Pharmaceutical composition for delivery to eye

Abstract

In particular, the present disclosure provides pharmaceutical compositions of avacactide polyethylene glycol (avacactide pegol) that have sufficient purity and efficacy to be suitable for administration to human patients in the treatment of a variety of ocular disorders and diseases.

Description

[0001] Citation of Related Applications

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 435,168, filed on December 23, 2022, the disclosure of which is incorporated herein by reference in its entirety.

[0003] Electronic Sequence Listing Citation

[0004] The contents of the electronic sequence listing (OPHT_037_01WO_SeqList_ST26.xml; size: 17,715 bytes; created on November 21, 2023) are incorporated herein by reference in their entirety. Technical Field

[0005] The present invention relates to pharmaceutical compositions of avacincaptad pegol that have sufficient purity to be suitable for administration to human patients in the treatment of various ocular disorders and diseases. Background Art

[0006] In the industrialized world, many of the most common blinding diseases are associated with diseases and injuries of the posterior segment tissues of the eye, including the retina and choroid. Age-related macular degeneration (AMD) alone affects more than 10 million Americans. Severe vision loss (visual impairment) caused by AMD and other diseases affecting the posterior segment, including diabetic retinopathy, glaucoma, and retinitis pigmentosa, is responsible for the majority of irreversible blindness cases globally. AMD is divided into one of two major subgroups: the non-neovascular ("dry") form of the disease ("dry AMD") and the neovascular form of the disease ("wet AMD"). Dry AMD is more common, accounting for approximately 90% of all AMD cases. Dry AMD is characterized by the presence of drusen (yellow crystalline deposits formed within the macula) beneath the retinal pigment epithelial cells (RPE). When the condition is severe, dry AMD results in significant thinning and / or atrophy of the macula, which is caused by the loss of the RPE and associated capillaries (choroidal capillaries). This form of advanced dry AMD is associated with thinning and loss of function of the neurosensory retina above the affected RPE. This collective phenotype of advanced dry AMD is known as geographic atrophy ("GA"). The progressive degeneration of photosensitive photoreceptor cells in GA leads to severe vision loss in the affected eye. Currently, the treatment of posterior segment diseases is largely limited by the difficulty of delivering effective doses of drugs to the posterior segment target tissues.

[0007] Accordingly, despite significant efforts in treating GA, AMD, or other ophthalmic disorders, there remains a lack of pharmaceutical compositions suitable for administration to human patients to treat ocular diseases that require direct delivery of a therapeutic agent to the eye. Summary of the Invention

[0008] The present invention provides a highly purified pharmaceutical substance and pharmaceutical product of avacincaptad pegol (ACP). In one embodiment, the present invention provides a composition comprising a non-PEGylated aptamer intermediate having the sequence 5′NH2-fCmGfCfCGfCmGmGfUfCfUfCmA mGmGfCGfCfUmGmAmGfUfCfUmGmAmGfUfUfUAfCfCfUmGfCmG-3T-3′ (SEQ ID NO:1), wherein the composition has the following purity profile:

[0009] (a) More than 85% of the aptamers in the composition are full-length aptamers;

[0010] (b) Less than 3% in total of fluoride degradation products and n-1 deletion products; and

[0011] (c) 1% or less of deprotection failure products.

[0012] In some embodiments, the composition further has:

[0013] (d) Less than 1.8% of G cleavage products;

[0014] (e) Less than 0.1% of A cleavage products; and

[0015] (f) Less than 1.1% in total of n-4, n-3, and n-2 deletion products.

[0016] In some embodiments, the present invention provides a PEGylated aptamer or a salt thereof comprising the ultra-pure composition of the above embodiments, and the aptamer has the following structure:

[0017]

[0018] wherein, n = ~485.

[0019] In another embodiment, the present invention provides an ultra-pure pharmaceutical substance comprising avacincaptad pegol, wherein the pharmaceutical substance has the following purity profile:

[0020] (a) More than 92% of the aptamers in the pharmaceutical substance are full-length aptamers;

[0021] (b) Less than 1.5% of the drug substance has a relative retention time (RRT) of 1 (≥0.93 - < full-length product (FLP)); and

[0022] (c) Less than 5% of the drug substance has an RRT of 2 (>FLP - ≤1.2).

[0023] In another embodiment, the present invention provides a drug substance, wherein the potency of the drug substance is greater than 95% as measured by ELISA.

[0024] In another embodiment, the present invention provides a pharmaceutical composition, which comprises the ultra-pure drug substance described herein and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition is formulated as a sterile aqueous solution in phosphate buffered saline at a concentration of 20 mg / mL (oligonucleotide mass) at pH 6.8 - 7.8. In some embodiments, the pharmaceutical composition has an osmolality between 350 - 500 mOsM / kg.

[0025] In another embodiment, the present invention provides methods for treating ophthalmic diseases, disorders, and / or conditions, which comprise: intravitreally administering to a subject in need thereof the ultra-pure avacapatide polyethylene glycol pharmaceutical composition described herein at a dose between 3 - 5 mg / eye. In a preferred embodiment, the method of the present invention provides for an administered dose of about 2 mg / eye. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 Shows pre-FLP and post-FLP impurity fraction collections from the purification process of polyethylene glycolated ACP. DETAILED DESCRIPTION

[0027] The present disclosure provides highly purified drug substances and drug products comprising avacapatide polyethylene glycol (ACP). These compositions are produced by improved manufacturing methods. The highly purified compositions are advantageous compared to compositions produced by prior art methods, at least in part because the highly purified compositions contain lower proportions of ACP impurities or variants that do not contribute to efficacy but can be used to induce an immune response.

[0028] As used herein, including in the appended claims, singular terms such as "a", "an", and "the" include their corresponding plural references unless the context clearly dictates otherwise. All references cited herein are incorporated by reference to the same extent as if each individual publication, patent application, or patent was specifically and individually indicated to be incorporated by reference.

[0029] DEFINITIONS

[0030] Throughout this application, the term "about" is used to indicate that a value includes the inherent error variations of the device or method used to determine that value, or the variations that exist between the samples being measured. Unless otherwise stated or apparent from the context, the term "about" means within 10% above or below the reported value (unless the value would exceed 100% of the possible value or be less than 0%). When used in conjunction with a range or a series of values, unless otherwise stated, the term "about" applies to the endpoints of the range or each value enumerated in the series. As used in this application, "about" and "approximately" are used as equivalent terms.

