Zifibancimig for use in methods for treating ocular diseases via an ocular implant

Abstract

The present invention relates to to zifibancimig for the treatment of an ocular disease in a patient having an ocular implant, wherein the zifibancimig is administered at a concentration of about 5 to about 160 mg / ml, methods of treating ocular diseases using zifibancimig as well as pharmaceutical compositions comprising zifibancimig for treatment of ocular diseases.

Description

[0001]P39361-WO-1 ZIFIBANCIMIG FOR USE IN METHODS FOR TREATING OCULAR DISEASES VIA AN OCULAR IMPLANT 5 FIELD OF THE INVENTION The present invention relates to zifibancimig for treatment of an ocular disease, wherein the zifibancimig is administered into an ocular implant in a defined administration schedule. BACKGROUND OF THE INVENTION 10 Current marketed therapies for administering VEGF antagonists in order to treat ocular diseases require regular intravitreal administration of the drug. Such treatments typically start with a loading phase of 3-5 monthly doses, followed by maintenance dosing, either with fixed (e g. every 4 or 8 weeks or every 12 weeks) or individualized treatment intervals, based on pro re nata15 (PRN) or Treat- and-Extend (T&E) concepts (Wykoff et al., 2018). Monthly treatment or treatment every 2 months poses a significant burden not only for the generally older patients with visual impairments but also for their caregivers and physicians. Also, although the treatments have proven to have a positive benefit / risk ratio, they are not without risk. Each injection carries with it the possibility of pain, sub-conjunctival hemorrhage, vitreous hemorrhage, retinal tear, retinal20 detachment, iatrogenic cataract, and endophthalmitis (Ohr et al., Expert Opin. Pharmacother. 2012;13:585-591), as well as a sustained rise in intraocular pressure (IOP) with serial injections of anti-VEGF agents (Tseng et al., J Glaucoma. 2012;21:241-47). Despite the treatment success of existing anti-VEGFs, there remains a need for further treatment options to improve response rate and / or reduce resource use and injection frequency in patients. 25 Zifibancimig is a bispecific Fab fragment specifically binding to VEGF and ANG2 (WO2022 / 049165) in clinical development for the treatment of ocular diseases. The expected durability and dosage range as well as the maximum tolerated dose level applicable for each new therapeutic antibody depends on the individual characteristics of a clinical candidate. Implantable ocular drug delivery devices having reservoirs for the sustained release of30 therapeutic agents have been described before, e.g. in WO2017 / 176886 or the SUSVIMO(R) implant, which allows application of the medicament, a VEGF inhibitor, twice a year. The present invention provides treatment criteria for the therapy of ocular diseases using zifibancimig with high safety and tolerability, and also improving the treatment burden for patients suffering from ocular diseases. 35 - 2 - SUMMARY OF THE INVENTION The present invention relates to zifibancimig for the treatment of an ocular disease in a patient having an ocular implant, wherein the zifibancimig is administered at a concentration of 5 about 5 to 160 mg / ml. In one embodiment about 0.02 ml of a pharmaceutical composition comprising zifibancimig in a concentration of about 5 to about 160 mg / ml is administered into the ocular implant. In one embodiment about 0.02 ml of a pharmaceutical composition comprising10 zifibancimig in a concentration of about 40 to about 80 mg / ml is administered into the ocular implant. In one embodiment of the invention, zifibancimig is released into the vitreous humour of the eye via an ocular implant. In one embodiment the concentration of zifibancimig in the vitreous humour is at least 40 ng / ml. 15 Another aspect of the invention is a method for treating an ocular disease in a patient having an ocular implant, the method comprising administering zifibancimig to the patient at a concentration of about 5 to about 160 mg / ml. Another aspect of the invention is a pharmaceutical composition comprising zifibancimig for use in the treatment of an ocular disease in a patient, wherein the pharmaceutical composition20 comprises zifibancimig in a concentration of about 5 to about 160 mg / ml. In one embodiment the concentration of zifibancimig that is administered is about 80 mg / ml. In one embodiment the concentration of zifibancimig that is administered is about 40 mg / ml. 25 In one embodiment of the invention, zifibancimig is intravitreally administered. In one embodiment of the invention, zifibancimig is intravitreally administered into an ocular implant. In one embodiment of the invention, zifibancimig is intravitreally administered into a refillable ocular implant. In one embodiment of the invention, an initial dose of zifibancimig is administered30 followed by a second dose at least 8 to 12 months after the initial dose. In one embodiment a third - 3 - or any subsequent dose of zifibancimig is administered at least 9 to 18 months after the second dose. In one embodiment of the invention, zifibancimig is administered every 8 months or more. In one embodiment of the invention, zifibancimig is administered every 10 months or more. In 5 one embodiment of the invention, zifibancimig is administered every 11 months or more. In one embodiment of the invention, zifibancimig is administered every 12 months or more. In one embodiment of the invention, zifibancimig is administered every 34 weeks or more. In one embodiment of the invention, zifibancimig is administered every 42 weeks or more. In one embodiment of the invention, zifibancimig is administered every 48 weeks or more. In one10 embodiment of the invention, zifibancimig is administered every 52 weeks or more. In one embodiment of the invention, the ocular disease is selected from the list consisting of abnormal angiogenesis, choroidal neovascularization (CNV), retinal vascular permeability, retinal edema, diabetic retinopathy (particularly proliferative diabetic retinopathy (PDR) and non- proliferative diabetic retinopathy (NPDR)), macular edema (ME), diabetic macular edema (DME),15 neovascular (exudative) age-related macular degeneration (nAMD), choroidal neovascularization (CNV) associated with nAMD, sequela associated with retinal ischemia, Retinal Vein Occlusion (RVO), Central Retinal Vein Occlusion (CRVO), Branch Retinal Vein Occlusion (BRVO), macular edema following retinal vein occlusion, and posterior segment neovascularization. In one embodiment of the invention, the ocular disease is neovascular age-related macular20 degeneration (nAMD). In one embodiment of the invention, the ocular disease is choroidal neovascularization (CNV) associated with nAMD. In one embodiment of the invention, the ocular disease is Diabetic Macular Edema (DME). In one embodiment of the invention, the ocular disease is diabetic retinopathy (DR). In one embodiment of the invention, In one embodiment of the invention, the ocular disease is Retinal Vein Occlusion (RVO). 