CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to United States Provisional Patent Application serial number 63/344,687, filed May 23, 2022, the contents of which are hereby incorporated by reference in their entirety.

FIELD OF THE INVENTION

[0002] The invention provides methods, compositions, and kits containing an integrin inhibitor, such as a fluoroalkoxyheteroaryl-dihydronaphthyridine, for treating diabetic retinopathy.

BACKGROUND

[0003] Diabetic retinopathy is a disease generally characterized by damage to the retina in a patient suffering from diabetes mellitus. The likelihood of a patient suffering from diabetic retinopathy typically increases the longer a person has diabetes, such that the majority of patients who have had diabetes for more than 20 years also suffer from diabetic retinopathy. In developed countries, diabetic retinopathy is a leading cause of blindness, particularly among young and middle-aged adults.

[0004] Existing drug therapies for diabetic retinopathy are not effective for all patients and/or have undesirable side effects. For example, panretinal photocoagulations and anti-VEGF agents have been prescribed for patients suffering from moderately severe and severe nonproliferative diabetic retinopathy and proliferative diabetic retinopathy. Panretinal photocoagulations can be destructive and cause permanent peripheral vision loss that may interfere with driving, and impairment of night vision, color vision, and contrast sensitivity.

Panretinal photocoagulations may also exacerbate diabetic macular edema. Anti-VEGF therapies are approved for diabetic retinopathy, regardless of severity, but they can require monthly intravitreal injections (with the continuous risk of serious side effects such as endophthalmitis or retinal detachment) and the inconvenience of traveling to a retina specialist’ s office for every injection. As a result, the need exists for improved therapies for treating diabetic retinopathy. [0005] The present invention addresses the aforementioned need for methods and compositions for treating patients suffering from diabetic retinopathy.

SUMMARY

[0006] The invention provides methods, compositions, and kits containing an integrin inhibitor, such as a fluoroalkoxyheteroaryl-dihydronaphthyridine, for treating diabetic retinopathy. Exemplary aspects and embodiments of the invention are described below.

[0007] One aspect of the invention provides a method of treating diabetic retinopathy in a human patient, wherein the method comprises topically administering to an eye of the human patient in need thereof an ophthalmic formulation comprising a compound of Formula T in an amount of from about 4% w/w to about 6% w/w, to thereby treat the diabetic retinopathy, wherein the ophthalmic formulation is topically administered to an eye of the human patient two, three, or four times per day, which results in delivering from about 4 mg to about 12 mg compound of Formula I per day to the eye of the human patient, and Formula I is represented by pharmaceutically acceptable salt thereof. The method may be further characterized by additional features, such as the disorder being treated, the patient to be treated, dosing parameters, and general considerations described herein.

[0008] Another aspect of the invention provides a method of reducing central retinal thickness in a human patient suffering from diabetic retinopathy, wherein the method comprises topically administering to an eye of the human patient in need thereof an ophthalmic formulation comprising a compound of Formula I in an amount of from about 4% w/w to about 6% w/w, to thereby reduce central retinal thickness, wherein the ophthalmic formulation is topically administered to an eye of the human patient two, three, or four times per day, which results in delivering from about 4 mg to about 12 mg compound of Formula I per day to the eye of the human patient, and Formula I is represented pharmaceutically acceptable salt thereof. The method may be further characterized by additional features, such as the patient to be treated, dosing parameters, and general considerations described herein.

DETAILED DESCRIPTION OF THE INVENTION

[0009] The invention provides methods, compositions, and kits containing an integrin inhibitor, such as a fluoroalkoxyheteroaryl-dihydronaphthyridine, for treating diabetic retinopathy. Various aspects of the invention are set forth below in sections; however, aspects of the invention described in one particular section are not to be limited to any particular section.

Definitions

[0006] The terms used herein have their ordinary meaning and the meaning of such terms is independent at each occurrence thereof. That notwithstanding and except where stated otherwise, the following definitions apply throughout the specification and claims. Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. If a chemical compound is referred to using both a chemical structure and a chemical name, and an ambiguity exists between the structure and the name, the structure predominates. These definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise indicated. Hence, the definition of “alkyl” applies to “alkyl” as well as the “alkyl” portions of “-O-alkyl” etc.

[0010] The terms “a,” “an” and “the” as used herein mean “one or more” and include the plural unless the context is inappropriate.

[0011] As used herein, the term “patient” refers to organisms to be treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and most preferably includes humans. [0012] As used herein, the term “effective amount” refers to the amount of a compound sufficient to effect beneficial or desired results. Unless specified otherwise, an effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route. As used herein, the term “treating” includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.

[0013] As used herein, the term “pharmaceutical composition” refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for therapeutic use in vivo or ex vivo.

[0014] As used herein, the term “pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions (e.g., such as an oil/water or water/oil emulsions), and various types of wetting agents. The compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers and adjuvants, see Martin in Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA [1975],

[0015] As used herein, the term “pharmaceutically acceptable salt” refers to any pharmaceutically acceptable salt (e.g., acid or base) of a compound of the present invention which, upon administration to a subject, is capable of providing a compound of this invention.

As is known to those of skill in the art, “salts” of the compounds of the present invention may be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p- sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic acid, and the like. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.

[0016] Examples of bases include, but are not limited to, alkali metals (e.g., sodium) hydroxides, alkaline earth metals (e.g., magnesium), hydroxides, ammonia, and compounds of formula NW3, wherein W is C1-4 alkyl, and the like. [0017] Examples of salts include, but are not limited to: acetate, adipate, alginate, aspartate, benzoate, bcnzcncsulfonatc, bisulfatc, butyrate, citrate, camphorate, camphorsulfonatc, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate (mesylate), 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, sulfate, tartrate, thiocyanate, tosylate, undecanoate, and the like. Other examples of salts include anions of the compounds of the present invention compounded with a suitable cation such as Na ⁺ , NH4 ⁺ , and NW (wherein W is a Ci-4 alkyl group), and the like.