[0031] As used in this invention, the term "ocular" generally refers to the eye or any part or portion of the eye (since an "ocular implant" according to the invention can in principle be administered to any part or portion of the eye) or any eye disease (since in one aspect, the invention generally relates to treating any eye disease of various origins and natures ("ocular disease")). In certain embodiments, the invention relates to intravitreal injection of an ocular implant (and thus in this case, the "ocular implant" is an "intravitreal implant"), and to treating ocular diseases that affect the posterior segment of the eye, as further disclosed below.

[0032] The term "patient" as used herein includes human patients and animal patients. A "patient" is a subject in need of treatment due to a specific physiological or pathological condition.

[0033] The term "polymer network" describes a structure formed by polymer chains (having the same or different molecular structures and the same or different molecular weights) that are crosslinked to each other. Polymer types suitable for the purposes of this invention are disclosed herein. The polymer network can also be formed by means of crosslinking agents also disclosed herein.

[0034] As used herein, open-ended terms such as "comprising", "containing", etc. mean "including", and are intended to refer to an open-ended list or enumeration of elements, method steps, etc., and thus are not intended to be limited to the enumerated elements, method steps, etc., but are also intended to include additional unenumerated elements, method steps, etc.

[0035] The term "at most" when used herein in conjunction with a certain value or number means including the corresponding value or number. When using a range of values or numbers herein, the endpoints of the range are also included within the range.

[0036] The terms "API", "active (pharmaceutical) ingredient", "active (pharmaceutical) reagent", "active (pharmaceutical) constituent", "(active) therapeutic agent", "active substance", "drug", and "drug substance" are used interchangeably herein and refer to a substance used in a finished pharmaceutical product (FPP) or "medicinal product (drug)", and a substance used in the preparation of such a finished pharmaceutical product that is intended to provide pharmacological activity or otherwise have a direct effect on the diagnosis, cure, mitigation, treatment, or prevention of disease, or on the restoration, correction, or modification of a patient's physiological functions.

[0037] As used herein, the term "aptamer" refers to an oligonucleotide and / or nucleic acid analogue that can bind to a specific target molecule. Aptamers can include RNA, DNA, RNA / DNA, any nucleic acid analogue, and / or combinations thereof. Aptamers can be single-stranded oligonucleotides. Without wishing to be bound by theory, aptamers are thought to bind to the three-dimensional structure of the target molecule. Aptamers can be monomers (consisting of a single unit) or polymers (consisting of multiple units). Polymer aptamers can be homopolymers (consisting of multiple identical units) or heteropolymers (consisting of multiple different units).

[0038] Drug substance

[0039] The drug substance is a pegylated anti-C5 reagent, and the pegylated anti-C5 reagent is an aptamer = 5′NH2-fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfU mGmAmGfUfCfUmGmAmGfUfUfUAfCfCfUmGfCmG-3T-3′ (SEQ ID NO:1), wherein fC and fU = 2'-fluoronucleotides, mG and mA = 2'-OMe nucleotides, G and A = ribonucleotides, and 3T indicates reverse deoxythymidine. The structure is shown as follows:

[0040]

[0041] wherein, n = ~485.

[0042] ARC1905 (avacapatide polyethylene glycol) is a pegylated RNA aptamer, which is a potent and specific inhibitor of complement activation and is being developed as a therapy for the treatment of age-related macular degeneration (AMD), geographic atrophy (GA) secondary to AMD, and Stargardt disease. The molecular formula of avacapatide polyethylene glycol (free acid form) is C 395 H 492 N 142 O 262 P 39 F 21 ((CH2)2O)n , wherein, n~970, and the molecular weight is about 56 kDa. ARC1905 consists of a 12,882 Dalton-modified RNA aptamer that is conjugated to a polyethylene glycol (PEG) moiety at the 5'-end. The aptamer portion of ARC1905 (ARC672) is 39 nucleotides in length and is modified at the 5'-end with a primary amine to provide a reactive site for site-specific conjugation ("PEGylation"). Specifically, ARC1905 is a PEGylated aptamer containing 39 monomeric units (39-mer) with a hairpin structure. Certain activated PEG moieties for conjugation to the above-mentioned RNA aptamer are commercially available. Other activated PEG moieties can be prepared using known methods. It should be understood that the PEG moieties used in the present invention are a collection of individual PEG molecules with different molecular weights. In addition, the PEG moieties are typically characterized by a numerical description that indicates the average molecular weight of the PEG polymer contained therein. For example, a 40 kDa PEG moiety generally refers to a PEG moiety having an average molecular weight of about 40 kDa. In some embodiments, the PEG moiety of ARC1905 is a 2-arm branched PEG. In some embodiments, the PEG moiety of ARC1905 is a 2-arm branched PEG with an average molecular weight ranging from about 39 kDa to about 47 kDa (including the endpoints of the range). In some embodiments, the PEG moiety of ARC1905 is a 2-arm branched PEG with an average molecular weight of about 40 kDa. In other embodiments, the PEG moiety of ARC1905 is a 2-arm branched PEG with an average molecular weight of about 43 kDa. In some embodiments, the PEG moiety of ARC1905 is a 2-arm branched NHS carbonate PEG. In some embodiments, the PEG reagent of ARC1905 is GL2-400TS (2-arm branched NHS carbonate PEG) (NOF America Corporation). According to the manufacturer's specifications, GL2-400TS has an average molecular weight (Mp) range of 39-47 kDa. In some embodiments, the average molecular weight (Mp) of mPEG2-NHS ester as determined by gel permeation chromatography (GPC) is 39-47 kDa. Other suitable PEG reagents include, but are not limited to GL2-400NP, ME-200TS, ME-300TS, ME-400TS, ME-400HS, ME-400GS, ME-400CS, GL2-200TS, GL2-600TS or LY-400NS (NOF America Corporation).

[0043] The nucleotide composition consists of ribopurines and modified 2'-fluoropyrimidines and 2'-methoxypurines. The modified nucleotides minimize susceptibility to endonuclease digestion. The 3'-end is capped by a "reverse" 3'-3' phosphodiester bond linked to deoxythymidine nucleotide (idT) to maximize resistance to 3'-exonuclease degradation. PEGylation is used to improve in vivo longevity without reducing affinity or activity. The ARC1905 aptamer forms a hairpin structure with functionally critical internal asymmetric bulges, internal loops, and terminal hairpin loops.

[0044] ARC1905 inhibits C5, a core component of the complement cascade, which plays multiple roles in innate immunity and inflammatory diseases. ARC1905 binds to human C5 with high specificity and high affinity (K D = 0.69 ± 0.148 nM at 37°C) and is a potent inhibitor of C5 generated by activation of the classical and alternative complement (C’) pathways.