25 In one embodiment of the invention, the patient is a human. The therapy as disclosed herein as invention exhibits improvements for patients when compared to current marketed therapies for ocular diseases, such as higher durability, much reduced frequency of administrations, high safety and tolerability, and improved response rate. DESCRIPTION OF THE FIGURES 30 Figure 1: Suppression of free VEGF-A in aqueous humour for 0.5 mg / eye ranibizumab (top row) and 0.5 mg / eye zifibancimig (lower row) following ivt administration. Given comparable PK for both drugs at the same dose level (confirmed; not shown here), zifibancimig suppresses free - 4 - VEGF-A in aqueous humour longer compared to ranibizumab when administered in the dosages that were considered to fulfill the safety requirements as analyzed in the clinical study shown in Example 1. Figure 2: Comparison of simulated VEGF suppression profiles for a Port Delivery System with5 ranibizumab and zifibancimig over time. DETAILED DESCRIPTION OF THE INVENTION 1. DefinitionsUnless otherwise defined herein, scientific and technical terms used in connection with the10 present invention shall have the meanings that are commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. The methods and techniques of the present disclosure are generally performed according to conventional methods well known in the art. Generally, nomenclatures used in connection with, and techniques of biochemistry, enzymology, molecular,15 and cellular biology, microbiology, genetics and protein and nucleic acid chemistry and hybridization described herein are those well-known and commonly used in the art. The terms “a”, “an” and “the” generally include plural referents, unless the context clearly indicates otherwise. Unless otherwise defined herein the term “comprising of” shall include the term “consisting20 of”. The term “about” denotes a range of + / - 20 % of the following numerical value. In one embodiment the term “about” denotes a range of + / - 10 % of the thereafter following numerical value. In one embodiment the term ”about” denotes a range of + / - 5 % of the thereafter following numerical value. 25 The provision of two alternatives using the terms “either … or” designates mutually exclusive alternatives, unless the context clearly indicates otherwise. The term "antibody" is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments so long as they exhibit the desired30 antigen-binding activity. - 5 - An "antibody fragment" refers to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds the antigen to which the intact antibody binds. Examples of antibody fragments include but are not limited to Fv, Fab, Fab', Fab’-SH, F(ab')2; diabodies; linear antibodies; single-chain antibody molecules (e.g. scFv); and multispecific antibodies formed 5 from antibody fragments. The term “vascular endothelial growth factor”, abbreviated “VEGF”, as used herein, refers to any native VEGF from any vertebrate source, including mammals such as primates (e.g. humans) and rodents (e.g., mice and rats), unless otherwise indicated. The term encompasses “full-length”, unprocessed VEGF as well as any form of VEGF that results from processing in the10 cell. The term also encompasses naturally occurring variants of VEGF, e.g., splice variants or allelic variants. The terms “anti-VEGF-A antibody” and “an antibody that binds to VEGF-A” refer to an antibody that is capable of binding VEGF-A with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent in targeting VEGF-A. 15 The term “Angiopoietin-2”, abbreviated “ANG2”, as used herein, refers to any native ANG2 from any vertebrate source, including mammals such as primates (e.g. humans) and rodents (e.g., mice and rats), unless otherwise indicated. The term encompasses “full-length”, unprocessed ANG2 as well as any form of ANG2 that results from processing in the cell. The term also encompasses naturally occurring variants of ANG2, e.g., splice variants or allelic variants. 20 The terms “anti-ANG2 antibody” and “an antibody that binds to anti-ANG2” refer to an antibody that is capable of binding anti-ANG2 with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent in targeting anti-ANG2. “Zifibancimig” as referred to herein via its INN is a bispecific Fab fragment specifically binding to VEGF and ANG2 having a heavy chain amino acid sequence of SEQ ID NO: 1 and a25 light chain amino acid sequence of SEQ ID NO: 2. The term “composition” refers to an aqueous preparation of an active ingredient, i.e. the bispecific antibody. The term “pharmaceutical composition” or “pharmaceutical formulation” refers to a preparation which is in such form as to permit the biological activity of an active ingredient30 contained therein to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the pharmaceutical composition would be administered. - 6 - A “pharmaceutically acceptable carrier” refers to an ingredient in a pharmaceutical composition or formulation, other than an active ingredient, which is nontoxic to a subject. A pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative. 5 An “effective amount” of an agent, e.g., a pharmaceutical composition, refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result. As used herein, “treatment” (and grammatical variations thereof such as “treat” or “treating”) refers to clinical intervention in an attempt to alter the natural course of a disease in the10 individual being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved15 prognosis. In some embodiments, antibodies of the invention are used to delay development of a disease or to slow the progression of a disease. The term “ocular disease,” as used herein, includes any ocular disease associated with pathological angiogenesis and / or atrophy. An ocular disease may be characterized by altered or unregulated proliferation and / or invasion of new blood vessels into the structures of ocular tissues20 such as the retina or cornea. An ocular disease may be characterized by atrophy of retinal tissue (photoreceptors and the underlying retinal pigment epithelium (RPE) and choriocapillaris). Non- limiting ocular diseases include, for example, AMD (e.g., neovascular AMD, dry AMD, intermediate AMD, advanced AMD, and geographic atrophy (GA)), macular degeneration, macular edema, DME (e.g., focal, non-center DME and diffuse, center-involved DME),25 retinopathy, diabetic retinopathy (DR) (e.g., proliferative DR (PDR), non-proliferative DR (NPDR), and high-altitude DR), other ischemia-related retinopathies, ROP, retinal vein occlusion (RVO) (e.g., central (CRVO) and branched (BRVO) forms), CNV (e.g., myopic CNV), corneal neovascularization, diseases associated with corneal neovascularization, retinal neovascularization, diseases associated with retinal / choroidal neovascularization, central serous30 retinopathy (CSR), pathologic myopia, von Hippel-Lindau disease, histoplasmosis of the eye, FEVR, Coats’ disease, Norrie Disease, retinal abnormalities associated with osteoporosis- pseudoglioma syndrome (OPPG), subconjunctival hemorrhage, rubeosis, ocular neovascular disease, neovascular glaucoma, retinitis pigmentosa (RP), hypertensive retinopathy, retinal angiomatous proliferation, macular telangiectasia, iris neovascularization, intraocular35 neovascularization, retinal degeneration, cystoid macular edema (CME), vasculitis, papilloedema, retinitis, including but not limited to CMV retinitis, ocular melanoma, retinal blastoma, - 7 - conjunctivitis (e.g., infectious conjunctivitis and non-infectious (e.g,. allergic) conjunctivitis), Leber congenital amaurosis (also known as Leber’s congenital amaurosis or LCA), uveitis (including infectious and non-infectious uveitis), choroiditis (e.g., multifocal choroiditis), ocular histoplasmosis, blepharitis, dry eye, traumatic eye injury, Sjögren’s disease, and other ophthalmic 5 diseases wherein the disease or disease is associated with ocular neovascularization, vascular leakage, and / or retinal edema or retinal atrophy. Additional exemplary ocular diseases include retinoschisis (abnormal splitting of the retina neurosensory layers), diseases associated with rubeosis (neovascularization of the angle) and diseases caused by the abnormal proliferation of fibrovascular or fibrous tissue, including all forms of proliferative vitreoretinopathy. Exemplary10 diseases associated with corneal neovascularization include, but are not limited to, epidemic keratoconjunctivitis, vitamin A deficiency, contact lens overwear, atopic keratitis, superior limbic keratitis, terygium keratitis sicca, Sjögren’s syndrome, acne rosacea, phylectenulosis, syphilis, Mycobacteria infections, lipid degeneration, chemical burns, bacterial ulcers, fungal ulcers, Herpes simplex infections, Herpes zoster infections, protozoan infections, Kaposi sarcoma,15 Mooren ulcer, Terrien's marginal degeneration, marginal keratolysis, rheumatoid arthritis, systemic lupus, polyarteritis, trauma, Wegener’s sarcoidosis, scleritis, Stevens-Johnson syndrome, periphigoid radial keratotomy, and corneal graph rejection. Exemplary diseases associated with choroidal neovascularization and defects in the retina vasculature, including increased vascular leak, aneurisms and capillary drop-out include, but are not limited to, diabetic retinopathy, macular20 degeneration, sickle cell anemia, sarcoid, syphilis, pseudoxanthoma elasticum, Paget’s disease, vein occlusion, artery occlusion, carotid obstructive disease, chronic uveitis / vitritis, mycobacterial infections, Lyme's disease, systemic lupus erythematosis, retinopathy of prematurity, retina edema (including macular edema), Eales disease, Behcet’s disease, infections causing retinitis or choroiditis (e.g., multifocal choroidits), presumed ocular histoplasmosis, Best’s disease25 (vitelliform macular degeneration), myopia, optic pits, pars planitis, retinal detachment (e.g., chronic retinal detachment), hyperviscosity syndromes, toxoplasmosis, trauma, and post-laser complications. Exemplary diseases associated with atrophy of retinal tissues (photoreceptors and the underlying RPE) include, but are not limited to, atrophic or nonexudative AMD (e.g., geographic atrophy or advanced dry AMD), macular atrophy (e.g., atrophy associated with30 neovascularization and / or geographic atrophy), diabetic retinopathy, Stargardt’s disease, Sorsby Fundus Dystrophy, retinoschisis and retinitis pigmentosa. The term “ocular implant” as used herein refers to an implantable ocular drug delivery device having a reservoir for the sustained release of a therapeutic agent as known in the art, e.g. in WO2017 / 176886. - 8 - 2. Detailed description of the embodiments of the inventionThe invention provides a bispecific antibody that specifically binds to VEGF-A and ANG2, preferably comprising a heavy chain amino acid sequence of SEQ ID NO: 1 and a light chain amino acid sequence of SEQ ID NO: 2, particularly zifibancimig, for the treatment of an ocular 5 disease in a patient having an ocular implant, wherein the bispecific antibody is administered at a concentration of up to 160 mg / ml, in one embodiment about 5 to about 160 mg / ml. The invention also relates to a bispecific antibody that specifically binds to VEGF-A and ANG2, preferably comprising a heavy chain amino acid sequence of SEQ ID NO: 1 and a light chain amino acid sequence of SEQ ID NO: 2, particularly zifibancimig, for the treatment of an10 ocular disease in a patient, wherein a volume of up to 0.05 ml of a composition comprising the bispecific antibody at a concentration of up to 80 mg / ml is administered to the patient having an ocular implant. The invention further provides a method for treating an ocular disease in a patient, the method comprising administering a bispecific antibody that specifically binds to VEGF-A and15 ANG2, preferably comprising a heavy chain amino acid sequence of SEQ ID NO: 1 and a light chain amino acid sequence of SEQ ID NO: 2, particularly zifibancimig, to the patient at a concentration of up to 160 mg / ml, in one embodiment about 5 to about 160 mg / ml. The invention further provides a pharmaceutical composition comprising a bispecific antibody that specifically binds to VEGF-A and ANG2, preferably comprising a heavy chain20 amino acid sequence of SEQ ID NO: 1 and a light chain amino acid sequence of SEQ ID NO: 2, particularly zifibancimig, for use in the treatment of an ocular disease in a patient, wherein a volume of up to 0.05 ml of composition comprising the bispecific antibody at a concentration of up to 160 mg / ml is administered to the patient having an ocular implant. In one embodiment the bispecific antibody is zifibancimig. In one embodiment the25 bispecific antibody is administered in the form of an aqueous solution. In one embodiment the bispecific antibody is administered intravitreally. In one embodiment the bispecific antibody is released into the eye via an ocular implant. In one embodiment the patient is a human. In one embodiment the bispecific antibody is administered to a patient having an ocular disease. In one embodiment the bispecific antibody is administered to a patient having an ocular30 implant. In one embodiment the bispecific antibody is administered to a patient having an ocular disease and having an ocular implant. In one embodiment the bispecific antibody is administered to a patient having an ocular disease, wherein the diseased eye comprises an ocular implant. In one embodiment the bispecific antibody is administered to a patient having an ocular disease, wherein - 9 - the diseased eye comprises an ocular implant and the bispecific antibody is administered into the ocular implant. All individual embodiments of the invention that are described herein may be realized separately or in combinations with each other. Thus, it is understood that the disclosure of different 5 dosages, treatment intervals, ocular diseases and pharmaceutical compositions not only means that these features may be individually realized, but also in combination with each one of the individually disclosed features. Dosage In one embodiment, the bispecific antibody is administered at a concentration of up to10 about 160 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of up to 160 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of up to 150 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of up to 140 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of up to 13015 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of up to 120 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of up to 110 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of up to 100 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of up to 90 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of up to 8020 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of up to 70 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of up to 60 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of