Pharmaceutical Compositions for Ocular Delivery

Abstract

The present disclosure provides pharmaceutical compositions of avasincaptodapegol of sufficient purity and potency to be suitable for administration to human patients for the treatment of various ocular disorders and diseases.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 435,168, filed December 23, 2022, the disclosure of which is incorporated herein by reference in its entirety.

[0002] Electronic Sequence Listing Reference The contents of the electronic sequence listing (OPHT_037_01 WO_SeqList_ST26.xml; size: 17,715 bytes; and creation date: November 21, 2023) are incorporated herein by reference in their entirety.

[0003] Technical field to which the invention belongs The present invention relates to pharmaceutical compositions of avasincaptodapegol of sufficient purity to be suitable for administration to human patients in treating various ocular disorders and diseases. [Background technology]

[0002]

[0004] Disease and damage to tissues in the posterior segment of the eye, including the retina and choroid, are responsible for many of the most common blinding diseases in industrialized countries. Age-related macular degeneration (AMD) alone affects over 10 million Americans. Severe vision loss due to AMD and other diseases affecting the posterior segment of the eye (including diabetic retinopathy, glaucoma, and retinitis pigmentosa) accounts for most cases of irreversible blindness worldwide. AMD is classified into one of two general 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 that develop within the macula) located beneath the retinal pigment epithelium (RPE). In severe cases, dry AMD leads to significant thinning and / or atrophy of the macula, which is due to the loss of the RPE and associated capillaries (choriocapillaris). This form of late-stage dry AMD is associated with thinning and loss of function of the neural retina located above the affected RPE. This collective phenotype in late-stage dry AMD is called geographic atrophy (GA). Progressive degeneration of light-sensitive photoreceptor cells in GA leads to severe vision loss in affected eyes. Currently, treatment of posterior segment diseases is significantly limited due to the difficulty of delivering effective amounts of drugs to target tissues in the posterior eye.

[0003]

[0005] Therefore, despite significant contributions to the treatment of GA, AMD, or other ophthalmic disorders, there remains a need for pharmaceutical compositions suitable for administration to human patients to treat ocular diseases that require delivery of therapeutic agents directly to the eye. Summary of the Invention

[0004]

[0006] The present invention provides highly purified drug substance (drug substance) and pharmaceutical products of avasincaptodapegol (ACP). In one embodiment, the present invention provides a composition comprising a non-pegylated aptamer intermediate comprising a sequence represented by 5'NH2-fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmGmAmGfUfUfUAfCfCfUmGf CmG-3T-3' (SEQ ID NO: 1), wherein the purity profile of the composition is as follows: (a) greater than 85% of the unpegylated aptamers in the composition are full-length aptamers; (b) less than 1.8% G cleavage products; and (c) the amount of unsuccessful deprotection products is 1% or less; is. In one embodiment, the composition further comprises: (d) less than 0.1% A cleavage products; (e) the sum of n-4, n-3, and n-2 deletion products is less than 1.1%; and (f) the sum of fluorodegradation products and n-1 deletion products is less than 3%; It is a composition. In an embodiment, the present invention comprises an ultra-pure composition of any of the above embodiments, The following structure:

[0005] [ka] The present invention provides a PEGylated aptamer, which is a compound represented by the following formula:

[0006]

[0007] In another embodiment, the present invention provides an ultra-pure drug substance comprising avasincaptodapegol, wherein the drug substance has a purity profile of: (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 RRT2 (>FLP- ≤ 1.2); is.

[0008] In another embodiment, the present invention provides a drug substance with a potency of greater than 95% as measured by ELISA.

[0009] In another embodiment, the present invention provides a pharmaceutical composition comprising the ultrapure drug substance described herein and one or more pharmaceutically acceptable excipients. In one embodiment, the pharmaceutical composition is formulated as a sterile aqueous solution at a concentration of 20 mg / mL (oligonucleotide mass) in phosphate buffered saline at a pH of 6.8-7.8. In one embodiment, the osmolality of the pharmaceutical composition is 350-500 mOsM / kg.

[0007]

[0010] In another embodiment, the present invention provides a method for treating an ophthalmic disease, disorder, and / or condition, comprising intravitreally administering to a subject in need thereof an ultrapure avasincaptodapegol pharmaceutical composition described herein at a dose of 3-5 mg / eye. In a preferred embodiment, the method provides a method wherein the administered dose is about 2 mg / eye. [Brief explanation of the drawings]

[0008] [Figure 1]

[0011] FIG. 1 shows the collection of pre- and post-FLP impurity fractions from the purification process of PEGylated ACP. DETAILED DESCRIPTION OF THE INVENTION

[0009]

[0012] Provided herein are highly purified drug substances and drug products comprising avasincaptodapegol (ACP). The compositions are produced by improved manufacturing methods. Highly purified compositions are advantageous compared to compositions produced by prior art processes, at least in part because they contain lower proportions of ACP impurities or variants that do not contribute to efficacy but may be available to induce an immune response.

[0013] As used in the appended claims and this specification, the singular forms of words such as "a," "an," and "the" include their corresponding plural references unless the context clearly indicates 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.