[0018] For therapeutic use, salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable. However, salts of acids and bases that are non- pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0007] The term “alkyl” refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1-12, 1-10, or 1-6 carbon atoms, referred to herein as C1-C12 alkyl, Ci-C 10 alkyl, and Ci-Ce alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2-propyl, 2-methyl-l -butyl, 3- methyl-1 -butyl, 2-methyl-3-butyl, 2,2-dimethyl-l -propyl, 2-methyl-l -pentyl, 3-methyl-l -pentyl, 4-methyl-l -pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l- butyl, 3,3-dimethyl-l-butyl, 2-ethyl-l -butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc.

[0008] When any substituent or variable occurs more than one time in any constituent or the compound of the invention, its definition on each occurrence is independent of its definition at every other occurrence, unless otherwise indicated.

[0009] It should be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.

[00010] One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. “Hydrate” is a solvate wherein the solvent molecule is H2O.

[00011] Certain compounds contained in compositions of the present invention may exist in particular geometric or stereoisomeric forms. Further, certain compounds described herein may be optically active. The present invention contemplates all such compounds, including cis- and trans-isomers, 7?- and 5-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. The compounds may contain one or more stereogenic centers. For example, asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention, such as, for example, racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and it is intended that all of the possible optical isomers, diastereomers in mixtures, and pure or partially purified compounds are included within the ambit of this invention.

[00012] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Alternatively, a particular enantiomer of a compound of the present invention may be prepared by asymmetric synthesis. Still further, where the molecule contains a basic functional group (such as amino) or an acidic functional group (such as carboxylic acid) diastereomeric salts are formed with an appropriate optically- active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means known in the art, and subsequent recovery of the pure enantiomers.

[00013] Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. Chiral center(s) in a compound of the present invention can have the .S' or R configuration as defined by the IUPAC 1974 Recommendations. Further, to the extent a compound described herein may exist as a atropisomer (e.g., substituted biaryls), all forms of such atropisomer are considered part of this invention.

[00014] In addition, when a compound of the invention contains both a basic moiety (such as, but not limited to, a pyridine or imidazole) and an acidic moiety (such as, but not limited to, a carboxylic acid) zwitterions (“inner salts”) may be formed. Such acidic and basic salts used within the scope of the invention are pharmaceutically acceptable (/.<?.. non-toxic, physiologically acceptable) salts. Such salts of the compounds of the invention may be formed, for example, by reacting a compound of the invention with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

[00015] The present invention includes the compounds of the invention in all their isolated forms (such as any solvates, hydrates, stereoisomers, and tautomers thereof). Further, the invention includes compounds in which one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of the invention. For example, different isotopic forms of hydrogen (H) include protium ( ¹ H) and deuterium ( ² H). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. Deuterium labeled compounds may be characterized according to the term “deuterium enrichment factor”, which means the ratio between the deuterium abundance and the natural abundance of a deuterium. In one aspect, the deuterium label compound has a deuterium enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium incorporation at each deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Isotopically-enriched compounds can be prepared without undue experimentation by conventional techniques known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.

[0019] Throughout the description, where compositions and kits are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions and kits of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.

[0020] As a general matter, compositions specifying a percentage are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls.

I. Therapeutic Methods

[0021] The invention provides methods using an integrin inhibitor, such as a fhioroalkoxyheteroaryl-dihydronaphthyridine, for treating diabetic retinopathy. Various aspects and embodiments of the therapeutic methods are described in the sections below. The sections are arranged for convenience and information in one section is not to be limited to that section, but may be applied to methods in other sections.

A. First Method

[0022] One aspect of the invention provides a method of treating diabetic retinopathy in a human patient, wherein the method comprises topically administering to an eye of the human patient in need thereof an ophthalmic formulation comprising a compound of Formula I in an amount of from about 4% w/w to about 6% w/w, to thereby treat the diabetic retinopathy, wherein the ophthalmic formulation is topically administered to an eye of the human patient two, three, or four times per day, which results in delivering from about 4 mg to about 12 mg compound of Formula I per day to the eye of the human patient, and Formula I is represented by pharmaceutically acceptable salt thereof.

[0023] The method may be further characterized by additional features described below, such as the disorder being treated, the patient to be treated, dosing parameters, and other general considerations. The invention embraces all permutations and combinations of these features.

B. Second Method

[0024] Another aspect of the invention provides a method of treating diabetic retinopathy in a human patient, wherein the method comprises administering to an eye of the human patient in need thereof a therapeutically effective amount of a compound of Formula I, to thereby treat the diabetic retinopathy, wherein Formula I is represented or a pharmaceutically acceptable salt thereof.

