicing the invention. However, those skilled in the art should recognize that, in light of this disclosure, the spirit and scope of the present invention may be varied. Many changes may be made in the specific embodiments disclosed without departing from their scope. that these modifications can still produce the same or similar results. Those skilled in the art should recognize.

[0069] The following example illustrates a preferred method of the invention over a two year treatment period. The following modifications are within the scope of the present invention, and certain modifications and other preferred embodiments are included herein. It should be understood that the conditions described herein are not limited to those described herein. may be administered at the physician's discretion or on the same schedule as described for the 2-year period. The evaluation can be done in weeks (i.e., the beginning of year 3 is considered to be week 0, and the beginning of year 3 week 0 is considered to be week 1). It should be understood that the evaluation will be conducted after a certain number of weeks. EXAMPLES

[0070] RTH258 was administered to two treatment arms of subjects with untreated active CNV due to AMD. Multiple injections will be administered. Subjects will meet the criteria listed below for weeks 0 to 48 at any of the following visits: During the first year (48 weeks), you must first take the vaccine three times at four-week intervals ( on days 0, 4 and 8, followed by intravitreal injections every 12 weeks (q12). One group was administered 3mg / 50μL and the other group was administered 6mg / 50μL of RTH258. If this criterion is met, subjects will be followed up for a maximum of 48 weeks with 8-week (q8) Beginning at week 16, subjects will be assigned to a sham injection at visits where they are not actively receiving an injection. For sham injections, use the tip of an injection syringe (the hub without the needle attached). All doses are delivered in 50 μL (0.05 mL).

[0071] Before injection / sham, immediately after injection / sham (0–5 min), and 30 (±15 min) days after each injection / sham The study eye was evaluated after 1 min to determine whether the procedure and / or study medication was effective. Make sure it does not pose a risk to your eye health.

[0072] All subjects had their study eyes evaluated at Visit 6 / Week 16, Visit 7 / Week 20, 10th visit / week 32, 13th visit / week 44, 16th visit / week 56, 1 At visit 9 / week 68 and visit 22 / week 80. Specific details outlined below. If a subject exhibits new or worsening disease activity, as defined by the criteria set forth above, Subjects will be reassigned to an 8q treatment regimen.

[0073] At week 48, the study eye was examined for the absence of new or worsening disease activity. Subjects were switched to q8 treatment at week 16 or 20, as defined below. If there is no new or worsening disease activity, the subject is considered to be on q12 treatment. Reassign to regimen.

[0074] Disease activity assessments were performed at weeks 16, 20, 32, and 44 of the study. Subjects in q12 were reassigned to q8 treatment at 4 time points up to the primary endpoint (week 48) At week 16, early identification of subjects more suitable for the q8 dosing regimen can be achieved. Reassignment at later time points (weeks 20, 32, or 44) was also possible. Minimize the proportion of q12 subjects that would require reassignment is expected.

[0075] early treatment diabetic retinopathy study (ET DRS) visual acuity testing should be considered any test or test that requires the administration of eye drops to dilate the eye. Use before any test requiring eye contact. This will be carried out later and completed according to standard procedures.

[0076] SD-OCT will be used to measure central foveal subregion thickness (CSFT).

[0077] The medication regimen for each subject in this study will be determined using the following criteria in years 1 and 2: Make a decision.

[0078] 0 days to 44 weeks If the following criteria are met, the patient will be initially administered 3 times at 4-week intervals (day 0, week 4, and week 8) o) Injected subjects will be assigned to receive injections every 8 weeks (q8) for up to 48 weeks. Week 16: Neovascular AMD (n AMD) ≥ 5 letter loss of BCVA due to disease activity. ≥ 5-letter BC due to nAMD disease activity at Week 16 compared with Week 12 Decreased VA. ≥3 letter decline in VA and ≥75 μm CSFT at Week 16 compared to Week 12 increase. New or worsening intraretinal cysts (IRCs) at week 16 compared to week 12 / Intraretinal fluid (IRF). Weeks 20, 32 and 44: - ≥ 5 letter loss in BCVA due to nAMD disease activity compared to Week 12.