[0010] definition

[0014] Throughout this application, the term "about" is used to indicate that a value includes the inherent variation of error for the device or method being used to determine the value or the variation that exists between samples measured. Unless otherwise specified or clear from the context, the term "about" means within 10% above or below the reported numerical value (except where such number would exceed 100% or be less than 0% of the possible values). When used in conjunction with a range or series of values, the term "about" applies to each of the recited values ​​at the endpoints of the range or series of values ​​unless otherwise indicated. As used in this application, the terms "about" and "approximately" are used equivalently.

[0011]

[0015] As used herein, the term "ocular" generally refers to the eye, or any part or site of the eye (as an "ocular implant" according to the present invention can, in principle, be administered to any part or site of the eye), or any disease of the eye (as, in one aspect, the present invention generally refers to treating any disease of the eye ("ocular disease") of various origins and nature). The present invention, in certain embodiments, is directed to intravitreal injection of ocular implants (i.e., in this case, the "ocular implant" is an "intravitreal implant"), and to the treatment of ocular diseases affecting the posterior segment of the eye, as further disclosed below.

[0012]

[0016] As used herein, the term "patient" includes both human and animal patients. A "patient" is a subject in need of treatment for a particular physiological or pathological condition.

[0013]

[0017] The term "polymer network" refers to a structure formed from polymer chains (of the same or different molecular structure and the same or different molecular weight) that are crosslinked to one another. Types of polymers suitable for the purposes of the present invention are disclosed herein. Polymer networks may also be formed with the aid of crosslinking agents, as also disclosed herein.

[0018] As used herein, the terms "include," "including," "contain," "containing," and the like open-ended terms mean "comprising" and are intended to refer to an open-ended list or enumeration of elements, method steps, and the like, but are not intended to be limited to the enumerated elements, method steps, etc., and are intended to include additional, unenumerated elements, method steps, etc.

[0019] The term "up to," when used herein in conjunction with a particular value or number, is meant to include each value or number. When a range of values ​​or numbers is used herein, the endpoints of the range are included in the range.

[0014]

[0020] The terms "API," "active (pharmaceutical) ingredient," "active (pharmaceutical) agent," "active (pharmaceutical) ingredient," "(active) therapeutic agent," "active," "drug," and "drug substance" are used interchangeably herein and refer to substances used in finished pharmaceutical products (FPPs) or "medicinal products," and in the preparation of such finished pharmaceutical products, that are intended to provide pharmacological activity or otherwise exert a direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to exert a direct effect in restoring, correcting, or altering physiological function in a patient.

[0021] As used herein, the term "aptamer" refers to an oligonucleotide and / or nucleic acid analog capable of binding to a specific target molecule. Aptamers include RNA, DNA, RNA / DNA, any nucleic acid analog, and / or combinations thereof. Aptamers can be single-stranded oligonucleotides. Without wishing to be bound by theory, it is believed that aptamers bind to the three-dimensional structure of a target molecule. Aptamers can be monomeric (composed of a single unit) or multimeric (composed of multiple units). Multimeric aptamers can be homomeric (composed of multiple identical units) or heteromeric (composed of multiple non-identical units).

[0015] drug substance

[0022] The drug substance is the aptamer 5′NH2-fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmGmAmGfUfUfUAfCfCfUmGf CmG-3T-3′ (SEQ ID NO: 1). (wherein fC and fU are 2'-fluorine nucleotides, mG and mA are 2'-OMe nucleotides, G and A are ribonucleotides, and 3T represents inverted deoxythymidine) and the structure is shown below.

[0016] [ka]

[0023] ARC1905 (avacincaptod pegol) is a PEGylated RNA aptamer, a potent and specific inhibitor of complement activation, developed as a therapy for the treatment of age-related macular degeneration (AMD), geographic atrophy (GA) secondary to AMD, and Stargardt disease. The molecular structure of avacincaptod pegol (free acid form) is C 395 H 492 N 142 O 262 P 39 F 21((CH2)2O)n (where n is approximately 970) and has a molecular mass of approximately 56 kDa. ARC1905 consists of a 12,882 dalton modified RNA aptamer linked at its 5' end to a polyethylene glycol (PEG) moiety. The aptamer portion of ARC1905 (ARC672) is 39 nucleotides long and modified with a primary amine at its 5' end to provide a reactive site for site-specific conjugation ("PEGylation"). Specifically, ARC1905 is a PEGylated aptamer containing 39 monomer units (39-mer) with a hairpin structure. Certain activated PEG moieties for conjugation to the above-described RNA aptamers are commercially available. Other activated PEG moieties can be prepared using known methods. It is understood that the PEG moiety used in the present invention is a collection of individual PEG molecules of various molecular weights. Furthermore, PEG moieties are generally characterized by a numerical description indicating the average molecular weight of the PEG polymers 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 one embodiment, the PEG moiety of ARC1905 is a two-arm branched PEG. In one embodiment, the PEG moiety of ARC1905 is a two-arm branched PEG having an average molecular weight ranging from about 39 kDa to about 47 kDa (including the end points of the range). In one embodiment, the PEG moiety of ARC1905 is a two-arm branched PEG having an average molecular weight of about 40 kDa. In another embodiment, the PEG moiety of ARC1905 is a two-arm branched PEG having an average molecular weight of about 43 kDa. In one embodiment, the PEG moiety of ARC1905 is a two-arm branched NHS carbonate PEG. In one embodiment, the PEG reagent for ARC1905 is SUNBRIGHT® GL2-400TS (two-arm branched NHS carbonate PEG) (NOF America Corporation). According to the manufacturer's specifications, SUNBRIGHT® GL2-400TS has an average molecular weight (Mp) in the range of 39-47 kDa. In one embodiment, the average molecular weight (Mp) of the mPEG2-NHS ester is 39-47 kDa as determined by gel permeation chromatography (GPC).Other suitable PEG reagents include, but are not limited to, SUNBRIGHT® GL2-400NP, ME-200TS, ME-300TS, ME-400TS, ME-400HS, ME-400GS, ME-400CS, GL2-200TS, GL2-600TS, or LY-400NS (NOF America Corporation).