[0045] The pharmaceutical substances, pharmaceutical products, and compositions provided herein comprise avacapatide polyethylene glycol. In this specification, "avacapatide polyethylene glycol" or "ACP" refers to the free base form or a salt form thereof. In some embodiments, avacapatide polyethylene glycol may exist in the form of its salt. In some embodiments, the salt of avacapatide polyethylene glycol is a pharmaceutically acceptable salt of avacapatide polyethylene glycol. In a preferred embodiment, the salt of avacapatide polyethylene glycol is the sodium salt of avacapatide polyethylene glycol. In some embodiments, the salt of avacapatide polyethylene glycol is, for example, an alkali metal salt such as a sodium salt, a potassium salt, a lithium salt, etc. In some embodiments, the salt of avacapatide polyethylene glycol is, for example, an alkaline earth metal salt such as a calcium salt, a magnesium salt, etc. In some embodiments, the salt of avacapatide polyethylene glycol includes, but is not limited to, salts with organic bases (such as triethylamine, dicyclohexylamine, pyrrolidine, morpholine, pyridine, etc.); ammonium salts, etc. In some embodiments, the salt of avacapatide polyethylene glycol includes, but is not limited to, salts with inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.); and salts with organic acids (such as acetic acid, oxalic acid, citric acid, lactic acid, tartaric acid, p-toluenesulfonic acid, etc.).

[0046] Examples of pharmaceutically acceptable salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, hydrogen phosphate, isonicotinate, lactate, salicylate, hydrogen citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate (saccharate), formate, benzoate, glutamate, mesylate, esylate, benzenesulfonate, tosylate, camphorsulfonate, pamoate, phenylacetate, trifluoroacetate, acrylate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o - acetoxybenzoate, naphthalene - 2 - benzoate, isobutyrate, phenylbutyrate, α - hydroxybutyrate, butyne - 1,4 - dicarboxylate, hexyne - 1,4 - dicarboxylate, caprate, caprylate, cinnamate, glycolate, heptanoate, hippurate, malate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate, phthalate, terephthalate, propiolate, propionate, phenylpropionate, sebacate, suberate, p - bromobenzenesulfonate, chlorobenzenesulfonate, ethylsulfonate, 2 - hydroxyethylsulfonate, methylsulfonate, naphthalene - 1 - sulfonate, naphthalene - 2 - sulfonate, naphthalene - 1,5 - disulfonate, xylenesulfonate, and tartrate. The term "pharmaceutically acceptable salts" includes, but is not limited to, hydrates of avacopan - polyethylene glycol, and may also refer to salts of avacopan - polyethylene glycol having acidic functional groups (such as, but not limited to, carboxylic acid functional groups or hydrogen phosphate functional groups) with bases. Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxy - substituted mono -, di -, or tri - alkylamines, dicyclohexylamine; tributylamine; pyridine; N - methylamine, N - ethylamine; diethylamine; triethylamine; mono -, bis -, or tri - (2 - OH - lower alkylamines), such as mono -, bis -, or tri - (2 - hydroxyethyl)amine, 2 - hydroxy - tert - butylamine, or tris - (hydroxymethyl)methylamine; N,N - di - lower alkyl - N - (hydroxy - lower alkyl) - amines, such as N,N - dimethyl - N - (2 - hydroxyethyl)amine or tris - (2 - hydroxyethyl)amine; N - methyl - D - glucamine; and amino acids such as arginine, lysine, and the like.

[0047] In some embodiments, the present invention provides a composition comprising a non-PEGylated aptamer intermediate having the sequence 5′NH2-fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmA mGfUfCfUmGmAmGfUfUfUAfCfCfUmGf CmG-3T-3′ (SEQ ID NO:1), wherein the composition has the following purity profile:

[0048] (a) More than 85% of the aptamers in the composition are full-length aptamers;

[0049] (b) Less than 3% in total of fluoride degradation products and n-1 deletion products; and

[0050] (c) 1% or less of deprotection failure products.

[0051] In some embodiments, the composition further has:

[0052] (d) Less than 1.8% of G cleavage products;

[0053] (e) Less than 0.1% of A cleavage products; and

[0054] (f) Less than 1.1% in total of n-4, n-3 and n-2 deletion products.

[0055] In some embodiments, the present invention provides a PEGylated aptamer or a salt thereof comprising the ultra-pure composition in the above embodiments, and the PEGylated aptamer has the following structure:

[0056]

[0057] wherein, n = ~485.

[0058] In some embodiments, an ultra-pure drug substance comprising avacapatide polyethylene glycol is produced, wherein the drug substance has the following characteristics:

[0059] (a) More than 92% of the aptamers in the drug substance are full-length aptamers;

[0060] (b) Less than 1.5% of the drug substance is RRT1 (≥0.93 - <FLP); and

[0061] (c) Less than 5% of the drug substance is RRT2 (>FLP - ≤1.2).

[0062] The potency of the ultra-pure intermediate and the drug substance can be measured by ELISA. The ELISA assay is based on the complement cascade induced by lipopolysaccharide (LPS) and the quantification of the formation of C5b9. The higher the potency of ARC1905, the lower the amount of C5b9 detected. The results are expressed as relative potency (%) compared to a standard ARC1905 reference substance.

[0063] Based on the ELISA results, the potency of the ultra-pure drug substance is at least 5% higher compared to the product synthesized and prepared according to the prior art. In some embodiments, the ultra-pure drug substance has a drug substance potency of greater than 95% as measured by ELISA.

[0064] In some embodiments, the endotoxin content in the ultra-pure drug substance is less than 0.2 EU / dose. In one embodiment, the endotoxin content in the drug product is about 0.14 EU / dose, preferably about 0.05 EU / dose.

[0065] Exemplary methods for producing the ultra-pure drug substance are provided in Example 2.

[0066] Drug product

[0067] The ARC1905 drug product is a preservative-free sterile aqueous solution for intravitreal injection. The drug product is formulated as a sterile aqueous solution in phosphate-buffered saline at a concentration of 20 mg / mL (oligonucleotide mass) at a pH of 6.8 - 7.8. The drug product is presented in 2.0 mL clear Type I glass vials, sealed with a rubber stopper and sealed with an aluminum seal with a flip-top (aluminum seal). The drug product is stable for 43 months at 2°C - 8°C.

[0068] The osmotic pressure of ARC1905 at a concentration of 20 mg / mL (measured by freezing point depression) has a range between 350 - 500 mOsM / kg, preferably between 400 - 450 mOsM / kg (including the endpoints of the range).

[0069] Administration and dosage

[0070] ARC1905 is intended for intravitreal injection administration at a dose of 1 - 5 mg / eye per administration. In some embodiments, intravitreal injection administration is preferably at a dose of 2 mg / eye per administration. In some embodiments, intravitreal injection administration is preferably at a dose of 4 mg / eye (one or more injections are performed in each eye during the same patient visit). The administration can be once every two weeks, once a month, once every other month, or once a quarter. In some embodiments, the administration can be once a month. In some embodiments, the administration can be once a month for up to 12 months. In some embodiments, the administration can be approximately once every 28 ± 7 days.