[0025] The method may be further characterized by additional features, such as the route of administration of the compound of Formula I to the eye of the patient, the formulation of the compound of Formula I, and the identity of the compound of Formula I. For example, in certain embodiments, the administering comprises topically administering to an eye of the human patient in need thereof a therapeutically effective amount of a compound of Formula I. In certain embodiments, the compound of Formula I is formulated as an ophthalmic formulation. In certain embodiments, Formula I is represented pharmaceutically acceptable salt thereof. In certain embodiments, the administering delivers said compound of Formula I to the eye of the human patient in an amount of from about 0.0071 mmol to about 0.021 mmol per day. In certain embodiments, the administering delivers said compound of Formula I to the eye of the human patient in an amount of from about 0.0089 mmol to about 0.018 mmol per day. In certain embodiments, the administering delivers said compound of Formula I to the eye of the human patient in an amount of about 0.0089 mmol per day. In certain embodiments, the administering delivers said compound of Formula I to the eye of the human patient in an amount of 0.0089 mmol per day. In certain embodiments, the administering delivers said compound of Formula I to the eye of the human patient in an amount of about 0.018 mmol per day. In certain embodiments, the administering delivers said compound of Formula I to the eye of the human patient in an amount of 0.018 mmol per day. In certain embodiments, the ophthalmic formulation comprises a compound of Formula I in an amount of from about 80 mmol per liter to about 100 mmol per liter. In certain embodiments, the ophthalmic formulation comprises a compound of Formula I in an amount of from about 84 mmol per liter to about 94 mmol per liter. In certain embodiments, the ophthalmic formulation comprises a compound of Formula I in an amount of from about 87 mmol per liter to about 91 mmol per liter. In certain embodiments, the ophthalmic formulation comprises a compound of Formula I in an amount of about 89 mmol per liter.

[0026] The method may be further characterized by additional features described below, such as the disorder being treated, the patient to be treated, dosing parameters, and other general considerations. The invention embraces all permutations and combinations of these features.

C. Third Method

[0027] Another aspect of the invention provides a method of reducing central retinal thickness in a human patient suffering from diabetic retinopathy, wherein the method comprises topically administering to an eye of the human patient in need thereof an ophthalmic formulation comprising a compound of Formula I in an amount of from about 4% w/w to about 6% w/w, to thereby reduce central retinal thickness, wherein the ophthalmic formulation is topically administered to an eye of the human patient two, three, or four times per day, which results in delivering from about 4 mg to about 12 mg compound of Formula I per day to the eye of the human patient, and Formula I is represented pharmaceutically acceptable salt thereof.

[0028] The method may be further characterized by additional features described below, such as the disorder being treated, the patient to be treated, dosing parameters, and other general considerations. The invention embraces all permutations and combinations of these features.

D. Fourth Method

[0029] Another aspect of the invention provides a method of reducing central retinal thickness in a human patient suffering from diabetic retinopathy, wherein the method comprises administering to an eye of the human patient in need thereof a therapeutically effective amount of a compound of Formula I, to thereby reduce central retinal thickness, wherein Formula I is represented pharmaceutically acceptable salt thereof.

The method may be further characterized by additional features, such as the route of administration of the compound of Formula I to the eye of the patient, the formulation of the compound of Formula I, and the identity of the compound of Formula I. For example, in certain embodiments, the administering comprising topically administering to an eye of the human patient in need thereof a therapeutically effective amount of a compound of Formula I. In certain embodiments, the compound of Formula I is formulated as an ophthalmic formulation. In certain embodiments, Formula I is represented pharmaceutically acceptable salt thereof. In certain embodiments, the administering delivers said compound of Formula I to the eye of the human patient in an amount of from about 0.0071 mmol to about 0.021 mmol per day. In certain embodiments, the administering delivers said compound of Formula I to the eye of the human patient in an amount of from about 0.0089 mmol to about 0.018 mmol per day. In certain embodiments, the administering delivers said compound of Formula I to the eye of the human patient in an amount of about 0.0089 mmol per day. In certain embodiments, the administering delivers said compound of Formula I to the eye of the human patient in an amount of 0.0089 mmol per day. In certain embodiments, the administering delivers said compound of Formula I to the eye of the human patient in an amount of about 0.018 mmol per day. In certain embodiments, the administering delivers said compound of Formula I to the eye of the human patient in an amount of 0.018 mmol per day. In certain embodiments, the ophthalmic formulation comprises a compound of Formula I in an amount of from about 80 mmol per liter to about 100 mmol per liter. In certain embodiments, the ophthalmic formulation comprises a compound of Formula I in an amount of from about 84 mmol per liter to about 94 mmol per liter. In certain embodiments, the ophthalmic formulation comprises a compound of Formula I in an amount of from about 84 mmol per liter to about 94 mmol per liter. In certain embodiments, the ophthalmic formulation comprises a compound of Formula I in an amount of from about 87 mmol per liter to about 91 mmol per liter. In certain embodiments, the ophthalmic formulation comprises a compound of Formula I in an amount of about 89 mmol per liter.

[0030] The method may be further characterized by additional features described below, such as the disorder being treated, the patient to be treated, dosing parameters, and other general considerations. The invention embraces all permutations and combinations of these features. E. General Considerations for Therapeutic Methods

[0031] General considerations that may be applied to therapeutic methods described herein (e.g., the methods described in Parts A-D above) are provided below and include, for example, the condition being treated, and patient populations that may derive particular benefits from the therapeutic methods. A more thorough description of such features is provided below. The invention embraces all permutations and combinations of these features.

[0032] The methods may be further characterized according to the disorder being treated. For example, in certain embodiments, the diabetic retinopathy is mild diabetic retinopathy. In certain embodiments, the diabetic retinopathy is mild diabetic retinopathy. In certain embodiments, the diabetic retinopathy is moderate diabetic retinopathy. In certain embodiments, the diabetic retinopathy is moderately severe to severe diabetic retinopathy. In certain embodiments, the diabetic retinopathy is severe diabetic retinopathy. In certain embodiments, the diabetic retinopathy is non-proliferative. In certain embodiments, the diabetic retinopathy is proliferative.