[0024] The nucleotide composition consists of ribopurines and modified 2'-fluoropyrimidines and 2'-methoxypurines. The modified nucleotides minimize susceptibility to endonuclease digestion. Capping the 3' end with a "reverse" 3'-3' phosphodiester linkage to a deoxythymidine nucleotide (idT) maximizes 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 a functionally important internal asymmetric bulge, internal loop, and terminal hairpin loop.

[0025] ARC1905 inhibits C5, a central component of the complement cascade with multiple functions in innate immune and inflammatory diseases. ARC1905 binds to human C5 with high specificity and affinity (KD = 0.69 ± 0.148 nM at 37°C) and is a potent inhibitor of C5 resulting from activation of the classical and alternative complement (C') pathways.

[0026] The drug substance, pharmaceutical product, and composition provided herein comprise avasincaptodapegol. As used herein, "avacincaptodapegol" or "ACP" refers to either its free base form or its salt form. In some embodiments, avasincaptodapegol can exist in the form of a salt. In some embodiments, the salt of avasincaptodapegol is a pharmaceutically acceptable salt of avasincaptodapegol. In a preferred embodiment, the salt of avasincaptodapegol is the sodium salt of avasincaptodapegol. In some embodiments, the salt of avasincaptodapegol is an alkali metal salt, such as a sodium salt, a potassium salt, or a lithium salt. In some embodiments, the salt of avasincaptodapegol is an alkaline earth metal salt, such as a calcium salt or a magnesium salt. In some embodiments, salts of abacincaptodapegol include, but are not limited to, salts with organic bases (e.g., triethylamine, dicyclohexylamine, pyrrolidine, morpholine, pyridine, etc.); ammonium salts, etc. In some embodiments, salts of abacacaptodapegol include, but are 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.

[0027] Examples of pharmaceutically acceptable salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucaronate, saccharinate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, pamoate, phenylacetate, trifluoroacetate, acrylate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, Examples of suitable esters include ter, 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, teraphthalate, propiolate, propionate, phenylpropionate, sebacate, suberate, p-bromobenzenesulfonate, chlorobenzenesulfonate, ethylsulfonate, 2-hydroxyethylsulfonate, methylsulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, naphthalene-1,5-sulfonate, xylenesulfonate, and tartrate. The term "pharmaceutically acceptable salt" may be a salt of avacincaptadpegol having an acidic functional group, such as a carboxylic acid functional group or a hydrogen phosphate functional group, and a base, including, but not limited to, a hydrate of avacincaptadpegol.Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, lithium, etc.; hydroxides of alkaline earth metals such as calcium, magnesium, etc.; hydroxides of other metals such as aluminum, zinc, etc.; ammonia and organic amines such as unsubstituted or hydroxy-substituted mono-, di-, or tri-alkylamines, dicyclohexylamine; tributylamine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH-lower alkylamines), such as mono-, bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine; N,N-di-lower alkyl-N-(hydroxyl-lower alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such as arginine and lysine.

[0017]

[0028] In one embodiment, the present invention provides a composition comprising an unpegylated aptamer intermediate comprising a sequence represented by 5′NH2-fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmGmAmGfUfUfUAfCfCfUmGf CmG-3T-3′ (SEQ ID NO: 1), wherein the purity profile of the composition is as follows: (a) greater than 85% of the unpegylated aptamers in the composition are full-length aptamers; (b) less than 1.8% G cleavage products; and (c) the amount of unsuccessful deprotection products is 1% or less; is. In some embodiments, the composition further comprises: (d) less than 0.1% A cleavage products; (e) the sum of n-4, n-3, and n-2 deletion products is less than 1.1%; and (f) The sum of fluorodegradation products and n-1 deletion products is less than 3%. In an embodiment, the present invention comprises an ultra-pure composition of any of the above embodiments, The following structure:

[0018] [ka] The present invention provides a PEGylated aptamer, which is a compound represented by the following formula:

[0029] In one embodiment, an ultra-pure drug substance comprising avasincaptodapegol is produced, the drug substance comprising: (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 is RRT2 (>FLP-≦1.2).

[0030] The potency of ultrapure intermediates and drug substances can be measured by ELISA. The ELISA assay is based on the induction of the complement cascade by lipopolysaccharide (LPS) and quantification of C5b9 formation. The more potent ARC1905 has, the lower the amount of C5b9 detected. Results are expressed as relative potency (%) compared to the standard ARC1905 reference substance.