up to 50 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of up to 40 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of up to 3025 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of up to 20 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of up to 10 mg / ml. In one embodiment, the bispecific antibody is administered at a dose at least about 5 mg / ml. In one embodiment, the bispecific antibody is administered at a dose at least 5 mg / ml. In30 one embodiment, the bispecific antibody is administered at a dose at least 10 mg / ml. In one embodiment, the bispecific antibody is administered at a dose at least 20 mg / ml. In one embodiment, the bispecific antibody is administered at a dose at least 30 mg / ml. In one embodiment, the bispecific antibody is administered at a dose at least 40 mg / ml. In one embodiment, the bispecific antibody is administered at a dose at least 50 mg / ml. In one - 10 - embodiment, the bispecific antibody is administered at a dose at least 60 mg / ml. In one embodiment, the bispecific antibody is administered at a dose at least 70 mg / ml. In one embodiment, the bispecific antibody is administered at a dose at least 80 mg / ml. In one embodiment, the bispecific antibody is administered at a dose at least 90 mg / ml. In one 5 embodiment, the bispecific antibody is administered at a dose at least 100 mg / ml. In one embodiment, the bispecific antibody is administered at a dose at least 110 mg / ml. In one embodiment, the bispecific antibody is administered at a dose at least 120 mg / ml. In one embodiment, the bispecific antibody is administered at a dose at least 130 mg / ml. In one embodiment, the bispecific antibody is administered at a dose at least 140 mg / ml. In one10 embodiment, the bispecific antibody is administered at a dose at least 150 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of about 5 mg / ml to about 10 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of about 5 mg / ml to about 20 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of about 5 mg / ml to about 30 mg / ml. In one embodiment, the15 bispecific antibody is administered at a concentration of about 5 mg / ml to about 40 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of about 5 mg / ml to about 50 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of about 5 mg / ml to about 60 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of about 5 mg / ml to about 70 mg / ml. In one embodiment, the bispecific antibody is20 administered at a concentration of about 5 mg / ml to about 80 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of about 5 mg / ml to about 90 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of about 5 mg / ml to about 100 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of about 5 mg / ml to about 110 mg / ml. In one embodiment, the bispecific antibody is administered at a25 concentration of about 5 mg / ml to about 120 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of about 5 mg / ml to about 130 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of about 5 mg / ml to about 140 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of about 5 mg / ml to about 150 mg / ml. 30 In one embodiment, the bispecific antibody is administered at a concentration of about 5 mg / ml to about 160 mg / ml. In one embodiment the bispecific antibody is administered at a concentration of about 10 mg / ml to about 160 mg / ml. In one embodiment the bispecific antibody is administered at a concentration of about 1035 mg / ml to about 20 mg / ml. In one embodiment the bispecific antibody is administered at a - 11 - concentration of about 10 mg / ml to about 30 mg / ml. In one embodiment the bispecific antibody is administered at a concentration of about 10 mg / ml to about 40 mg / ml. In one embodiment the bispecific antibody is administered at a concentration of about 10 mg / ml to about 50 mg / ml. In one embodiment the bispecific antibody is administered at a concentration of about 10 mg / ml to 5 about 60 mg / ml. In one embodiment the bispecific antibody is administered at a concentration of about 10 mg / ml to about 70 mg / ml. In one embodiment the bispecific antibody is administered at a concentration of about 10 mg / ml to about 80 mg / ml. In one embodiment the bispecific antibody is administered at a concentration of about 10 mg / ml to about 90 mg / ml. In one embodiment the bispecific antibody is administered at a concentration of about 10 mg / ml to about 100 mg / ml. In10 one embodiment the bispecific antibody is administered at a concentration of about 10 mg / ml to about 110 mg / ml. In one embodiment the bispecific antibody is administered at a concentration of about 10 mg / ml to about 120 mg / ml. In one embodiment the bispecific antibody is administered at a concentration of about 10 mg / ml to about 130 mg / ml. In one embodiment the bispecific antibody is administered at a concentration of about 10 mg / ml to about 140 mg / ml. In one15 embodiment the bispecific antibody is administered at a concentration of about 10 mg / ml to about 150 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of about 30 mg / ml to about 160 mg / ml. In one embodiment the bispecific antibody is administered at a concentration of about 30 mg / ml to about 80 mg / ml. In one embodiment the bispecific antibody is20 administered at a concentration of about 30 mg / ml to about 90 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of about 40 mg / ml to about 160 mg / ml. In one embodiment the bispecific antibody is administered at a concentration of about 40 mg / ml to about 80 mg / ml. In one embodiment the bispecific antibody is administered at a concentration of about 30 mg / ml to about 90 mg / ml. 25 In one embodiment the bispecific antibody is administered at a concentration of about 80 mg / ml to about 160 mg / ml. In one embodiment the bispecific antibody is administered at a concentration of about 100 mg / ml to about 160 mg / ml. In one embodiment the bispecific antibody is administered at a concentration of about 120 mg / ml to about 160 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of about 4030 mg / ml to about 80 mg / ml. In one embodiment the bispecific antibody is administered at a concentration of about 50 mg / ml to about 80 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of about 60 mg / ml to about 80 mg / ml. In one embodiment the bispecific antibody is administered at a concentration of about 70 mg / ml to about 80 mg / ml. - 12 - In one embodiment, the bispecific antibody is administered at a concentration of 40 mg / ml to 80 mg / ml. In one embodiment the bispecific antibody is administered at a concentration of 50 mg / ml to 80 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of 60 mg / ml to 80 mg / ml. In one embodiment the bispecific antibody is administered at a 5 concentration of 70 mg / ml to 80 mg / ml. In one embodiment the bispecific antibody is administered at a concentration of about 40 mg / ml to about 70 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of about 40 mg / ml to about 60 mg / ml. In one embodiment the bispecific antibody is administered at a concentration of about 40 mg / ml to about 50 mg / ml. 10 In one embodiment, the bispecific antibody is administered at a concentration