[0033] The methods may be further characterized according to the identity of the compound of Formula I. For example, in certain embodiments, the compound of Formula I is a pharmaceutically acceptable salt certain embodiments, the compound of Formula I is . In certain embodiments, Formula I is , salt or a potassium salt).

[0034] The methods may be further characterized according to the amount of the compound of Formula I delivered per day to the eye of the human patient. For example, in certain embodiments, the administering delivers said compound of Formula I to the eye of the human patient in an amount ranging from about 5 mg to about 10 mg per day. Tn certain embodiments, the administering delivers said compound of Formula I to the eye of the human patient in an amount ranging from about 4 mg to about 6 mg per day. In certain embodiments, the administering delivers said compound of Formula I to the eye of the human patient in an amount of about 5 mg per day. In certain embodiments, the administering delivers said compound of Formula I to the eye of the human patient in an amount of 5 mg per day. In certain embodiments, the administering delivers said compound of Formula I to the eye of the human patient in an amount ranging from about 9 mg to about 11 mg per day. In certain embodiments, the administering delivers said compound of Formula I to the eye of the human patient in an amount of about 10 mg per day. In certain embodiments, the administering delivers said compound of Formula I to the eye of the human patient in an amount of 10 mg per day.

[0035] In certain embodiments, the administering delivers said compound of Formula I to the eye of the human patient in an amount ranging from about 4 mg to about 5 mg per day. In certain embodiments, the administering delivers said compound of Formula I to the eye of the human patient in an amount ranging from 4.0 mg to 4.5 mg per day. In certain embodiments, the administering delivers said compound of Formula I to the eye of the human patient in an amount of about 4.2 mg per day. Tn certain embodiments, the administering delivers said compound of Formula I to the eye of the human patient in an amount of 4.2 mg per day. In certain embodiments, the administering delivers said compound of Formula I to the eye of the human patient in an amount of about 4.4 mg per day. In certain embodiments, the administering delivers said compound of Formula I to the eye of the human patient in an amount of 4.4 mg per day.

[0036] In certain embodiments, the administering delivers said compound of Formula 1 to the eye of the human patient in an amount ranging from about 8 mg to about 10 mg per day. In certain embodiments, the administering delivers said compound of Formula I to the eye of the human patient in an amount ranging from 8 mg to 9 mg per day. In certain embodiments, the administering delivers said compound of Formula I to the eye of the human patient in an amount of about 8.4 mg per day. In certain embodiments, the administering delivers said compound of Formula I to the eye of the human patient in an amount of 8.4 mg per day. In certain embodiments, the administering delivers said compound of Formula I to the eye of the human patient in an amount of about 8.8 mg per day. In certain embodiments, the administering delivers said compound of Formula I to the eye of the human patient in an amount of 8.8 mg per day.

[0037] The methods may be further characterized according to the frequency with which the ophthalmic formulation is administered to the eye of the human patient. For example, in certain embodiments, the ophthalmic formulation is topically administered to an eye of the human patient two times per day. In certain embodiments, the ophthalmic formulation is topically administered to an eye of the human patient three times per day. In certain embodiments, the ophthalmic formulation is topically administered to an eye of the human patient four times per day.

[0038] The methods may be further characterized according to characteristics of the ophthalmic formulation, such as the concentration of the compound of Formula I, diluents in the ophthalmic formulation, and the form of a unit dosage. For example, in certain embodiments, the ophthalmic formulation comprises a compound of Formula I in an amount of from 4% w/w to 6% w/w. In certain embodiments, the ophthalmic formulation comprises a compound of Formula I in an amount of about 5% w/w. In certain embodiments, the ophthalmic formulation comprises a compound of Formula I in an amount of 5% w/w. Tn certain embodiments, the ophthalmic formulation is an aqueous ophthalmic solution.

[0039] In certain embodiments, the ophthalmic formulation comprises a compound of Formula I in an amount of from about 4% w/w to about 5% w/w. In certain embodiments, the ophthalmic formulation comprises a compound of Formula I in an amount of from 4.0% w/w to 4.5% w/w. In certain embodiments, the ophthalmic formulation comprises a compound of Formula 1 in an amount of about 4.2% w/w. In certain embodiments, the ophthalmic formulation comprises a compound of Formula I in an amount of 4.2% w/w. In certain embodiments, the ophthalmic formulation comprises a compound of Formula I in an amount of about 4.4% w/w. In certain embodiments, the ophthalmic formulation comprises a compound of Formula I in an amount of 4.4% w/w.

[0040] In certain embodiments, the ophthalmic formulation is topically administered to the eye of the human patient in the form of an eye drop. In certain embodiments, the eye drop has a volume of about 50 pL.

[0041] The methods may be further characterized according to the duration of dosing the ophthalmic formulation. For example, in certain embodiments, the ophthalmic formulation is topically administered to an eye of the human patient in need thereof for a duration of at least 7 consecutive days. In certain embodiments, the ophthalmic formulation is topically administered to an eye of the human patient in need thereof for a duration of at least 14 consecutive days. In certain embodiments, the ophthalmic formulation is topically administered to an eye of the human patient in need thereof for a duration of at least 28 consecutive days. In certain embodiments, the ophthalmic formulation is topically administered to an eye of the human patient in need thereof for a duration of at least 56 consecutive days. In certain embodiments, the ophthalmic formulation is topically administered to an eye of the human patient in need thereof for a duration of at least 84 consecutive days. In certain embodiments, the ophthalmic formulation is topically administered to an eye of the human patient in need thereof for a duration of at least 168 consecutive days. In certain embodiments, the ophthalmic formulation is topically administered to an eye of the human patient in need thereof daily.