[0079] 48 weeks to 96 weeks Patients assigned to q8 treatment at weeks 16 and 20 met any of the following criteria: If not, patients may be reassigned to a q12 treatment regimen in the second year of treatment: Week 48: ≥ 5-letter BC due to nAMD disease activity at Week 48 compared with Week 32 Decreased VA. New or worsening IRC / IRF at Week 48 compared with Week 32.

[0080] Patients entering their second year of treatment with a q12 treatment regimen were randomized to receive May be maintained on a q12 regimen unless the following criteria are met: Weeks 56, 68, and 80: ≥ 5 letter loss in BCVA due to nAMD disease activity compared to Week 48.

[0081] The subject is compared to current treatment regimens available for the treatment of subjects with neovascular eye disease. Based on the results, we will determine the most beneficial and less frequent treatment regimen for a particular subject, and then perform a baseline study at 48 weeks. Beneficial change in BCVA from line and subject reported over the 96-week study period It is expected to have improved results.

[0082] The present invention and embodiments thereof have been described in detail. However, the scope of the present invention is not limited to the above. Any process, manufacture, composition, compound, means, method and / or method described in the specification It is not intended to be limited to any particular embodiment of the steps. Various modifications, substitutions and variations of the disclosed subject matter may be made without departing from the essential characteristics thereof. Modifications can be made, thus providing substantially the same functionality as the embodiments described herein. Subsequent modifications, substitutions and / or variations which achieve or substantially the same results are within the scope of the present invention. Those skilled in the art will readily recognize from this disclosure that the present invention can be utilized in accordance with such related embodiments. Therefore, the following claims are to be construed as including within their scope the invention disclosed herein. Modifications to the processes, manufacture, compositions, compounds, means, methods and / or steps described herein. , substitutions and modifications are intended to be encompassed within the scope of the claims. To the extent that the present invention is not limited to the described order or elements, the appended claims should not be construed as limiting the scope of the invention. It is understood that various changes in form and detail may be made without departing from the scope of the invention. It should be. The present invention may include the following aspects. [1] 1. A method of treating neovascular age-related macular degeneration (nAMD) in a mammal, comprising: a) administering to said mammal three separate doses of a VEGF antagonist spaced four weeks apart; To do, b) At 12 weeks, best corrected visual acuity (BCVA), visual acuity (VA), foveal subregional thickness (CSF T) and evaluating the mammal for the presence of intraretinal cysts / fluid; c) At 16 weeks, BCVA, VA, CSFT, and the presence of intraretinal cysts / fluid evaluating said mammal as a d) Once every 8 weeks (q8 regimen) if the following criteria are met: If not met, once every 12 weeks (q12 regimen), administering to said mammal an additional dose of: a) ≥ 5 letters attributable to nAMD disease activity at Week 16 compared to baseline Decrease in BCVA of b) ≥ 5 letter Bs attributable to nAMD disease activity at Week 16 compared with Week 12 Decrease in CVA, c) ≥3 letter decline in VA and ≥75 μm CSF at Week 16 compared to Week 12 Increased T, and d) New or worsening intraretinal cysts (IRCs) at week 16 compared to week 12 ) / Intraretinal fluid (IRF) A method comprising: [2] Regarding BCVA, at weeks 20, 32, and 44, patients were selected for the q12 regimen. The selected mammals were evaluated and, after further evaluation, n was compared to 12 weeks. Patients selected for q8 regimen if BCVA is ≥ 5 letters due to AMD disease activity The method according to [1] above, further comprising administering to a selected mammal. [3] BCVA and the presence of intraretinal cysts / fluid (IRC / IRF) were assessed at 20 weeks, 3 Evaluate mammals selected for the q8 regimen at weeks 2 and 48. In addition, after the 48-week evaluation, there was a statistically significant difference in nAMD disease activity at 48 weeks compared to 32 weeks. Therefore, if no BCVA loss of ≥ 5 letters occurred, and if the mean age was 48 weeks compared with 32 weeks Every 12 weeks, if the eye has no new or worsening IRC / IRF The method according to claim 1, further comprising administering to the mammal an additional dose of the antagonist. How to. [4] The method according to [1] above, wherein the mammal is a human. [5] The method according to [1] above, wherein the VEGF antagonist is an anti-VEGF antibody. [6] The method according to [5] above, wherein the anti-VEGF antibody comprises the sequence of SEQ ID NO:3. [7] The method according to [1] above, wherein the VEGF antagonist is administered by intravitreal injection. [8] A method for treating neovascular AMD (nAMD) comprising administering VEGF antagonists at four week intervals. administering to the mammal three separate doses of the agonist, followed by administration of the first separate dose. Predefined outcomes were assessed at weeks 12, 16, 20, 32, and 44 after treatment. The patients were randomly assigned to receive a 12-week course of treatment based on disease activity assessment using visual and anatomical criteria. The method comprises administering an additional dose every (q12) and / or every 8 weeks (q8). [9] Additional evaluations will be conducted at weeks 48, 56, 68, and 80. The method described.