[0071] In some embodiments, a dosing regimen comprising a loading phase and a maintenance phase can be administered.

[0072] In some embodiments, avacincaptad pegol or a salt thereof can be administered according to a dosing regimen comprising: a loading phase that includes administering a dose of about 2 mg / eye once a month for a duration of up to one year; followed by a maintenance phase that includes administering a dose of avacincaptad pegol of about 0.3 mg / eye, or about 0.5 mg / eye, or about 0.75 mg / eye, or about 1 mg / eye, or about 1.25 mg / eye, or about 1.50 mg / eye, or about 1.75 mg / eye, or about 2 mg / eye, or about 2.25 mg / eye, or about 2.50 mg / eye, or about 2.75 mg / eye, or about 3 mg / eye, or about 3.25 mg / eye, or about 3.50 mg / eye, or about 3.75 mg / eye, or about 4 mg / eye once every 8 weeks, once every 9 weeks, once every 10 weeks, once every 11 weeks, once every 12 weeks, once every 13 weeks, once every 14 weeks, once every 14 weeks, once every 15 weeks, once every 16 weeks, once every 17 weeks, once every 18 weeks, once every 19 weeks, once every 20 weeks, once every 21 weeks, once every 22 weeks, once every 23 weeks, once every 24 weeks, once every 25 weeks, or once every 26 weeks.

[0073] Method of Use

[0074] The pharmaceutical products described herein are suitable for use in any of the methods of the invention described herein.

[0075] In some embodiments, the invention is a method of treating an ocular disease or disorder in a subject in need thereof, the method comprising: administering the pharmaceutical product of the invention to the ocular region of the subject.

[0076] As used herein, the term "treatment" refers to a therapeutic treatment, including a reduction or improvement in the progression, severity, and / or duration of a disease, disorder, or condition, or an improvement in one or more symptoms (specifically, one or more distinguishable symptoms) of a disease, disorder, or condition, resulting from the administration of a composition or implant of the invention. In a specific embodiment, the therapeutic treatment includes improving at least one measurable physical parameter of a disease, disorder, or condition. In other embodiments, the therapeutic treatment includes inhibiting the progression of a condition, either physically by, for example, stabilizing distinguishable symptoms, or physiologically by, for example, stabilizing physical parameters, or both. In other embodiments, the therapeutic treatment includes reducing or stabilizing a disease, disorder, or condition.

[0077] In some embodiments, an ocular disease refers to any disease that affects the retina, retinal pigment epithelium (RPE), and choroid. In some embodiments, the ocular disease is selected from the group consisting of geographic atrophy secondary to age-related macular degeneration (AMD), dry age-related macular degeneration (dry AMD), wet age-related macular degeneration (wet AMD), neovascular age-related macular degeneration (nAMD), retinal vein occlusion (RVO), diabetic macular edema (DME), diabetic retinopathy (DR), Usher syndrome type 1, Usher syndrome type 2, Usher syndrome type 3, Stargardt disease, uveitis, red-green color blindness, blue cone monochromacy, Leber congenital amaurosis (LCA), Leber hereditary optic neuropathy (LHON), neuromyelitis optica (NMO), choroideremia, X-linked retinoschisis (XLRS), Bardet-Biedl syndrome, cone dystrophy, optic atrophy, retinitis pigmentosa, age-related retinal ganglion cell (RGC) degeneration, Best disease, glaucoma, Graves ophthalmopathy, multiple sclerosis (MS)-associated vision loss, myopia, X-linked recessive ocular albinism, oculocutaneous albinism type 1, optic neuritis, polypoidal choroidal vasculopathy, X-linked retinitis pigmentosa (XLRP), achromatopsia (ACHM), biallelic RPE65 mutation-associated retinal dystrophy, idiopathic polypoidal choroidal vasculopathy, high-risk drusen, a disorder selected from the group consisting of risk factors for progression to iRORA (incomplete RPE and outer retinal atrophy), iRORA, neogeographic atrophy (nGA), and cRORA (complete RPE and outer retinal atrophy). In a preferred embodiment, the ocular disease is geographic atrophy secondary to AMD, or autosomal recessive Stargardt disease (STGD1). In some embodiments, the ocular disease is geographic atrophy secondary to AMD.

[0078] References in this specification to treatment methods should be construed as references to the compounds, pharmaceutical compositions, and medicaments of the invention used in those methods.

[0079] In some embodiments, provided herein is a pharmaceutical substance or pharmaceutical composition disclosed herein for use as a medicament. In some embodiments, provided herein is a pharmaceutical substance or pharmaceutical composition disclosed herein for the treatment of ophthalmic diseases, disorders, and / or conditions.

[0080] The pharmaceutical product can be used as a monotherapy or can be used in combination with a second suitable ocular therapy (ophthalmic therapeutic agent). In a preferred embodiment, the second ophthalmic therapeutic agent is a VEGF antagonist such as aflibercept, ranibizumab, bevacizumab or faricimab.

[0081] Numbered Embodiment

[0082] Notwithstanding the appended claims, the present disclosure sets forth the following numbered embodiments:

[0083] Embodiment 1. A composition comprising the non - polyethylene glycolylated aptamer 5′NH2 - fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfU mGmAmGfUfUfUAfCfCfUmGf CmG - 3T - 3′ (SEQ ID NO:1), wherein the composition comprises:

[0084] (a) More than 85% of the aptamers in the composition are full - length aptamers;

[0085] (b) Less than 1.8% of G cleavage products; and

[0086] (c) 1% or less of deprotection failure products.

[0087] Embodiment 2. The composition according to Embodiment 1, wherein the composition additionally has:

[0088] (d) Less than 0.1% of A cleavage products;

[0089] (e) A total of less than 1.1% of n - 4, n - 3 and n - 2 deletion products; and

[0090] (f) A total of less than 3% of fluorine degradation products and n - 1 deletion products.

[0091] Embodiment 3. A polyethylene glycolylated aptamer or a salt thereof, the polyethylene glycolylated aptamer comprising the composition according to Embodiment 1 or 2, the polyethylene glycolylated aptamer having the following structure:

[0092]

[0093] wherein n = ~ 485.

[0094] Embodiment 4. The polyethylene glycolylated aptamer according to Embodiment 3, wherein the polyethylene glycolylated aptamer comprises a 2 - arm branched PEG in the range of about 39 kDa to about 47 kDa.