[0031] Based on the ELISA results, the ultrapure drug substance was at least 5% more potent than products made by prior art synthetic methods. In one embodiment, the potency of the ultrapure drug substance is greater than 95% when measured by ELISA.

[0032] In some embodiments, the endotoxin content of the ultra-pure drug substance is less than 0.2 EU / dose. In one embodiment, the endotoxin content of the formulation is about 0.14 EU / dose, preferably about 0.05 EU / dose.

[0033] An exemplary method for producing ultra-pure drug substance is provided in Example 2.

[0019] Pharmaceuticals

[0034] The ARC1905 formulation is a preservative-free, sterile aqueous solution for intravitreal injection. It is formulated as a sterile aqueous solution at a concentration of 20 mg / mL (oligonucleotide mass) in phosphate-buffered saline at pH 6.8-7.8. The drug product is contained in a 2.0 mL clear, type I glass vial, stoppered with a rubber stopper and sealed with an aluminum seal with a flip-off cap. The drug product is stable for 43 months at 2-8°C.

[0035] The osmolality (measured by freezing point depression) of ARC1905 at a concentration of 20 mg / mL is in the range of 350-500 mOsM / kg, preferably 400-450 mOsM / kg (endpoints of the range included).

[0020] Administration and Dosage

[0036] ARC1905 is intended for administration by intravitreal injection at between 1 and 5 mg / eye per administration. In some embodiments, the intravitreal administration is preferably 2 mg / eye per administration. In some embodiments, the intravitreal administration is preferably 4 mg / eye per administration (with one or more injections per eye during the same patient visit). Dosing can be biweekly, monthly, bimonthly, or quarterly. In some embodiments, dosing can be monthly. In some embodiments, dosing can be monthly for up to 12 months. In some embodiments, dosing can be approximately every 28±7 days.

[0037] In some embodiments, the administration can be in a dosing regimen that includes a loading phase and a maintenance phase.

[0038] In one embodiment, avasincaptodapegol or a salt thereof is administered at about 2 mg / eye once a month for up to one year, followed by a loading phase of about 0.3 mg / eye, about 0.5 mg / eye, about 0.75 mg / eye, about 1 mg / eye, about 1.25 mg / eye, about 1.50 mg / eye, about 1.75 mg / eye, about 2 mg / eye, about 2.25 mg / eye, about 2.50 mg / eye, about 2.75 mg / eye, about 3 mg / eye, about 3.25 mg / eye, or about 3.50 mg / eye. g / eye, approximately 3.75 mg / eye, or approximately 4 mg / eye is administered once every 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, or 26 weeks.

[0021] How to use

[0039] The pharmaceutical agents described herein are suitable for use in any of the methods of the invention described herein.

[0040] In one embodiment, the present invention is a method of treating an ocular disease or disorder in a subject in need thereof, comprising administering a pharmaceutical agent of the present invention to the ocular region of the subject.

[0041] As used herein, the terms "treat," "treatment," and "treating" refer to therapeutic treatment, including a reduction or amelioration of the progression, severity, and / or duration of a disease, disorder, or condition, or an improvement in one or more symptoms (particularly, one or more discernible symptoms) of a disease, disorder, or condition, resulting from administration of a composition or implant of the invention. In certain embodiments, therapeutic treatment includes an improvement in at least one measurable physical parameter of the disease, disorder, or condition. In other embodiments, therapeutic treatment includes inhibiting the progression of the condition, either physically, e.g., by stabilization of a discernible symptom, physiologically, e.g., by stabilization of a physical parameter, or both. In other embodiments, therapeutic treatment includes a reduction or stabilization of the disease, disorder, or condition.

[0042] In one embodiment, ocular disease refers to any disease that affects the retina, retinal pigment epithelium (RPE), and choroid. In certain embodiments, the ocular disease is 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 retinopathy (XLRS), Bardet-Biedl syndrome, cone dystrophy, optic nerve anomaly, optic neuropathy, optic nerve anomaly, optic nerve dystrophy, optic nerve neuropathy ... The retinal dysplasia is selected from the group consisting of retinopathy of prematurity, retinitis pigmentosa, age-related retinal ganglion cell (RGC) degeneration, Best's disease, glaucoma, Graves' ophthalmopathy, multiple sclerosis (MS)-related vision loss, myopia, X-linked recessive ocular albinism, oculocutaneous albinism type 1, optic neuritis, polypoidal choroidal vasculopathy, X-linked retinitis pigmentosa (XLRP), achromatopsia (ACHM), bigenic RPE65 mutation-associated retinal dystrophy, idiopathic polypoidal choroidal vasculopathy, high risk of drusen, and 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 eye disease is geographic atrophy secondary to AMD or autosomal recessive Stargardt disease (STGD1). In one embodiment, the eye disease is geographic atrophy secondary to AMD.

[0043] References herein to methods of treatment should be construed as references to the compounds, pharmaceutical compositions and medicaments of the invention for use in those methods.

[0044] In some embodiments, provided herein is a drug substance or pharmaceutical composition disclosed herein for use as a medicament. In some embodiments, provided herein is a drug substance or pharmaceutical composition disclosed herein in the treatment of an ophthalmic disease, disorder, and / or condition.