[0042] In certain embodiments, the ophthalmic formulation is topically administered to an eye of the human patient in need thereof for a duration of 7 consecutive days. In certain embodiments, the ophthalmic formulation is topically administered to an eye of the human patient in need thereof for a duration of 14 consecutive days. In certain embodiments, the ophthalmic formulation is topically administered to an eye of the human patient in need thereof for a duration of 28 consecutive days. In certain embodiments, the ophthalmic formulation is topically administered to an eye of the human patient in need thereof for a duration of 56 consecutive days. In certain embodiments, the ophthalmic formulation is topically administered to an eye of the human patient in need thereof for a duration of 84 consecutive days. In certain embodiments, the ophthalmic formulation is topically administered to an eye of the human patient in need thereof for a duration of 168 consecutive days.

[0043] Tn certain embodiments, the method prevents the progression of diabetic retinopathy. In certain embodiments, the method prevents or delays any increase in DRSS score in the patient. In certain embodiments, the method prevents or delays a step increase (e.g., 1 step, 2 step, 3 step, 4 step, or greater step increase) in DRSS score in the patient. In certain embodiments, the method prevents or delays any 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% increase in DRSS score in the patient.

[0044] The methods may be further characterized according to a reduction in the patient’s Diabetic Retinopathy Severity Score (DRSS) produced by the method. In certain embodiments, the method achieves at least a 1-step reduction in the patient’s Diabetic Retinopathy Severity Score. In certain embodiments, the method achieves at least a 2-step reduction in the patient’s Diabetic Retinopathy Severity Score. In certain embodiments, the method achieves at least a 3- step reduction in the patient’s Diabetic Retinopathy Severity Score. In certain embodiments, the method achieves at least a 4-step reduction in the patient’s Diabetic Retinopathy Severity Score. In certain embodiments, the method achieves a reduction in the patient’s Diabetic Retinopathy Severity Score ranging from 1 to 4 steps. In certain embodiments, the method achieves a reduction in the patient’s Diabetic Retinopathy Severity Score ranging from 1 to 3 steps. In certain embodiments, the method achieves a reduction in the patient’s Diabetic Retinopathy Severity Score ranging from 1 to 2 steps. In certain embodiments, the method achieves a reduction in the patient’s Diabetic Retinopathy Severity Score ranging from 2 to 4 steps. In certain embodiments, the method achieves a reduction in the patient’s Diabetic Retinopathy Severity Score ranging from 3 to 4 steps. In certain embodiments, the method achieves a reduction in the patient’s Diabetic Retinopathy Severity Score ranging from 2 to 3 steps. [0045] Tn certain embodiments, the method is characterized by reducing the patient’s Diabetic Retinopathy Severity Score so that the patient’s Diabetic Retinopathy Severity Score is no greater than 47 on the Diabetic Retinopathy Severity Scale of 10-90. In certain embodiments, the method is characterized by reducing the patient’s Diabetic Retinopathy Severity Score so that the patient’s Diabetic Retinopathy Severity Score is no greater than 43 on the Diabetic Retinopathy Severity Scale of 10-90. In certain embodiments, the method is characterized by reducing the patient’s Diabetic Retinopathy Severity Score so that the patient’s Diabetic Retinopathy Severity Score is no greater than 35 on the Diabetic Retinopathy Severity Scale of 10-90. In certain embodiments, the method is characterized by reducing the patient’s Diabetic Retinopathy Severity Score so that the patient’s Diabetic Retinopathy Severity Score is no greater than 20 on the Diabetic Retinopathy Severity Scale of 10-90. In certain embodiments, the method is characterized by reducing the patient’s Diabetic Retinopathy Severity Score so that the patient’s Diabetic Retinopathy Severity Score is no greater than 65, 61, or 53 on the Diabetic Retinopathy Severity Scale of 10-90.

[0046] For example, in certain embodiments, the method is characterized by reducing the patient’s Diabetic Retinopathy Severity Score by at least 10 on the Diabetic Retinopathy Severity Scale of 10-90. In certain embodiments, the method is characterized by reducing the patient’s Diabetic Retinopathy Severity Score by at least 15 on the Diabetic Retinopathy Severity Scale of 10-90. In certain embodiments, the method is characterized by reducing the patient’s Diabetic Retinopathy Severity Score by at least 20 on the Diabetic Retinopathy Severity Scale of 10-90. In certain embodiments, the method is characterized by reducing the patient’s Diabetic Retinopathy Severity Score by at least 25 on the Diabetic Retinopathy Severity Scale of 10-90. In certain embodiments, the method is characterized by reducing the patient’s Diabetic Retinopathy Severity Score by at least 30 on the Diabetic Retinopathy Severity Scale of 10-90.

[0047] In certain embodiments, the method is characterized by reducing the patient’s Diabetic Retinopathy Severity Score by at least 10% on the Diabetic Retinopathy Severity Scale of 10-90. In certain embodiments, the method is characterized by reducing the patient’s Diabetic Retinopathy Severity Score by at least 20% on the Diabetic Retinopathy Severity Scale of 10-90. In certain embodiments, the method is characterized by reducing the patient’s Diabetic Retinopathy Severity Score by at least 30% on the Diabetic Retinopathy Severity Scale of 10-90. In certain embodiments, the method is characterized by reducing the patient’s Diabetic Retinopathy Severity Score by at least 40% on the Diabetic Retinopathy Severity Scale of 10-90. In certain embodiments, the method is characterized by reducing the patient’s Diabetic Retinopathy Severity Score by at least 50% on the Diabetic Retinopathy Severity Scale of 10-90.