of about 5 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of 5 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of about 10 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of 10 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of about 20 mg / ml. In one15 embodiment, the bispecific antibody is administered at a concentration of 20 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of about 30 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of 30 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of about 40 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of 40 mg / ml. In one20 embodiment, the bispecific antibody is administered at a concentration of about 50 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of 50 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of about 60 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of 60 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of about 70 mg / ml. In one25 embodiment, the bispecific antibody is administered at a concentration of 70 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of about 80 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of 80 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of about 90 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of 90 mg / ml. In one30 embodiment, the bispecific antibody is administered at a concentration of about 100 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of 100 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of about 110 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of 110 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of about 120 mg / ml. In one35 embodiment, the bispecific antibody is administered at a concentration of 120 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of about 130 mg / ml. In one - 13 - embodiment, the bispecific antibody is administered at a concentration of 130 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of about 140 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of 140 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of about 150 mg / ml. In one 5 embodiment, the bispecific antibody is administered at a concentration of 150 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of about 160 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of 160 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of less than 100 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of less10 than 90 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of less than 80 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of less than 70 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of less than 60 mg / ml. In one embodiment, the bispecific antibody is administered at a concentration of less than 50 mg / ml. In one embodiment, the bispecific antibody is15 administered at a concentration of less than 40 mg / ml. In one embodiment of the invention, the concentration of bispecific antibody, preferably zifibancimig, in the vitreous humour is at least 40 ng / ml, which is the median minimal efficacious concentration of the antibody. In one embodiment, a volume of about 0.01 to about 0.02 ml of a composition comprising20 the bispecific antibody is administered into the ocular implant. In one embodiment, a volume of 0.01 to 0.02 ml of a composition comprising the bispecific antibody is administered into the ocular implant. In one embodiment, a volume of about 0.01 ml of a composition comprising the bispecific antibody is administered into the ocular implant. In one embodiment, a volume of about 0.02 ml25 of a composition comprising the bispecific antibody is administered into the ocular implant. In one embodiment, a volume of 0.01 ml of a composition comprising the bispecific antibody is administered into the ocular implant. In one embodiment, a volume of 0.02 ml of a composition comprising the bispecific antibody is administered into the ocular implant. Treatment interval 30 In one embodiment, the bispecific antibody is administered every month or more. Thus, in the treatment according to the invention, an initial dose of the bispecific antibody is administered to the patient in a dose as disclosed herein, followed by a second dose at least one month after the initial dose. Further doses are administered accordingly, at least one month after the previous dose. - 14 - In one embodiment, the bispecific antibody is administered every month or more, in one embodiment every two months or more, in one embodiment every three months or more, in one embodiment every 4 months or more, in one embodiment every 5 months or more, in one embodiment every 6 months or more, in one embodiment every 7 months or more, in one 5 embodiment every 8 months or more, in one embodiment every 9 months or more, in one embodiment every 10 months or more, in one embodiment every 11 months or more, in one embodiment every 12 months or more. In one embodiment, the bispecific antibody is administered every 8 months to every 36 months. In one embodiment, the bispecific antibody is administered every 8 months to every 3010 months. In one embodiment, the bispecific antibody is administered every 8 months to every 24 months. In one embodiment, the bispecific antibody is administered every 8 months to every 18 months. In one embodiment, the bispecific antibody is administered every 8 months to every 12 months. In one embodiment, the bispecific antibody is administered every 9 months to every 3615 months. In one embodiment, the bispecific antibody is administered every 9 months to every 30 months. In one embodiment, the bispecific antibody is administered every 9 months to every 24 months. In one embodiment, the bispecific antibody is administered every 9 months to every 18 months. In one embodiment, the bispecific antibody is administered every 9 months to every 12 months. 20 In one embodiment the bispecific antibody is zifibancimig and is administered every 12 months or more, preferably every 12 months. In one embodiment of the invention, zifibancimig is administered every 34 weeks or more, every 35 weeks or more, every 36 weeks or more, every 37 weeks or more, every 38 weeks or more, every 39 weeks or more, every 40 weeks or more, every 41 weeks or more, every 42 weeks25 or more, every 43 weeks or more, every 44 weeks or more, every 45 weeks or more, every 46 weeks or more, every 47 weeks or more, every 48 weeks or more, every 49 weeks or more, every 50 weeks or more, every 51 weeks or more, or every 52 weeks or more. In one embodiment the bispecific antibody is zifibancimig and is administered every 52 weeks or more, preferably every 52 weeks. 30 In one embodiment of the invention zifibancimig is administered every 12 months or more, preferably every 12 months, wherein zifibancimig is administered at a concentration of about 40 mg / ml to about 80 mg / ml. - 15 - In one embodiment of the invention zifibancimig is administered every 52 weeks or more, preferably every 52 weeks, wherein zifibancimig is administered at a concentration of about 40 mg / ml to about 80 mg / ml. In one embodiment of the invention zifibancimig is administered every 12 months or more, 5 preferably every 12 months, wherein a volume of about 0.02 to about 0.05 ml of a composition comprising zifibancimig is administered into the ocular implant. In one embodiment of the invention zifibancimig is administered every 52 weeks or more, preferably every 52 weeks, wherein a volume of about 0.02 to about 0.05 ml of a composition comprising zifibancimig is administered into the ocular implant. 