[0045] The formulations may be used as monotherapy or in combination with a second suitable ocular therapy, hi preferred embodiments, the second ocular therapy is a VEGF antagonist such as aflibercept, ranibizumab, bevacizumab, or faricimab.

[0022] Numbered Embodiments

[0046] Without limiting the scope of any appended claims, the present disclosure describes the following numbered embodiments.

[0047] Embodiment 1. A composition comprising the non-pegylated aptamer 55'NH2-fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmGmAmGfUfUfUAfCfCfUmGf CmG-3T-3' (SEQ ID NO: 1), wherein: (a) greater than 85% of the unpegylated aptamers in the composition are full-length aptamers; (b) less than 1.8% G cleavage products; and (c) the amount of unsuccessful deprotection products is 1% or less; A composition comprising:

[0048] Embodiment 2. Further, the following: (d) less than 0.1% A cleavage products; (e) the sum of n-4, n-3, and n-2 deletion products is less than 1.1%; and (f) the sum of fluorodegradation products and n-1 deletion products is less than 3%; 2. The composition of embodiment 1.

[0049] Embodiment 3. The following structure:

[0023] [ka] 3. A PEGylated aptamer comprising the composition of embodiment 1 or 2, wherein the aptamer is a compound represented by the formula:

[0050] Embodiment 4. The PEGylated aptamer of embodiment 3, comprising a two-arm branched PEG in the range of about 39 kDa to about 47 kDa.

[0051] Embodiment 5. The PEGylated aptamer of embodiment 3, comprising a two-arm branched PEG of about 40 kDa.

[0052] Embodiment 6. The PEGylated aptamer of embodiment 3, comprising a two-arm branched PEG of about 43 kDa.

[0053] Embodiment 7. The PEGylated aptamer of any one of embodiments 3 to 6, wherein the salt is a sodium salt.

[0054] Embodiment 8. A drug substance comprising avacincaptodapegol, comprising: (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 RRT2 (>FLP- ≤ 1.2); The active pharmaceutical ingredient, including

[0055] Embodiment 9 The drug substance of embodiment 8, comprising the sodium salt of avasincaptodapegol.

[0056] Embodiment 10. The drug substance of embodiment 8 or 9, having a potency of greater than 95% as measured by ELISA.

[0057] Embodiment 11. A pharmaceutical composition comprising the drug substance of any one of embodiments 8 to 10 and one or more pharmaceutically acceptable excipients.

[0058] Embodiment 12. The pharmaceutical composition of embodiment 11, formulated as a sterile aqueous solution in phosphate buffered saline at a pH of 6.8 to 7.8 at a concentration of 20 mg / mL (oligonucleotide mass).

[0059] Embodiment 13. The pharmaceutical composition of embodiment 12, wherein the osmolality is 350-500 mOsM / kg.

[0060] Embodiment 14. A method for treating an ophthalmic disease, disorder and / or condition, comprising intravitreally administering to a subject in need thereof the pharmaceutical composition of any one of claims 6 to 8 at a dose of 3 to 5 mg / eye.

[0061] Embodiment 15. The method of embodiment 14, wherein the administered dose is about 2 mg / eye.

[0062] Embodiment 16 The method of embodiment 15, wherein 100 μL is injected per eye.

[0063] Embodiment 17. The ophthalmologic disease, disorder, and / or condition is 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 retinopathy (XLRS), Bardet-Biedl syndrome, cone dystrophy, optic atrophy, retinal 17. The method of any one of embodiments 14-16, wherein the risk factors for progression to iRORA (incomplete RPE and outer retinal atrophy), iRORA, neogeographic atrophy (nGA), and cRORA (complete RPE and outer retinal atrophy) are selected from the group consisting of: pigmentary degeneration, age-related retinal ganglion cell (RGC) degeneration, Best's disease, glaucoma, Graves' ophthalmopathy, multiple sclerosis (MS)-related 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 of drusen, and iRORA (incomplete RPE and outer retinal atrophy), iRORA, neogeographic atrophy (nGA), and cRORA (complete RPE and outer retinal atrophy).

[0064] Embodiment 18. The method of any one of embodiments 14-17, wherein the dose is administered once a month.

[0065] Embodiment 19. The method of any one of embodiments 14-18, wherein the dose is administered once a month for up to 12 months.

[0066] Embodiment 20. The drug substance according to any one of embodiments 8 to 10 or the pharmaceutical composition according to any one of embodiments 11 to 13 for use as a medicament.

[0067] Embodiment 21. The drug substance of any one of embodiments 8 to 10 or the pharmaceutical composition of any one of embodiments 11 to 13 for use in the treatment of an ophthalmic disease, disorder, and / or condition.

[0068] Embodiment 22. The ophthalmic disease, disorder, and / or condition is 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's 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 nerve anomaly, optic neuropathy, optic nerve anomaly, optic nerve dystrophy, optic nerve neuropathy ... 22. The drug substance or pharmaceutical composition of embodiment 21, wherein the drug substance or pharmaceutical composition is selected from the group consisting of a condition selected from the group consisting of: retinal atrophy, retinitis pigmentosa, age-related retinal ganglion cell (RGC) degeneration, Best's disease, 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 risk factors for progression to iRORA, iRORA, nGA, and cRORα.