[0048] The methods may be further characterized according to an improvement in Best Corrected Visual Acuity in the patient’s vision produced by the method. For example, in certain embodiments, the method results in an improvement in Best Corrected Visual Acuity by at least one line in the patient’s vision measured using a Snellen vision chart. In certain embodiments, the method results in an improvement in Best Corrected Visual Acuity by at least two lines in the patient’s vision measured using a Snellen vision chart. In certain embodiments, the method results in an improvement in Best Corrected Visual Acuity by at least three lines in the patient’s vision measured using a Snellen vision chart. In certain embodiments, the method results in an improvement in Best Corrected Visual Acuity by at least four lines in the patient’s vision measured using a Snellen vision chart.

[0049] The methods may be further characterized according to a reduction in the thickness of the patient’s retina achieved by the method. For example, in certain embodiments, the method is characterized by reducing the patient’s retina thickness by at least 10%. In certain embodiments, the method is characterized by reducing the patient’s retina thickness by at least 20%. In certain embodiments, the method is characterized by reducing the patient’s retina thickness by at least 30%. In certain embodiments, the method is characterized by reducing the patient’s retina thickness by at least 40%. In certain embodiments, the method is characterized by reducing the patient’s retina thickness by at least 50%.

[0050] The methods may be further characterized according to a reduction in the patient’s central retina thickness produced by the method. For example, in certain embodiments, the method is characterized by reducing the patient’s central retina thickness by at least 10%. In certain embodiments, the method is characterized by reducing the patient’s central retina thickness by at least 20%. In certain embodiments, the method is characterized by reducing the patient’s central retina thickness by at least 30%. In certain embodiments, the method is characterized by reducing the patient’s central retina thickness by at least 40%. In certain embodiments, the method is characterized by reducing the patient’s central retina thickness by at least 50%. [0051] The methods may be further characterized according to a reduction in the patient’s non-ccntral retina thickness produced by the method. For example, in certain embodiments, the method is characterized by reducing the patient’s non-central retina thickness by at least 10%. In certain embodiments, the method is characterized by reducing the patient’s non-central retina thickness by at least 20%. In certain embodiments, the method is characterized by reducing the patient’s non-central retina thickness by at least 30%. In certain embodiments, the method is characterized by reducing the patient’s non-central retina thickness by at least 40%. In certain embodiments, the method is characterized by reducing the patient’s non-central retina thickness by at least 50%.

[0052] The methods may be further characterized according to a delay produced by the method in the development of a vision-threatening complication. For example, in certain embodiments, the method is characterized by delaying by at least 2 months the development of a vision-threatening complication. In certain embodiments, the method is characterized by delaying by at least 4 months the development of a vision-threatening complication. In certain embodiments, the method is characterized by delaying by at least 6 months the development of a vision-threatening complication. In certain embodiments, the vision-threatening complication is a neovascular vision-threatening complication. In certain embodiments, the vision-threatening complication is diabetic macular edema. In certain embodiments, the vision-threatening complication is center-involved diabetic macular edema. In certain embodiments, the visionthreatening complication is proliferative diabetic retinopathy having a severity greater than mild.

[0053] The methods may be further characterized according to additional conditions suffered by the patient. For example, in certain embodiments, the patient has Type 1 diabetes. In certain embodiments, the patient has Type 2 diabetes. In certain embodiments, the patient does not have visually significant diabetic macular edema.

[0054] In certain embodiments, the method prevents the development of diabetic macular edema.

Exemplary More Specific Embodiments [0055] The methods may be further characterized by reference to more specific embodiments. For example, in certain embodiments, Formula I is represented by one or more of the following apply:

• the administering delivers said compound of Formula I to the eye of the human patient in an amount ranging from about 4 mg to about 5 mg per day; the administering delivers said compound of Formula 1 to the eye of the human patient in an amount ranging from 4.0 mg to 4.5 mg per day;

• the administering delivers said compound of Formula I to the eye of the human patient in an amount of about 4.2 mg; or

• the administering delivers said compound of Formula I to the eye of the human patient in an amount of 4.2 mg.

[0056] In relation to the immediately preceding embodiment, in certain embodiments, the administering delivers said compound of Formula I to the eye of the human patient in an amount ranging from about 4 mg to about 5 mg per day. In certain embodiments, the administering delivers said compound of Formula I to the eye of the human patient in an amount ranging from 4.0 mg to 4.5 mg per day. In certain embodiments, the administering delivers said compound of Formula I to the eye of the human patient in an amount of about 4.2 mg. In certain embodiments, the administering delivers said compound of Formula I to the eye of the human patient in an amount of 4.2 mg.

[0057] Tn certain embodiments, Formula I is represented by one or more of the following apply:

• the administering delivers said compound of Formula I to the eye of the human patient in an amount ranging from about 8 mg to about 10 mg per day;

• the administering delivers said compound of Formula I to the eye of the human patient in an amount ranging from 8 mg to 9 mg per day; the administering delivers said compound of Formula I to the eye of the human patient in an amount of about 8.4 mg; or

• the administering delivers said compound of Formula I to the eye of the human patient in an amount of 8.4 mg.

[0058] In relation to the immediately preceding embodiment, in certain embodiments, the administering delivers said compound of Formula I to the eye of the human patient in an amount ranging from about 8 mg to about 10 mg per day. In certain embodiments, the administering delivers said compound of Formula I to the eye of the human patient in an amount ranging from 8 mg to 9 mg per day. In certain embodiments, the administering delivers said compound of Formula I to the eye of the human patient in an amount of about 8.4 mg. In certain embodiments, the administering delivers said compound of Formula I to the eye of the human patient in an amount of 8.4 mg.