10 In one embodiment of the invention zifibancimig is administered every 12 months or more, preferably every 12 months, wherein zifibancimig is administered at a concentration of about 40 mg / ml to about 80 mg / ml, wherein a volume of about 0.02 to about 0.05 ml of a composition comprising zifibancimig is administered into the ocular implant. In one embodiment of the invention zifibancimig is administered every 52 weeks or more,15 preferably every 52 weeks, wherein zifibancimig is administered at a concentration of about 40 mg / ml to about 80 mg / ml, wherein a volume of about 0.02 to about 0.05 ml of a composition comprising zifibancimig is administered into the ocular implant. Ocular diseases In one embodiment of the invention the ocular disease is selected from the list consisting20 of abnormal angiogenesis, choroidal neovascularization (CNV), retinal vascular permeability, retinal edema, diabetic retinopathy (particularly proliferative diabetic retinopathy (PDR) and non- proliferative diabetic retinopathy (NPDR)), macular edema (ME), diabetic macular edema (DME), neovascular (exudative) age-related macular degeneration (nAMD), choroidal neovascularization (CNV) associated with nAMD, sequela associated with retinal ischemia, Retinal Vein Occlusion25 (RVO), Central Retinal Vein Occlusion (CRVO), Branch Retinal Vein Occlusion (BRVO), macular edema following retinal vein occlusion, and posterior segment neovascularization. In one embodiment the ocular disease is neovascular age-related macular degeneration (nAMD). In one embodiment the ocular disease is choroidal neovascularization (CNV) associated with nAMD. In one embodiment the ocular disease is Diabetic Macular Edema (DME). In one30 embodiment the ocular disease is diabetic retinopathy (DR). In one embodiment the ocular disease is Retinal Vein Occlusion (RVO). - 16 - In one embodiment the bispecific antibody is zifibancimig and used for the treatment of nAMD. In one embodiment zifibancimig is administered such that the concentration of zifibancimig in the vitreous humour is 0.125 mg / ml or less, preferably 0.025 mg / ml or less for the treatment of nAMD. In one embodiment zifibancimig is administered every 12 months or more, 5 preferably every 12 months, such that the concentration of zifibancimig in the vitreous humour is 0.125 mg / ml or less, preferably 0.025 mg / ml or less for the treatment of nAMD. Pharmaceutical compositions In certain embodiments of the invention a composition, particularly a pharmaceutical composition, comprising the bispecific antibody is administered to the patient having an ocular10 implant. Pharmaceutical compositions of an antibody that binds to human VEGF-A and human ANG2 as described herein are prepared by mixing such antibody having the desired degree of purity with one or more optional pharmaceutically acceptable carriers (Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), in the form of lyophilized15 compositions or aqueous solutions. Pharmaceutically acceptable carriers are generally nontoxic to recipients at the dosages and concentrations employed, and include, but are not limited to: buffers such as histidine, phosphate, citrate, acetate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride;20 phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including25 glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-proteincomplexes); and / or non-ionic surfactants such as polyethylene glycol (PEG). Exemplary pharmaceutically acceptable carriers herein further include insterstitial drug dispersion agents such as soluble neutral-active hyaluronidase glycoproteins (sHASEGP), for example, human soluble30 PH-20 hyaluronidase glycoproteins, such as rHuPH20 (HYLENEX®, Halozyme, Inc.). Certain exemplary sHASEGPs and methods of use, including rHuPH20, are described in US Patent Publication Nos.2005 / 0260186 and 2006 / 0104968. In one aspect, a sHASEGP is combined with one or more additional glycosaminoglycanases such as chondroitinases. - 17 - Exemplary lyophilized antibody compositions are described in US Patent No. 6,267,958. Aqueous antibody compositions include those described in US Patent No. 6,171,586 and WO 2006 / 044908, the latter compositions including a histidine-acetate buffer. The pharmaceutical composition herein may also contain more than one active ingredients 5 as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. Such active ingredients are suitably present in combination in amounts that are effective for the purpose intended. Active ingredients may be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or10 gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano- particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington'sPharmaceutical Sciences 16th edition, Osol, A. Ed. (1980). Pharmaceutical compositions for sustained-release may be prepared. Suitable examples of15 sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g., films, ormicrocapsules. The pharmaceutical compositions to be used for in vivo administration are generally sterile.Sterility may be readily accomplished, e.g., by filtration through sterile filtration membranes.20 Administration route In certain embodiments of the invention the bispecific antibody is intravitreally administered to a patient having an ocular disease, preferably a patient having an ocular implant. In one embodiment the bispecific antibody is intravitreally administered into an ocular implant. In one embodiment the bispecific antibody is intravitreally administered into a refillable ocular implant. 25 Methods of treatment One aspect of the invention is a method for treating an ocular disease in a patient having an ocular disease, the method comprising administering to the patient an initial dose of the bispecific antibody that specifically binds to VEGF-A and ANG2, preferably comprising a heavy chain amino acid sequence of SEQ ID NO: 1 and a light chain amino acid sequence of SEQ ID NO: 2,30 particularly zifibancimig, followed by a second dose at least 4 weeks after the initial dose, wherein the zifibancimig is administered at a a concentration of up to about 80 mg / ml. - 18 - In one embodiment the method is for treating an ocular disease in a patient having an ocular disease, wherein the diseased eye comprises an ocular implant. Antibodies, concentrations, applied volumina of the antibody, and treatment intervals used in the methods of treatment of the invention are as disclosed above, alone or in combination with 5 each other. DESCRIPTION OF THE AMINO ACID SEQUENCES EXAMPLES 10 The following examples are provided to aid the understanding of the present invention, the true scope of which is set forth in the appended claims. It is understood that modifications can be made in the procedures set forth without departing from the spirit of the invention. Example 1: Clinical study (dosage evaluation) 15 A clinical study was designed to evaluate safety, PK and PD of zifibancimig in nAMD patients. Within the study, patients received 2 ivt injections of aqueous zifibancimig solution separated by 6 weeks. Ascending doses were tested with the