[0069] The following examples are provided for illustrative purposes only and are not intended to limit the invention in any way. [Example] [Example]

[0024] Synthesis of abasincaptodapegol by conventional methods

[0070] The oligonucleotide 5′NH2-fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmGmAmGfUfUfUAfCfCfUmGf CmG-3T-3′ (SEQ ID NO: 1) was synthesized on an Expedite DNA synthesizer (ABI, Foster City, CA) according to the manufacturer's recommended procedure using standard commercially available 2′-OMe RNA and 2′-F RNA and TBDMS-protected RNA phosphoramidites (Glen Research, Sterling, VA) and reverse deoxythymidine CPG support. The terminal amine function was attached with the 5′-amino modifier C6-TFA (Glen Research, Sterling, VA). After deprotection, the oligonucleotide was purified by ion-exchange chromatography on Super Q 5 PW(30) resin (ToSoh BioSciences) and ethanol precipitated.

[0071] Amine-modified aptamers were conjugated to different PEG moieties post-synthesis. The aptamer was dissolved in a water / DMSO (1:1) solution to a concentration of 1.5–3 mM. Sodium carbonate buffer, pH 8.5, was added to a final concentration of 100 mM, and the oligo was reacted overnight with a 1.7 molar excess of the desired PEG reagent (e.g., SUNBRIGHT® GL2-400NP, SUNBRIGHT® GL2-400TS (NOF Corp, Japan), or ARC187 40 kDa mPEG2-NHS ester (Nektar, Huntsville, AL)) dissolved in an equal volume of acetonitrile. The resulting product was purified by ion-exchange chromatography on SuperQ5PW(30) resin (Tosoh Biosciences), desalted using reverse-phase chromatography performed on Amberchrom™ CG300-S resin (Rohm and Haas), and lyophilized. [Example]

[0025] Improved synthesis method for ultra-high purity avacincaptodapegol

[0072] An improved synthetic method for producing the ultra-high purity avasincaptodapegol of the present invention is described below.

[0073] The oligonucleotide 5′NH2-fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmGmAmGfUfUfUAfCfCfUmGf CmG-3T-3′ (SEQ ID NO: 1) was synthesized using commercially available 2′-OMe RNA and 2′-F RNA and TBDMS-protected RNA phosphoramidites (Thermo Scientific, Milwaukee, WI; Hongene Biotech, Shanghai, China; Sigma-Aldrich, Hamburg, Germany) and inverted deoxythymidine CPG support (Prime Synthesis, Aston, PA) according to the manufacturer's recommended procedure on an OligoPilot 400 (Cytiva Life Sciences, Marlborough, MA) or other similar synthesizer. The terminal amine function was attached with the 5′-amino modifier C6-TFA (Sigma-Aldrich, Hamburg, Germany). After cleavage and deprotection, the oligonucleotide (ARC672) was concentrated and desalted through a 5 kDa molecular weight (MW) cutoff Hydrosart membrane (Sartorius Stedim Biotech) or similar membrane from other manufacturers, followed by purification using ion exchange chromatography with TSK Gel SuperQ-5PW resin (ToSoh BioSciences). Prior to PEGylation, the purified pool of oligonucleotide (ARC672) was concentrated, desalted through a 5 kDa MW cutoff membrane, and further concentrated.

[0074] The amine-modified aptamer (ARC672) was conjugated to 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., Merck) for less than 1 hour. Sunbright® GL2-400TS was dissolved in DMSO. The resulting product, ARC1905, was purified by ion exchange chromatography using TSK Gel SuperQ-5PW resin (Tosoh Biosciences). Ultrafiltration of the purified pool of ARC1905 was desalted using a 10 kDa molecular weight cutoff membrane and then lyophilized.

[0026]

[0075] The improved synthesis method is described in further detail below. Step I: Synthesis and isolation of non-PEGylated ACP 1.Synthesis

[0076] The preparation of avasincaptodapegol began with the iterative synthesis of non-PEGylated avasincaptodapegol (non-PEGylated ACP) on a solid support. The oligonucleotide 5'NH2-fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmGmAmGfUfUfUAfCfCfUmGf CmG-3T-3' (SEQ ID NO: 1) was synthesized on an OligoProcess™ oligonucleotide synthesizer (Cytiva Life Sciences, Marlborough, MA) or an oligonucleotide synthesizer from a different supplier, using commercially available 2'-OMe RNA and 2'-F RNA and TBDMS-protected RNA phosphoramidites and an inverted deoxythymidine CPG support (LGC BioSearch Technologies, Novato, CA) according to the manufacturer's recommended procedure. The oligonucleotide synthesis process consisted of four chemical reactions performed in the following order: 1. Deblocking (detritylation) of protected nucleosides or nascent oligonucleotides 2. Activation and Coupling of the Incoming Phosphoramidite (Coupling) 3. Oxidation of the resulting phosphite triester P(III) to a P(V) phosphate bond (oxidation); and 4. Capping of failed coupling oligonucleotide strands (capping)

[0077] The above four steps were repeated in order until the desired oligonucleotide terminated with a hexylamino linker was synthesized. The terminal amine function was attached with the 5′-amino modifier C6-TFA (Sigma-Aldrich, Hamburg, Germany).