[0059] In certain embodiments, the ophthalmic formulation comprises a compound of Formula I in an amount of from about 4% w/w to about 5% w/w. In certain embodiments, the ophthalmic formulation comprises a compound of Formula I in an amount of from 4.0% w/w to 4.5% w/w. In certain embodiments, the ophthalmic formulation comprises a compound of Formula I in an amount of about 4.2% w/w. In certain embodiments, the ophthalmic formulation comprises a compound of Formula I in an amount of 4.2% w/w. III. Pharmaceutical Compositions

[0060] A pharmaceutical composition of the present application is desirably formulated to be compatible with the intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. In certain embodiments, the invention provides a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula I) and a pharmaceutically acceptable carrier.

[0061] The compounds of the present application can be formulated for oral administration in forms such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. The compounds of the present application can also be formulated for intravenous (bolus or infusion), intraperitoneal, topical (e.g., ocular eye-drop), subcutaneous, intramuscular or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts.

[0062] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

[0063] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0064] Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0065] For administration by inhalation, the compound is delivered in the form of an aerosol spray from pressured container or dispenser, which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

[0066] Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compound is formulated into ointments, salves, gels, or creams as generally known in the art.

[0067] The compounds of the present application can be formulated for topical administration, such as solution, suspension, gel, oil, spray, drops, patches, cream, ointment, and lotion. The topic formulation of the present application may be in the form of an aqueous solution comprising an aqueous vehicle. The aqueous vehicle component of the ophthalmic formulation may comprise water and at least one pharmaceutically acceptable excipient.

Suitable pharmaceutically acceptable excipients include those selected from the group consisting of a solubility enhancing agent, chelating agent, preservative, tonicity agent, viscosity/suspending agent, buffer, and pH modifying agent, and a mixture thereof.

[0068] Examples of a solubility enhancing agent include cyclodextrin, such as those selected from the group consisting of hydroxypropyl-P-cyclodcxtrin, mcthyl-P-cyclodcxtrin, randomly methylated-P-cyclodextrin, ethylated-P-cyclodextrin, triacetyl-P-cyclodextrin, peracetylated-P- cyclodextrin, carboxymethyl-P-cyclodextrin, hydroxyethyl-P-cyclodextrin, 2-hydroxy-3- (trimethylammonio)propyl-P-cyclodextrin, glucosyl-P-cyclodextrin, sulphated P-cyclodextrin (S- p-CD), maltosyl-p-cyclodextrin, P-cyclodextrin sulfobutyl ether, branched-p-cyclodextrin, hydroxypropyl-y-cyclodextrin, randomly methylated-y-cyclodextrin, and trimethyl-'y- cyclodextrin, and mixtures thereof. Preferably, solubility enhancing agent includes P- cyclodextrin sulfobutyl ether, hyrdoxypropyl-P-cyclodextrin, sulphated P-cyclodextrin (S-P-CD), and maltosyl-P-cyclodextrin, and mixtures thereof. The solubility enhancing agent(s) may be added in an amount of about 1 to about 20 wt%, preferably about 1 to about 10 wt%, and more preferably about 5 to about 10 wt%.

[0069] Examples of a chelating agent include those selected from the group consisting of ethylenediaminetetraacetic acid and metal salts thereof, disodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof. Disodium edetate is a particularly preferred chelating agent. The chelating agent(s) may be added in an amount of about 0.001 to about 0.05 wt%, preferably about 0.001 to about 0.02 wt%, more preferably about 0.002 to about 0.01 wt%, and most preferably about 0.002 to about 0.005 wt%.

[0070] Preferably, the aqueous vehicle includes a preservative. Preferred preservatives include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury nitrate, phenylmercury acetate, phenylmercury neodecanoate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p- hydroxybenzoate, propylaminopropyl biguanide, and butyl-p-hydroxybenzoate, sorbic acid, and mixtures thereof. More preferably, the preservative is a quaternary ammonium salt such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, potassium sorbate, sodium benzoate, ethyl p- hydroxybenzoate, butyl p-hydroxybenzoate, or propylaminopropyl biguanide, or mixtures thereof. Propylaminopropyl biguanide is an especially preferred preservative. The preservative(s) may be used in an amount of about 0.00001 to about 0.0001 wt%, preferably about 0.00001 to about 0.00008 wt%, and more preferably about 0.00002 to about 0.00005 wt%.

[0071] The aqueous vehicle may also include a tonicity agent to adjust the tonicity (osmotic pressure). The tonicity agent can be selected from the group consisting of a glycol (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and a mixture thereof. Preferably, the tonicity agent is selected from the group consisting of glycerin, mannitol, potassium chloride, and sodium chloride. More preferably mannitol and/or sodium chloride (and most preferably a mixture thereof) are employed. The tonicity agent(s) may be used in an amount of about 0.05 to about 8 wt%, preferably about 0.1 to about 6 wt%, more preferably about 0.1 to about 4 wt%, and most preferably about 0.2 to about 4 wt%.

[0072] The aqueous vehicle preferably also contains a viscosity/suspending agent. Suitable viscosity/suspending agents include those selected from the group consisting of cellulose derivatives, such as methyl cellulose, ethyl cellulose, hydroxycthylccllulosc, polyethylene glycols (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethyl cellulose, hydroxypropylmethyl cellulose, and cross-linked acrylic acid polymers (carbomers), such as polymers of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol (Carbopols - such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P), and a mixture thereof. In preferred embodiments of the present application, the viscosity/suspending agent is a carbomer, more preferably Carbopol 974P. The viscosity/suspending agent(s) may be present in an amount of about 0.05 to about 2 wt%, preferably 0.1 to about 1 wt%, more preferably about 0.2 to about 0.8 wt%, and most preferably about 0.3 to about 0.5 wt%.