[0095] Embodiment 5. The pegylated aptamer according to Embodiment 3, wherein the pegylated aptamer comprises a 2-arm branched PEG of about 40 kDa.

[0096] Embodiment 6. The pegylated aptamer according to Embodiment 3, wherein the pegylated aptamer comprises a 2-arm branched PEG of about 43 kDa.

[0097] Embodiment 7. The pegylated aptamer according to any one of Embodiments 3 to 6, wherein the salt is sodium salt.

[0098] Embodiment 8. A drug substance comprising its avacaptide PEG, wherein the drug substance comprises:

[0099] (a) More than 92% of the aptamer in the drug substance is full-length aptamer;

[0100] (b) Less than 1.5% of the drug substance is relative retention time (RRT) 1 (≥0.93 - < full-length product (FLP)); and

[0101] (c) Less than 5% of the drug substance is RRT2 (>FLP - ≤1.2).

[0102] Embodiment 9. The drug substance according to Embodiment 8, wherein the drug substance comprises the sodium salt of avacaptide PEG.

[0103] Embodiment 10. The drug substance according to Embodiment 8 or 9, wherein the potency of the drug substance is greater than 95% as measured by ELISA.

[0104] Embodiment 11. A pharmaceutical composition comprising the drug substance according to any one of Embodiments 8 to 10 and one or more pharmaceutically acceptable excipients.

[0105] Embodiment 12. The pharmaceutical composition according to Embodiment 11, wherein the composition is formulated as a sterile aqueous solution in phosphate buffered saline at a concentration of 20 mg / mL (oligonucleotide mass) at pH 6.8 - 7.8.

[0106] Embodiment 13. The pharmaceutical composition according to Embodiment 12, wherein the composition has an osmotic pressure between 350 - 500 mOsM / kg.

[0107] Embodiment 14. A method for treating ophthalmic diseases, disorders and / or conditions, the method comprising: intravitreally administering to a subject in need thereof a pharmaceutical composition according to any one of Embodiments 6 to 8 at a dose between 3 - 5 mg / eye.

[0108] Embodiment 15. The method according to Embodiment 14, wherein the administered dose is about 2 mg / eye.

[0109] Embodiment 16. The method according to Embodiment 15, wherein 100 μL is injected into each eye.

[0110] Embodiment 17. The method according to any one of Embodiments 14 to 16, wherein the ophthalmic disease, disorder and / or condition is selected from the group consisting of: geographic atrophy secondary to age-related macular degeneration, dry age-related macular degeneration (dry AMD), wet age-related macular degeneration (wet AMD), neovascular age-related macular degeneration (nAMD), retinal vein occlusion (RVO), diabetic macular edema (DME), diabetic retinopathy (DR), Usher syndrome type 1, Usher syndrome type 2, Usher syndrome type 3, Stargardt disease, uveitis, red-green color blindness, blue cone monochromacy, Leber congenital amaurosis (LCA), Leber hereditary optic neuropathy (LHON), neuromyelitis optica (NMO), choroideremia, X-linked retinoschisis (XLRS), Bardet-Biedl syndrome, cone dystrophy, optic atrophy, retinitis pigmentosa, age-related retinal ganglion cell (RGC) degeneration, Best disease, glaucoma, Graves ophthalmopathy, multiple sclerosis (MS)-associated visual loss, myopia, X-linked recessive ocular albinism, type 1 oculocutaneous albinism, optic neuritis, polypoidal choroidal vasculopathy, X-linked retinitis pigmentosa (XLRP), achromatopsia (ACHM), biallelic RPE65 mutation-associated retinal dystrophy, idiopathic polypoidal choroidal vasculopathy, high-risk drusen, and a condition selected from the group consisting of risk factors for progression to iRORA (incomplete RPE and outer retinal atrophy), iRORA, neogeographic atrophy (nGA), and cRORA (complete RPE and outer retinal atrophy).

[0111] Embodiment 18. The method according to any one of Embodiments 14 to 17, wherein the dose is administered once a month.

[0112] Embodiment 19. The method according to any one of Embodiments 14 to 18, wherein the dose is administered once a month for up to 12 months.

[0113] Embodiment 20. The pharmaceutical substance according to any one of Embodiments 8 to 10 or the pharmaceutical composition according to any one of Embodiments 11 to 13, wherein the pharmaceutical substance or pharmaceutical composition is used as a medicine.

[0114] Embodiment 21. The pharmaceutical substance according to any one of Embodiments 8 to 10 or the pharmaceutical composition according to any one of Embodiments 11 to 13, wherein the pharmaceutical substance or pharmaceutical composition is for treating ophthalmic diseases, disorders and / or conditions.

[0115] Embodiment 22. The pharmaceutical substance or pharmaceutical composition for use in Embodiment 21, wherein the ophthalmic diseases, disorders and / or conditions are selected from the group consisting of: geographic atrophy secondary to age-related macular degeneration, dry age-related macular degeneration (dry AMD), wet age-related macular degeneration (wet AMD), neovascular age-related macular degeneration (nAMD), retinal vein occlusion (RVO), diabetic macular edema (DME), diabetic retinopathy (DR), Usher syndrome type 1, Usher syndrome type 2, Usher syndrome type 3, Stargardt disease, uveitis, red-green color blindness, blue cone monochromacy, Leber congenital amaurosis (LCA), Leber hereditary optic neuropathy (LHON), neuromyelitis optica (NMO), choroideremia, X-linked retinoschisis (XLRS), Bardet-Biedl syndrome, cone dystrophy, optic atrophy, retinitis pigmentosa, age-related retinal ganglion cell (RGC) degeneration, Best disease, glaucoma, Graves ophthalmopathy, multiple sclerosis (MS)-associated visual loss, myopia, X-linked recessive ocular albinism, type 1 oculocutaneous albinism, optic neuritis, polypoidal choroidal vasculopathy, X-linked retinitis pigmentosa (XLRP), achromatopsia (ACHM), biallelic RPE65 mutation-associated retinal dystrophy, idiopathic polypoidal choroidal vasculopathy, high-risk drusen, and conditions selected from the group consisting of risk factors for progression to iRORA, iRORA, nGA and cRORA.

[0116] The following examples are provided for illustrative purposes only and are not intended to limit the invention in any way.

[0117] Examples

[0118] Example 1 : Synthesis of afacamotide polyethylene glycol according to prior art methods

[0119] Oligonucleotide 5′NH2-fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfUfUAfCfCfUmGfCmG-3T-3′ (SEQ ID NO:1), was synthesized on an Expedite DNA synthesizer (ABI, Foster City, Calif.) using standard commercially available 2′-OMe RNA and 2′-F RNA and TBDMS protected RNA phosphoramidites (Glen Research, Sterling, Va.) and a reverse deoxythymidine CPG support according to the recommended manufacturer's procedures. The terminal amine functionality was ligated with a 5′-amino modifier C6-TFA (Glen Research, Sterling, Va.). After deprotection, the oligonucleotide was purified by ion exchange chromatography on Super Q 5PW(30) resin (ToSoh BioSciences) and precipitated with ethanol.