[0078] The use of 0.2 M amidite and 0.5 M activator during the synthesis process improved purity. After the synthesis was completed, the synthesis column was washed with diethylamine to remove the cyanoethyl protecting group, which also improved purity. 2. Cleavage and deprotection

[0079] Subsequent steps included cleavage of the unPEGylated ACP from the solid support, removal of the base protecting groups, and deprotection of the silyl-protected ribonucleoside. Ammonia and / or alkylamine bases were added to a heated deprotection tank and then recirculated through the synthesis column. The cleavage and deprotection reaction mixture was collected. Triethylamine trihydrofluoride (TEA-3HF) was added to the deprotection tank, and the mixture was heated to promote desilylation, and the pH was adjusted to 6-8.

[0080] Using the specified amounts of ammonia and alkylamine base, the deprotection reaction resulted in fewer non-PEGylatable and silylatable species, thus improving purity. Carrying out the desilylation reaction for a specified time increased the yield, thereby improving purity.

[0027] Step II: Purification of non-PEGylated ACP 1. Crude Ultrafiltration / Dialysis

[0081] After cleavage and deprotection, crude ultrafiltration / dialysis was performed to reduce the volume and remove the solvent. The crude mixture from the cleavage and deprotection steps was concentrated and diafiltered using a 5 kDa or 10 kDa nominal molecular weight cutoff (MWCO) ultrafiltration (UF) Hydrosart membrane (Sartorius Stedim Biotech) or similar membranes from other manufacturers. 2. Pre-PEGylated Anion Exchange Chromatography

[0082] Anion exchange (AX) chromatography was then performed to purify the non-PEGylated ACP prior to PEGylation. The crude retentate was loaded onto a chromatography column containing Tosoh Bioscience TSKgel® SuperQ-5PW chromatography resin or similar resins from other manufacturers. A sodium bromide salt gradient was used to purify the non-PEGylated ACP at temperatures above 45°C. 3. Ultrafiltration / Diafiltration (UF / DF2) before PEGylation

[0083] A pre-PEGylation UF / DF step was then performed to reduce the volume and remove the solvent. The purified non-PEGylated ACP solution was concentrated and desalted using 5 kDa or 10 kDa MWCO UF membranes or similar membranes from other manufacturers. 4. Concentration

[0084] The retentate from the previous step was further concentrated to reduce the volume prior to PEGylation using vacuum distillation (ie, rotary evaporator, concentrator) or thin film evaporator.

[0028] Step III. PEGylation

[0085] The crude drug avasincaptodapegol was formed by site-specific covalent bond formation between the primary amine on the 5' end of non-PEGylated ACP and the PEGylation reagent (mPEG2-NHS ester). The non-PEGylated ACP solution was diluted with sodium borate buffer and DMSO to a pH of 8.8-9.5. The required amount of the PEGylation reagent, mPEG2-NHS ester, based on a predetermined molar ratio to non-PEGylated ACP was dissolved in DMSO, and then the buffered non-PEGylated ACP solution was added to initiate PEGylation. Upon completion, PEGylation was quenched by adding water.

[0086] The mPEG2-NHS ester reaction efficiency was increased and the process time was shortened. Using 1.1 to 1.5 equivalents of mPEG2-NHS ester resulted in less residual free PEG to remove, and performing the PEGylation at temperatures above room temperature reduced heat exposure, thereby increasing yield and efficiency.

[0029] Step IV. Purification of Avacincaptodapegol 1. Anion exchange chromatography after PEGylation

[0087] Anion exchange (AX) chromatography was used to purify the crude drug substance after PEGylation. The crude drug substance from the PEGylation step was loaded onto a chromatography column containing Tosoh Bioscience TSKgel® SuperQ-5PW chromatography resin or similar resins from other manufacturers. A sodium bromide salt gradient was used to purify the drug substance at temperatures above 45°C. 2. Ultrafiltration / Diafiltration after PEGylation

[0088] A post-PEGylation UF / DF step was then performed to achieve volume reduction and buffer exchange. The purified avacincaptodapegol was concentrated and desalted using a 10 kDa nominal MWCO membrane or similar membranes from other manufacturers, which increased product retention.

[0030] Step V. Freeze-drying

[0089] The drug solution was filtered, lyophilized to reduce the water content, and the product was packaged. [Example]

[0031] Pharmaceuticals

[0090] ARC1905 was formulated as a preservative-free, sterile aqueous solution for intravitreal injection. It was formulated as a sterile aqueous solution at a concentration of 20 mg / mL (oligonucleotide mass) in phosphate-buffered saline at pH 6.8-7.8. The drug product was stable for 43 months at 2-8°C.

[0091] The osmolality of one batch of drug product is shown in Table 1 below. Table 1

[0032] [Table 1] [Example]

[0033] Comparison of purity profiles between conventional and ultra-high purity manufacturing methods

[0092] The differences in purity profiles of the ACP products produced by the prior art method and the improved method are set forth in Tables 2 and 3 below.