[10] The disease activity assessment is BCVA, VA, central foveal subfield thickness (CSFT) and / or [8] above, including assessing the presence of intraretinal cysts / fluid (IRC / IRF). method.

[11] The mammal is treated every 8 weeks (q8) if the following criteria are met: If the criteria are not met, treatment will be performed every 12 weeks (q12), as described above in

[10] . How to: a) Neovascular AMD (nAMD) disease activity at week 16 compared to baseline ≥5 letter loss of BCVA due to b) ≥ 5 letter BC attributable to nAMD disease activity at Week 16 compared with Week 1 Decreased VA, c) ≥3 letter decline in VA and ≥75 μm CSF at Week 16 compared to Week 12 Increased T, and d) New or worsening intraretinal cysts (IRCs) at week 16 compared to week 12 ) / Intraretinal fluid (IRF).

[12] Regarding BCVA, at weeks 20, 32, and 44, patients were selected for the q12 regimen. The selected mammals were evaluated and, after further evaluation, n was compared to 12 weeks. Patients selected for q8 regimen if BCVA is ≥ 5 letters due to AMD disease activity The method according to

[11] above, further comprising administering to a selected mammal.

[13] BCVA and the presence of intraretinal cysts / fluid (IRC / IRF) were assessed at 20 weeks, 3 Evaluate mammals selected for the q8 regimen at weeks 2 and 48. In addition, after the 48-week evaluation, there was a statistically significant difference in nAMD disease activity at 48 weeks compared to 32 weeks. Therefore, if no BCVA loss of ≥ 5 letters occurred, and if the mean age was 48 weeks compared with 32 weeks Every 12 weeks, if the eye has no new or worsening IRC / IRF The method according to any one of claims 1 to 11, further comprising administering to the mammal an additional dose of the antagonist. Method of posting.

[14] The method according to [8] above, wherein the mammal is a human.

[15] The method according to [8] above, wherein the VEGF antagonist is an anti-VEGF antibody.

[16] The method according to

[15] above, wherein the anti-VEGF antibody comprises the sequence of SEQ ID NO:3.

[17] The method according to [8] above, wherein the VEGF antagonist is administered by intravitreal injection.

Claims

1. 1. A method of treating neovascular age-related macular degeneration (nAMD) in a mammal, comprising: a) administering to said mammal three separate doses of a VEGF antagonist spaced four weeks apart; To do, b) At 12 weeks, best corrected visual acuity (BCVA), visual acuity (VA), foveal subfield thickness (CSF) T) and evaluating said mammal for the presence of intraretinal cysts / fluid; c) At 16 weeks, for BCVA, VA, CSFT, and the presence of intraretinal cysts / fluid. evaluating said mammal as a d) Once every 8 weeks (q8 regimen) if the following criteria are met: If not met, the VEGF antagonist is administered once every 12 weeks (q12 regimen). administering to said mammal an additional dose of a) ≥ 5 letters attributable to nAMD disease activity at Week 16 compared to baseline A decrease in BCVA of b) ≧5 letter Bs attributable to nAMD disease activity at Week 16 compared to Week 12 Decrease in CVA, c) ≥ 3 letter reduction in VA and ≥ 75 μm CSF at Week 16 compared to Week 12 Increased T, and d) New or worsening intraretinal cysts (IRCs) at week 16 compared to week 12 ) / Intraretinal fluid (IRF) A method comprising:

2. For BCVA, patients were selected for the q12 regimen at weeks 20, 32, and 44. and evaluating the selected mammals and, after further evaluation, comparing n at week 12 with week 14. Patients selected for the q8 regimen if BCVA is ≥ 5 letters due to AMD disease activity.