[0120] The amine-modified aptamer was conjugated with different PEG moieties after synthesis. The aptamer was dissolved in a water / DMSO (1:1) solution to a concentration between 1.5 mM and 3 mM. Sodium carbonate buffer at pH 8.5 was added to a final concentration of 100 mM and the oligonucleotide was reacted overnight with a 1.7 molar excess of the desired PEG reagent (e.g., GL2-400NP, GL2-400TS (NOF Corp, Japan) or ARC187 40 kDa mPEG2-NHS ester (Nektar, Huntsville, Ala.)) dissolved in an equal volume of acetonitrile. The resulting product was purified by ion exchange chromatography on Super Q 5PW(30) resin (ToSoh BioSciences) and desalted using reverse phase chromatography on AMBERCHROM TM CG300-S resin (Rohm and Haas) and lyophilized.

[0121] Example 2 : Improved synthetic method for ultra-pure alfacalcidol polyethylene glycol

[0122] An improved synthetic method for generating the ultra-pure alfacalcidol polyethylene glycol of the present invention is described below.

[0123] Oligonucleotide (ARC672) 5′NH2-fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmGmAmGfUfUfUAfCfCfUmGfCmG-3T-3′ (SEQ ID NO:1) was synthesized on an OligoPilot 400 (Cytiva Life Sciences, Marlborough, Massachusetts) or other similar synthesizer using commercially available 2'-OMe RNA, 2'-F RNA, and TBDMS-protected RNA phosphoramidites (Thermo Scientific, Milwaukee, Wisconsin; Hongene Biotech, Shanghai, China; Sigma-Aldrich, Hamburg, Germany) and a reverse deoxythymidine CPG support (Prime Synthesis, Aston, Pennsylvania) according to the recommended manufacturer's procedures. The terminal amine functionality was coupled with a 5'-amino modifier C6-TFA (Sigma-Aldrich, Hamburg, Germany). After cleavage and deprotection, the oligonucleotide (ARC672) was concentrated and desalted using a 5 kDa molecular weight (MW) cut-off Hydrosart membrane (Sartorius Stedim Biotech) or a similar membrane from other manufacturers, and then purified by ion exchange chromatography using a TSK Gel SuperQ-5PW resin (ToSoh BioSciences). Prior to PEGylation, the oligonucleotide purification pool (ARC672) was concentrated and desalted via a 5 kDa MW cut-off membrane and further concentrated.

[0124] The amine-modified aptamer (ARC672) was conjugated with a PEG moiety after synthesis. A concentrated solution of the aptamer (ARC672) was diluted in sodium borate buffer (pH 8 - 10) and DMSO. The aptamer was reacted with less than 1.5 equivalents of the desired PEG reagent (e.g., GL2-400TS from NOF Corp, Japan) dissolved in DMSO for less than one hour. The resulting product ARC1905 was purified by ion exchange chromatography using a TSK Gel SuperQ-5PW resin (ToSoh BioSciences). Ultrafiltration of the ARC1905 purification pool was performed using a 10 kDa MW cut-off membrane for desalting and then lyophilized.

[0125] The improved synthesis method is described in more detail below:

[0126] Stage I: Synthesis and Isolation of Non-Pegylated ACP

[0127] 1. Synthesis

[0128] ​The manufacture of afacamotide polyethylene glycol starts with the iterative synthesis of non-polyethylene glycolated afacamotide polyethylene glycol (non-PEGylated ACP) on a solid support. The oligonucleotide 5′NH2-fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmGmAmGfUfUfUAfCfCfUmGf CmG-3T-3′ (SEQ ID NO:1) was synthesized on an OligoProcess TM oligonucleotide synthesizer (Cytiva Life Sciences, Marlborough, Massachusetts) or an oligonucleotide synthesizer from a different vendor using commercially available 2′-OMe RNA and 2′-F RNA and TBDMS-protected RNA phosphoramidites and a reverse deoxythymidine CPG support (LGC BioSearch Technologies, Novato, California). The oligonucleotide synthesis process consists of four chemical reactions that occur in the following order:

[0129] 1. Removal of the protecting group (deprotection of the trityl group) from the protected nucleoside or the nascent oligonucleotide;

[0130] 2. Activation and coupling of the introduced phosphoramidite (coupling);

[0131] 3. Oxidation of the resulting phosphite triester P(III) to a P(V) phosphate bond (oxidation); and

[0132] 4. Capping of the oligonucleotide chains that did not couple successfully (capping)

[0133] The above four steps are repeated in sequence until the desired oligonucleotide terminated with a hexylamino linker is synthesized. The terminal amine functional group is linked to a 5′-amino modifier C6-TFA (Sigma-Aldrich, Hamburg, Germany).

[0134] Using 0.2 M phosphoramidite and 0.5 M activator during the synthesis steps results in improved purity. After synthesis, the synthesis column is washed with diethylamine to remove the cyanoethyl protecting group, which also results in improved purity.

[0135] 2. Cleavage and Deprotection

[0136] The next steps include cleaving non - pegylated ACP from the solid support, removing base protecting groups, and deprotecting silyl - protected ribonucleosides. Ammonia and / or alkylamine bases are added to a heated deprotection vessel, and then the ammonia and / or alkylamine bases are circulated through a synthesis column. The cleavage and deprotection reaction mixtures are collected. Triethylamine trihydrofluoride (TEA - 3HF) is added to the deprotection vessel, and the mixture is heated to facilitate desilylation and the pH is adjusted to 6 - 8.

[0137] Using a certain volume of ammonia and alkylamine bases results in less non - pegylated and desilylated material in the deprotection reaction and thus leads to an increase in purity. Conducting the desilylation reaction within a defined time results in an increase in yield and thus leads to an increase in purity.

[0138] Stage II: Purification of Non-Pegylated ACP

[0139] 1. Crude Ultrafiltration / Diafiltration

[0140] After cleavage and deprotection, a coarse ultrafiltration / diafiltration is performed to achieve volume reduction and remove solvents. The crude mixture from the cleavage and deprotection steps is concentrated and diafiltered using a 5 kDa or 10 kDa nominal molecular weight cut - off (MWCO) ultrafiltration (UF) Hydrosart membrane (Sartorius Stedim Biotech) or a similar membrane from other manufacturers.