[0034] [Table 2] Table 3

[0035] [Table 3]

[0093] In some embodiments, the endotoxin content of the ultra-pure drug substance is less than 0.2 EU / dose. In one embodiment, the endotoxin content of the formulation is about 0.14 EU / dose, preferably about 0.05 EU / dose. [Example]

[0036] The efficacy of ultra-pure drug substances

[0094] The potency of the ultrapure intermediates and drug substance was measured by ELISA. The ELISA assay is based on the induction of the complement cascade by lipopolysaccharide (LPS) and quantification of C5b9 formation. The more potent the ACP drug substance, the lower the amount of C5b9 detected. Results are expressed as relative potency (%) compared to a standard ACP reference material.

[0095] Based on the ELISA results, it can be seen that the ultra-pure drug substance was at least 5% more potent than the product made according to the prior art synthesis. [Example]

[0037] Example 6: Comparison of the efficacy of conventional and ultra-pure manufacturing methods

[0096] The potency of the impurity fractions of the ACP products made by the prior art method and the improved method was measured by ELISA. The collection of impurity fractions is shown in Figure 1. A data comparison is shown in Table 4.

[0097] The results show that the pre- and post-FLP impurity fractions of the prior art method are more potent than those from the improved manufacturing method, demonstrating the higher purification resolution and efficiency of the improved method. Table 4

[0038] [Table 4]

Claims

1. Non-PEGylated aptamer 5'NH ２ -fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmGmAmGfUfUfUAfCfCfUmGf CmG-3T-3' (SEQ ID NO: 1), wherein: (a) greater than 85% of the unpegylated aptamers in the composition are full-length aptamers; (b) less than 1.8% G cleavage products; and (c) the amount of incomplete deprotection products is 1% or less; A composition comprising:

2. Additionally, the following: (d) less than 0.1% A cleavage products; (e) the sum of n-4, n-3, and n-2 deletion products is less than 1.1%; and (f) the sum of fluorodegradation products and n-1 deletion products is less than 3%; 10. The composition of claim 1.

3. The following structure: 【Chemistry 1】 A PEGylated aptamer comprising the composition according to claim 1 or 2, which is a compound represented by the formula:

4. The PEGylated aptamer of claim 3, comprising a two-arm branched PEG ranging from about 39 kDa to about 47 kDa.

5. The PEGylated aptamer of claim 3 , comprising a two-arm branched PEG of approximately 40 kDa.

6. The PEGylated aptamer of claim 3 , comprising a two-arm branched PEG of approximately 43 kDa.

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

8. 1. A drug substance comprising avacincaptodapegol, the drug substance being: (a) greater 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 is RRT2 (>FLP-≦1.2); The active pharmaceutical ingredient, including

9. 9. The drug substance of claim 8, comprising the sodium salt of avasincaptodapegol.

10. 10. The drug substance of claim 8 or 9, having a potency of greater than 95% as measured by ELISA.

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

12. 12. The pharmaceutical composition of claim 11, formulated as a sterile aqueous solution in phosphate buffered saline at a pH of 6.8 to 7.8 at a concentration of 20 mg / mL (by oligonucleotide mass).

13. The pharmaceutical composition according to claim 12, having an osmotic pressure of 350 to 500 mOsM / kg.

14. 10. A method for treating an ophthalmic disease, disorder and / or condition, comprising intravitreally administering to a subject in need thereof the pharmaceutical composition of any one of claims 6 to 8 at a dose of 3 to 5 mg / eye.

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

16. 16. The method of claim 15, wherein 100 μL is injected per eye.

17. The ophthalmologic disease, disorder, and / or condition may be 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 retinopathy (XLRS), Bardet-Biedl syndrome, cone dystrophy, optic atrophy, retinal pigmentary degeneration 17. The method of any one of claims 14 to 16, wherein the risk factors for progression to iRORA (incomplete RPE and outer retinal atrophy), iRORA, neogeographic atrophy (nGA), and cRORA (complete RPE and outer retinal atrophy) are selected from the group consisting of: myopia, X-linked recessive ocular albinism, age-related retinal ganglion cell (RGC) degeneration, Best's disease, glaucoma, Graves' ophthalmopathy, multiple sclerosis (MS)-related 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 of drusen, and iRORA (incomplete RPE and outer retinal atrophy), iRORA, neogeographic atrophy (nGA), and cRORA (complete RPE and outer retinal atrophy).

18. 18. The method of any one of claims 14 to 17, wherein the dose is administered once a month.

19. 19. The method of any one of claims 14 to 18, wherein the dose is administered once a month for up to 12 months.

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

21. A drug substance according to any one of claims 8 to 10 or a pharmaceutical composition according to any one of claims 11 to 13 for use in the treatment of an ophthalmic disease, disorder and / or condition.

22. The ophthalmologic disease, disorder, and / or condition is 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 retinopathy (XLRS), Bardet-Biedl syndrome 22. The drug substance or pharmaceutical composition of claim 21, wherein the drug substance or pharmaceutical composition is selected from the group consisting of: iRORA, cone dystrophy, optic atrophy, retinitis pigmentosa, age-related retinal ganglion cell (RGC) degeneration, Best's disease, glaucoma, Graves' ophthalmopathy, multiple sclerosis (MS)-related 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 of drusen, and risk factors for progression to iRORA, nGA, and cRORA.

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