aim to assess safety, PK and PD up - 19 - to 4 mg of zifibancimig. Tested dose levels were 0.1 mg, 0.5 mg, 1.5 mg, and 4 mg. The starting dose of 0.1 mg zifibancimig ivt was selected based on a toxicology study in cynomolgus monkey. The main safety concerns of existing intravitreal anti-VEGF therapies include local ocular effects, most prominently reversible dose-dependent inflammatory reactions. Increases in 5 intraocular pressure may be observed which normalize the next day and are considered secondary to the acute increase in intraocular volume. A total of 49 patients with nAMD were enrolled in the study: 13 in Cohort 1 (0.1 mg), 15 in Cohort 2 (0.5 mg), 10 15 in Cohort 3 (1.5 mg), and 6 in Cohort 4 (4 mg). Zifibancimig 0.1 mg / eye (Cohort 1) and zifibancimig 0.5 mg / eye (Cohort 2) were generally safe and well tolerated. There were no adverse events in Cohort 1 considered to be related to zifibancimig. One participant in Cohort 2 experienced an event of study eye pain which was15 considered related to zifibancimig. No serious ocular events occurred in either Cohort 1 or Cohort 2. In the zifibancimig 1.5 mg / eye dose group (Cohort 3), 3 participants (20 %) experienced events of uveitis, related to zifibancimig. In the zifibancimig 4 mg / eye dose group (Cohort 4), 1 participant (16.7%) experienced a serious adverse event of uveitis, related to zifibancimig and 1 participant (16.7%) experienced a related event of vitreous opacities. There were no non-ocular20 AEs related to zifibancimig and no deaths occurred during Part 1 of the study. No clinically significant abnormalities in ECGs, vital signs, or laboratory safety parameters were observed during Part 1. Target engagement, measured as reduction of free Ang-2 and VEGF-A in aqueous humor (AH) was also observed at all analyzed dose levels but not in plasma. Zifibancimig PK data were25 monophasic and dose-proportional with a general consistency between AH and plasma PK. There was a trend towards stable or improved BCVA in all dose cohorts. In all cohorts, BCVA in the study eye increased from baseline to Week 2 and generally remained stable through Week 24. An anatomical response on SD-OCT was observed for all dose cohorts. Retinal thickness in the study eye generally decreased from baseline to Week 4 and changes from baseline were30 generally maintained through Week 24 across all dose cohorts. Due to the small sample size and heterogenous population across cohorts, no robust cross-cohort comparisons can be made, however a trend towards an apparent dose response with regards to duration of treatment can be observed. - 20 - Immunogenicity was assessed in all 49 participants. One (2.1%) sample from Cohort 1 was positive at baseline, all other samples were negative at baseline. No treatment-emergent anti drug antibodies (ADAs) occurred in Cohort 1. In Cohort 2, 4 (26.7%) participants had persistent treatment-induced ADAs. In Cohort 3, 5 (33.3%) participants had treatment-induced ADAs, 4 of 5 which were persistent. In Cohort 4, 5 (83.3%) participants had treatment-induced ADAs, 4 of which were persistent. All 4 events of uveitis were associated with positive ADA titers at or shortly after the onset of the event; whereas 11 participants had positive ADA titers at some point during the study without having an event of uveitis. Based on these clinical safety data, zifibancimig appears safe and well tolerated at doses of10 0.1 and 0.5 mg administered via IVT injection twice, 6 weeks apart (as in Cohorts 1 and 2) in patients with nAMD with no unexpected safety events. As 0.5 mg ivt of zifibancimig has been safe and tolerable to date (see Section 1.4), exposure margins compared to 0.5 mg ivt zifibancimig were calculated to support further dose selection (Table 1). As the relationship between exposure and safety events is currently unknown, different15 exposure metrics were considered. All exposure metrics for doses of up to 80 mg / mL are covered by 0.5 mg ivt zifibancimig. Table 1 illustrates the exposure margins of the PDS doses compared to Ph1a 0.5 mg zifibancimig ivt. Values indicate the coverage of PDS doses, e.g. a value of 2 means that the Ph1a exposure is 2-fold larger than what is expected in the PDS dose ranges claimed. As illustrated in none of the claimed ranges the exposure margin is exceeded. 20 Table 1: Exposure margins of PDS doses va ivt doses Example 2: Translational PK / PD in vitro modelA PK / PD model to quantify the impact of dose, ocular retention time and binding affinity25 (KD) on durability has been established in house. According to the model, durability of target engagement increases with increasing dose, longer ocular T1 / 2 and higher ligand binding affinity (KD). - 21 - As in vitro KD’s are difficult to translate to clinically relevant in vivo KD’s, preclinical PK / PD studies in NHP have been conducted to obtain in vivo relevant KD values. These studies have shown the improved durability of VEGF and Ang2 suppression for zifibancimig, consistent with the improved VEGF (~3-fold more potent as compared to ranibizumab) and Ang2 (~20-fold 5 more potent as compared to faricimab) binding affinity of zifibancimig. Clinical data from the faricimab phase 2 studies suggest clinical durability (time to disease activity recurrence between 8 and 16 weeks after last injection) beyond VEGF and Ang2 suppression (8-9 weeks) suggesting a synergistic effect of combined VEGF and Ang2 suppression resulting in a longer clinical durability. Mechanistic understanding on this potential synergistic effect is not yet fully elucidated,10 but longer VEGF and Ang2 target suppression is suggested to result in incremental improvements in clinical durability. The improved clinical durability resulting from the VEGF and Ang2 target combination over anti-VEGF treatment alone has been confirmed by the faricimab phase 3 studies in both nAMD and DME, where nearly 80% of faricimab-treated patients were able to go three months or longer between treatments during the first year. 15 The parameters of the translational PK / PD model have been updated with available clinical data from the clinical study Burgundy (BP41670). The results confirm the current assumptions on ocular T1 / 2, which is comparable to ranibizumab. The ligand binding affinity (KD) for VEGF-A has been estimated as ~20-fold compared to ranibizumab (Figure 1), which is larger than the 3- fold increase expected from the 8-week GLP toxicology study in cynomolgus monkey. 20 Example 3: Simulation of target suppression kinetics based on in vitro dataSimulations from an exploratory translational PK / PD model including in vitro release kinetics from the implant and VEGF-inhibition potency increase as determined preclinically suggest sustained VEGF suppression for at least 12 months after loading the implant with the doses25 of 40 mg / mL or 80 mg / mL of Zifibancimig (Figure 2). Ang2 was predicted to be suppressed even longer than VEGF. As a reference, Port Delivery System with ranibizumab (Susvimo™) showed equivalent efficacy to monthly intravitreal ranibizumab with a fixed 6-monthly refill regimen at the primary endpoint of the ongoing Phase 3 Archway study. In addition to the incremental VEGF suppression time, zifibancimig has the potential for additional synergistic clinical efficacy due to30 prolonged Ang2 suppression.