[0141] 2. Anion Exchange Chromatography Before Pegylation

[0142] Next, before pegylation, anion - exchange (AX) chromatography is performed to purify non - pegylated ACP. The crude retentate is loaded onto a chromatography column containing Tosoh Bioscience SuperQ - 5PW chromatography resin or a similar resin from other manufacturers. At a temperature above 45 °C, a sodium bromide salt gradient is used to purify non - pegylated ACP.

[0143] 3. Ultrafiltration / Diafiltration (UF / DF2) Before Pegylation

[0144] Then a pre - pegylation ultrafiltration / diafiltration step is performed to achieve volume reduction and buffer exchange. The purified non - pegylated ACP solution is concentrated and desalted using a 5 kDa or 10 kDa MWCO ultrafiltration membrane or a similar membrane from other manufacturers.

[0145] 4. Concentration

[0146] Before pegylation, the retentate obtained from the previous step is further concentrated using vacuum distillation (i.e., rotary evaporator, concentrator) or thin film evaporator to reduce the volume.

[0147] Stage III: Pegylation

[0148] A site-specific covalent bond is formed between the primary amine on the 5'-end of the non-pegylated ACP and the pegylation reagent (mPEG2-NHS ester) to form the crude drug substance, avacapatide pegyl. The non-pegylated ACP solution is diluted with sodium borate buffer and DMSO, and the pH is 8.8 - 9.5. The required amount of the pegylation reagent mPEG2-NHS ester is dissolved in DMSO based on a defined molar ratio with the non-pegylated ACP, and then the buffered non-pegylated ACP solution is added to initiate the pegylation reaction. After completion, the pegylation reaction is quenched by adding water.

[0149] The mPEG2-NHS ester improves the reaction efficiency and reduces the process time. Using 1.1 - 1.5 equivalents of mPEG2-NHS ester results in less residual free PEG to be removed, and performing the pegylation reaction at a temperature above room temperature leads to reduced thermal exposure, thus improving the yield and efficiency.

[0150] Stage IV: Purification of Avacapatide Peg

[0151] 1. Anion Exchange Chromatography After Pegylation

[0152] After pegylation, the crude drug substance is purified using anion exchange (AX) chromatography. The crude drug substance from the pegylation step is loaded onto a chromatography column containing Tosoh Bioscience SuperQ-5PW chromatography resin or a similar resin from other manufacturers. The drug substance is purified using a sodium bromide salt gradient at a temperature above 45 °C.

[0153] 2. Ultrafiltration / Diafiltration After Pegylation

[0154] Then a post-pegylation ultrafiltration / diafiltration step is performed to achieve volume reduction and buffer exchange. The purified avacapatide pegyl is concentrated and desalted using a 10 kDa nominal MWCO membrane or a similar membrane from other manufacturers, which results in an improved product retention.

[0155] Stage V: Lyophilization

[0156] The drug substance solution is filtered and lyophilized to reduce the water content and the product is packaged.

[0157] Example 3 : Pharmaceutical Product

[0158] The ARC1905 pharmaceutical product is formulated as a preservative-free sterile aqueous solution for intravitreal injection. The pharmaceutical product is formulated as a sterile aqueous solution in phosphate buffer at a concentration of 20 mg / mL (oligonucleotide mass) at pH 6.8 - 7.8. The pharmaceutical product is stable for 43 months at 2°C - 8°C.

[0159] The osmolality of a batch of the pharmaceutical product is shown in Table 1 below:

[0160] Table 1

[0161]

[0162] Example 4 : Comparison of Purity Profiles of Prior Art and Ultra-Pure Manufacturing Methods

[0163] The differences in the purity profiles of ACP products made by prior art methods and the improved method are described in Tables 2 and 3 below:

[0164] Table 2

[0165] Aptamer Before Pegylation Prior Art Methods Scope of Improvement FLP 80.9％* 88.3-91.8％ RRT Range 1 (G Cleavage) 2.07％ 1.06-1.71％ RRT Range 2 (A Cleavage) 0.17％ 0-0.08％ RRT Range 3 (n-4, n-3, n-2 Deletion) 1.86％ 0.79-1.05％ RRT Range 4 (Fluoride Degradant, n-1 Deletion) 5.45％ 2.12-2.86％ RRT Range 5 (n+1 Addition) 0.66％ 0.38-0.66％ RRT Range 6 (Failed Deprotection) 3.94％ 0.55-1.00％

[0166] *FLP may contain ~4% methylated impurities

[0167] FLP = full-length product

[0168] G cleavage = product of cleavage of non-PEGylated ACP at the G position in the sequence

[0169] A cleavage = product of cleavage of non-PEGylated ACP at the A position in the sequence

[0170] Table 3

[0171] ACP Prior Art Methods Scope of Improvement FLP 90.6％* 93.0-94.0％ RRT 1(≥0.93 - <FLP) 1.30％ 1.97-2.65％ RRT 2 (>FLP - ≤1.20) 8.15％ 3.00-4.74％

[0172] *FLP may contain ~4% methylated impurities

[0173] In some embodiments, the endotoxin content in the ultra-pure drug substance is less than 0.2 EU / dose. In one embodiment, the endotoxin content in the pharmaceutical product is about 0.14 EU / dose, preferably about 0.05 EU / dose.

[0174] Example 5 : Potency of Ultra-Pure Drug Substance

[0175] The potency of ultra-pure intermediates and drug substances was measured by ELISA. The ELISA assay is based on the lipopolysaccharide (LPS)-induced complement cascade and quantification of the formation of C5b9. The higher the potency of the ACP drug substance, the lower the amount of C5b9 detected. The results were expressed as relative potency (%) compared to a standard ACP reference substance.

[0176] Based on the ELISA results, the potency of the ultra-pure drug substance was at least 5% higher compared to products synthesized and prepared according to the prior art.

[0177] Example 6 : Comparison of Potency between the Prior Art and the Ultra-Pure Manufacturing Method

[0178] The potency of the impurity fractions of ACP products prepared by the prior art method and the improved method was measured by ELISA. The collection of the impurity fractions is shown in Figure 1 . The data comparison is shown in Table 4.

[0179] The results showed that the pre-FLP and post-FLP impurity fractions from the prior art method had higher potency than the impurity fractions from the improved manufacturing method. This indicates that the improved method has high purification resolution and efficiency.

[0180] Table 4. Data Comparison of the Potency of Impurity Fractions between the Prior Art Method and the Improved Manufacturing Method

[0181] Purified Fraction After Pegylation Improved Method Prior Art Impurity Fraction 1 Before FLP 12％ 21％ Impurity Fraction 2 Before FLP 53％ 53％ Impurity Fraction 1 After FLP 22％ 57％ Impurity Fraction 2 After FLP 21％ 35％ .