10. The method of claim 1, further comprising administering to a selected mammal.

3. The presence of BCVA and intraretinal cysts / fluid (IRC / IRF) was assessed at 20 weeks, 3 Evaluating mammals selected for the q8 regimen at weeks 2 and 48; In addition, after the 48-week evaluation, there was a significant difference in nAMD disease activity at 48 weeks compared to 32 weeks. Therefore, if a decline in BCVA of ≥ 5 letters does not occur, and if the decline is greater at 48 weeks compared to 32 weeks, Every 12 weeks, if the eye has no new or worsening IRC / IRF.

10. The method of claim 1, further comprising administering to the mammal an additional dose of the antagonist. method.

4. The method of claim 1 , wherein the mammal is a human.

5. The method of claim 1 , wherein the VEGF antagonist is an anti-VEGF antibody.

6. The method of claim 5, wherein the anti-VEGF antibody comprises the sequence of SEQ ID NO:

3.

7. The method of claim 1 , wherein the VEGF antagonist is administered by intravitreal injection.

8. A method for treating neovascular AMD (nAMD) comprising administering a VEGF antagonist at four week intervals. administering to the mammal three separate doses of the agonist, followed by administration of the first separate dose. Predefined outcomes were assessed at weeks 12, 16, 20, 32, and 44 after administration. The patients were randomly assigned to receive a 12-week follow-up period based on disease activity assessment using visual and anatomical criteria. The method comprises administering a booster dose every (q12) and / or every 8 weeks (q8).

9. The method according to claim 8, further evaluations are performed at weeks 48, 56, 68 and 80. Method of posting.

10. The disease activity assessment is BCVA, VA, central foveal subregion thickness (CSFT) and / or 9. The method of claim 8, further comprising assessing the presence of intraretinal cysts / fluid (IRC / IRF). Law.

11. The mammal is treated every 8 weeks (q8) if the following criteria are met: and every 12 weeks (q12) if the criteria for method: a) Neovascular AMD (nAMD) disease activity at Week 16 compared to baseline a BCVA loss of ≧5 letters due to b) ≧5 letter BC attributable to nAMD disease activity at Week 16 compared to Week 1 Decreased VA, c) ≥ 3 letter reduction in VA and ≥ 75 μm CSF at Week 16 compared to Week 12 Increased T, and d) New or worsening intraretinal cysts (IRCs) at week 16 compared to week 12 ) / intraceretinal fluid (IRF).

12. For BCVA, patients were selected for the q12 regimen at weeks 20, 32, and 44. and evaluating the selected mammals and, after further evaluation, comparing n at week 12 with week 14. Patients selected for the q8 regimen if BCVA is ≥ 5 letters due to AMD disease activity.

12. The method of claim 11, further comprising administering to a selected mammal.

13. The presence of BCVA and intraretinal cysts / fluid (IRC / IRF) was assessed at 20 weeks, 3 Evaluating mammals selected for the q8 regimen at weeks 2 and 48; In addition, after the 48-week evaluation, there was a significant difference in nAMD disease activity at 48 weeks compared to 32 weeks. Therefore, if a decline in BCVA of ≥ 5 letters does not occur, and if the decline is greater at 48 weeks compared to 32 weeks, Every 12 weeks, if the eye has no new or worsening IRC / IRF.

12. The method of claim 11, further comprising administering to the mammal an additional dose of the antagonist. How to.

14. The method of claim 8, wherein the mammal is a human.

15. The method of claim 8 , wherein the VEGF antagonist is an anti-VEGF antibody.

16. The method of claim 15, wherein the anti-VEGF antibody comprises the sequence of SEQ ID NO:

3.

17. The method of claim 8 , wherein the VEGF antagonist is administered by intravitreal injection.

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