Claims

- 22 - PATENT CLAIMS 1. A method for treating an ocular disease in a patient having an ocular implant, the methodcomprising administering to the patient an initial dose of zifibancimig followed by a second 5 dose at least 8 months after the initial dose, wherein the zifibancimig is administered at a concentration of about 5 to about 160 mg / ml.

2. The method according to claim 1, wherein the zifibancimig is administered at a dose of lessthan 100 mg / ml.

3. Zifibancimig for the treatment of an ocular disease in a patient having an ocular implant,10 wherein the zifibancimig is administered at a concentration of about 5 to about 160 mg / ml.

4. Zifibancimig for the treatment according to claim 3, wherein the zifibancimig is administeredat a dose of less than 100 mg / ml.

5. Zifibancimig for the treatment according to one claims 3 to 4, wherein the zifibancimig isadministered at a dose of about 30 g / ml to about 90 mg / ml.15 6. Zifibancimig for the treatment according to one claims 3 to 5, wherein the zifibancimig isadministered at a dose of 30 mg / ml to 90 mg / ml.

7. Zifibancimig for the treatment according to one of claims 3 to 6, wherein the zifibancimig isadministered at a dose of about 40 mg / ml to about 80 mg / ml.

8. Zifibancimig for the treatment according to claims 3 to 7, wherein the zifibancimig is20 administered at a dose of 40 mg / ml to 80 mg / ml.

9. Zifibancimig for the treatment according to claims 3 to 8, wherein a volume of 0.01 to 0.02 mlzifibancimig is administered into the ocular implant.

10. Zifibancimig for the treatment of an ocular disease in a patient, wherein the concentration ofzifibancimig in the vitreous humour is at least 40 ng / ml.25 11. Zifibancimig for the treatment according to one of claims 3 to 10, wherein zifibancimig isintravitreally administered into an ocular implant.

12. Zifibancimig for the treatment according to one of claims 3 to 11, wherein zifibancimig isadministered every 8 months or more, preferably every 12 months, preferably every 9 to 18 months.- 23 - 13. Zifibancimig for the treatment according to one of claims 3 to 12, wherein the ocular diseaseis selected from the list consisting of abnormal angiogenesis, choroidal neovascularization (CNV), retinal vascular permeability, retinal edema, diabetic retinopathy (particularly proliferative diabetic retinopathy (PDR) and non-proliferative diabetic retinopathy (NPDR)), 5 macular edema (ME), diabetic macular edema (DME), neovascular (exudative) age-related macular degeneration (nAMD), choroidal neovascularization (CNV) associated with nAMD, sequela associated with retinal ischemia, Retinal Vein Occlusion (RVO), Central Retinal Vein Occlusion (CRVO), Branch Retinal Vein Occlusion (BRVO), macular edema following retinal vein occlusion, and posterior segment neovascularization.10 14. Zifibancimig for the treatment according to one of claims 3 to 13, wherein the ocular diseaseis neovascular age-related macular degeneration (nAMD).

15. Zifibancimig for the treatment according to one of claims 3 to 13, wherein the ocular diseaseis choroidal neovascularization (CNV) associated with nAMD.

16. Zifibancimig for the treatment according to one claims 3 to 13, wherein the ocular disease is15 Diabetic Macular Edema (DME).

17. Zifibancimig for the treatment according to one of claims 3 to 13, wherein the ocular diseaseis diabetic retinopathy (DR).

18. Zifibancimig for the treatment according to one of claims 3 to 13, wherein the ocular diseaseis Retinal Vein Occlusion (RVO).20 19. A pharmaceutical composition comprising zifibancimig for use in the treatment of an oculardisease in a patient, wherein the pharmaceutical composition comprises zifibancimig in a concentration of about 5 to about 160 mg / ml, preferably 40 to 80 mg / ml.

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