Claims

1. A composition comprising a non - polyethylene glycolylated aptamer 5′NH2 - fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmGmAmGfUfUfUAfCfCfUmGf CmG - 3T - 3′ (SEQ ID NO:1), wherein, The composition comprises: (a) More than 85% of the aptamers in the composition are full-length aptamers; (b) Less than 1.8% of G cleavage products; and (c) 1% or less of deprotection failure products.

2. The composition according to claim 1, wherein The composition further has: (d) Less than 0.1% of A cleavage products; (e) A total of less than 1.1% of n-4, n-3 and n-2 deletion products; and (f) A total of less than 3% of fluorine degradation products and n-1 deletion products.

3. A pegylated aptamer or a salt thereof, the pegylated aptamer comprising the composition of claim 1 or 2, the pegylated aptamer having the following structure: Among them, n＝～485。 4. The PEGylated aptamer according to claim 3, wherein, The pegylated aptamer comprises a 2-arm branched PEG in the range of about 39 kDa to about 47 kDa.

5. The PEGylated aptamer according to claim 3, wherein, The pegylated aptamer comprises a 2-arm branched PEG of about 40 kDa.

6. The PEGylated aptamer according to claim 3, wherein, The pegylated aptamer comprises a 2-arm branched PEG of about 43 kDa.

7. The PEGylated aptamer according to any one of claims 3 to 6, wherein, The salt is a sodium salt.

8. A pharmaceutical substance comprising avacapatide polyethylene glycol, wherein, The drug substance comprises: (a) More than 92% of the aptamers in the drug substance are full-length aptamers; (b) Less than 1.5% of the drug substance has a relative retention time (RRT) of 1 (≥0.93 - < full-length product (FLP)); and (c) Less than 5% of the drug substance has an RRT of 2 (>FLP - ≤1.2).

9. The pharmaceutical substance according to claim 8, wherein, The drug substance comprises the sodium salt of avacaptide polyethylene glycol.

10. The pharmaceutical substance according to claim 8 or 9, wherein, The potency of the drug substance as measured by ELISA is greater than 95%.

11. A pharmaceutical composition comprising the drug substance of any one of claims 8 to 10 and one or more pharmaceutically acceptable excipients.

12. The pharmaceutical composition according to claim 11, wherein, The composition is formulated as a sterile aqueous solution in phosphate buffered saline at a concentration of 20 mg / mL (oligonucleotide mass) at pH 6.8 - 7.

8.

13. The pharmaceutical composition according to claim 12, wherein The composition has an osmotic pressure between 350 - 500 mOsM / kg.

14. A method for treating ophthalmic diseases, disorders, and / or conditions, the method comprising: The pharmaceutical composition of any one of claims 6 - 8 is administered intravitreally to a subject in need thereof at a dose between 3 - 5 mg / eye.

15. The method according to claim 14, wherein, The administered dose is about 2 mg / eye.

16. The method according to claim 15, wherein, 100 μL is injected into each eye.

17. The method according to any one of claims 14 - 16, wherein, The ophthalmic diseases, disorders, and / or conditions are selected from the group consisting of: geographic atrophy secondary to age-related macular degeneration, dry age-related macular degeneration (dry AMD), wet age-related macular degeneration (wet AMD), neovascular age-related macular degeneration (nAMD), retinal vein occlusion (RVO), diabetic macular edema (DME), diabetic retinopathy (DR), Usher syndrome type 1, Usher syndrome type 2, Usher syndrome type 3, Stargardt disease, uveitis, red-green color blindness, blue cone monochromacy, Leber congenital amaurosis (LCA), Leber hereditary optic neuropathy (LHON), neuromyelitis optica (NMO), choroideremia, X-linked retinoschisis (XLRS), Bardet-Biedl syndrome, cone dystrophy, optic atrophy, retinitis pigmentosa, age-related retinal ganglion cell (RGC) degeneration, Best disease, glaucoma, Graves ophthalmopathy, multiple sclerosis (MS)-associated visual loss, myopia, X-linked recessive ocular albinism, oculocutaneous albinism type 1, optic neuritis, polypoidal choroidal vasculopathy, X-linked retinitis pigmentosa (XLRP), achromatopsia (ACHM), biallelic RPE65 mutation-associated retinal dystrophy, idiopathic polypoidal choroidal vasculopathy, high-risk drusen, and conditions selected from the group consisting of risk factors for progression to iRORA (incomplete RPE and outer retinal atrophy), iRORA, neovascular geographic atrophy (nGA), and cRORA (complete RPE and outer retinal atrophy).

18. The method according to any one of claims 14 - 17, wherein, The dose is administered once monthly.

19. The method according to any one of claims 14-18, wherein, The dose is administered once monthly for up to 12 months.

20. The pharmaceutical substance according to any one of claims 8 - 10 or the pharmaceutical composition according to any one of claims 11 - 13, for use as a medicament.

21. The pharmaceutical substance according to any one of claims 8 - 10 or the pharmaceutical composition according to any one of claims 11 - 13, for use in the treatment of ophthalmic diseases, disorders, and / or conditions.

22. The pharmaceutical substance or the pharmaceutical composition for an application according to claim 21, wherein, The ophthalmic diseases, disorders, and / or conditions are selected from the group consisting of: geographic atrophy secondary to age-related macular degeneration, dry age-related macular degeneration (dry AMD), wet age-related macular degeneration (wet AMD), neovascular age-related macular degeneration (nAMD), retinal vein occlusion (RVO), diabetic macular edema (DME), diabetic retinopathy (DR), Usher syndrome type 1, Usher syndrome type 2, Usher syndrome type 3, Stargardt disease, uveitis, red-green color blindness, blue cone monochromacy, Leber congenital amaurosis (LCA), Leber hereditary optic neuropathy (LHON), neuromyelitis optica (NMO), choroideremia, X-linked retinoschisis (XLRS), Bardet-Biedl syndrome, cone dystrophy, optic atrophy, retinitis pigmentosa, age-related retinal ganglion cell (RGC) degeneration, Best disease, glaucoma, Graves ophthalmopathy, multiple sclerosis (MS)-associated visual loss, myopia, X-linked recessive ocular albinism, oculocutaneous albinism type 1, optic neuritis, polypoidal choroidal vasculopathy, X-linked retinitis pigmentosa (XLRP), achromatopsia (ACHM), biallelic RPE65 mutation-associated retinal dystrophy, idiopathic polypoidal choroidal vasculopathy, high-risk drusen, and conditions selected from the group consisting of risk factors for progression to iRORA, iRORA, nGA, and cRORA.

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