[0073] The pH modifying agent is typically a mineral acid or metal hydroxide base, selected from the group of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, and preferably sodium hydroxide and/or hydrochloric acid. These acidic and/or basic pH modifying agents are added to adjust the formulation to the target ophthalmically acceptable pH range. Hence it may not be necessary to use both acid and base - depending on the formulation, the addition of one of the acid or base may be sufficient to bring the mixture to the desired pH range.

[0074] The aqueous vehicle may also contain a buffering agent to stabilize the pH. When used, the buffer is selected from the group consisting of a phosphate buffer (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), a borate buffer (such as boric acid, or salts thereof including disodium tetraborate), a citrate buffer (such as citric acid, or salts thereof including sodium citrate), and e-aminocaproic acid, and mixtures thereof. The buffer agent(s) may be present in an amount of about 0.05 to about 5 wt%, preferably 0.1 to about 5 wt%, more preferably about 0.2 to about 5 wt%, and most preferably about 0.5 to about 5 wt%.

[0075] The topical formulation may further comprise a wetting agent. In any embodiment of the present application the wetting agent is preferably a non- ionic wetting agent. More preferably, the wetting agent is water soluble or swellable. Most preferably the wetting agent is water soluble. “Water soluble” is to be understood in the manner used in standard texts such as the “Handbook of Pharmaceutical Excipients” (Raymond C Rowe, Paul J Shcskcy and Sian C Owen, Fifth Edition, Pharmaceutical Press and American Pharmacists Association 2006). Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oils, polyoxyethylenated sorbitan esters (polysorbates), polymers of oxyethylated octyl phenol (Tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty esters, and polyoxyethylene fatty esters, and mixtures thereof. Specific examples of suitable wetting agents include those selected from the group consisting of: polyoxyethylenepolyoxypropylene block copolymers (poloxamers) such as: polyoxyethylene (160) polyoxypropylene (30) glycol [Pluronic F68], polyoxyethylene (42) polyoxypropylene (67) glycol [Pluronic P123], polyoxyethylene (54) polyoxypropylene (39) glycol [Pluronic P85], polyoxyethylene (196) polyoxypropylene (67) glycol [Poloxamer 407, Pluronic F127], polyoxyethylene (20) polyoxypropylene (20) glycol [Pluronic L44], polyoxyethylenated sorbitan esters (polysorbates) such as poly (oxy ethylene) sorbitan monopalmitate (polysorbate 40), poly (oxy ethylene) sorbitan monostearate (polysorbate 60), poly(oxyethylene)sorbitan tristearate (polysorbate 65), poly(oxyethylene) sorbitan monooleate (polysorbate 80), poly(oxyethylene) sorbitan monolaurate, poly(oxyethylene) sorbitan trioleate, polyethoxylated ethers of castor oils such as polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50 and polyoxyethylene liydrogenated castor oil 60, polyoxyl 40 stearate, sucrose fatty esters, and polyoxyethylene fatty esters, and mixtures thereof.

IV. Medical Kits

[0076] Another aspect of the invention provides a medical kit comprising, for example, (i) a therapeutic agent described herein, and (ii) instructions for treating diabetic retinopathy according to methods described herein.

V. Enumerated Embodiments

[0077] Another aspect of the invention provides the following enumerated embodiments: [0078] Embodiment No. 1. A method of treating diabetic retinopathy in a human patient, comprising topically administering to an eye of the human patient in need thereof an ophthalmic formulation comprising a compound of Formula T in an amount of from about 4% w/w to about 6% w/w, to thereby treat the diabetic retinopathy, wherein the ophthalmic formulation is topically administered to an eye of the human patient two, three, or four times per day, which results in delivering from about 4 mg to about 12 mg compound of Formula I per day to the eye of the human patient, and Formula I is represented a pharmaceutically acceptable salt thereof.

[0079] Embodiment No. 2. The method of Embodiment No. 1, wherein the diabetic retinopathy is mild diabetic retinopathy.

[0080] Embodiment No. 3. The method of Embodiment No. 1, wherein the diabetic retinopathy is moderate diabetic retinopathy.

[0081] Embodiment No. 4. The method of Embodiment No. 1, wherein the diabetic retinopathy is moderately severe to severe diabetic retinopathy.

[0082] Embodiment No. 5. The method of Embodiment No. 1, wherein the diabetic retinopathy is severe diabetic retinopathy.

[0083] Embodiment No. 6. The method of any one of Embodiment Nos. 1-5, wherein the diabetic retinopathy is non-proliferative.

[0084] Embodiment No. 7. The method of any one of Embodiment Nos. 1-5, wherein the diabetic retinopathy is proliferative.

[0085] Embodiment No. 8. A method of reducing central retinal thickness in a human patient suffering from diabetic retinopathy, comprising topically administering to an eye of the human patient in need thereof an ophthalmic formulation comprising a compound of Formula I in an amount of from about 4% w/w to about 6% w/w, to thereby reduce central retinal thickness, wherein the ophthalmic formulation is topically administered to an eye of the human patient two, three, or four times per day, which results in delivering from about 4 mg to about 12 mg compound of Formula T per day to the eye of the human patient, and Formula 1 is represented pharmaceutically acceptable salt thereof.

[0086] Embodiment No. 9. The method of Embodiment No. 8, wherein the diabetic retinopathy is mild diabetic retinopathy.

[0087] Embodiment No. 10. The method of Embodiment No. 8, wherein the diabetic retinopathy is moderate diabetic retinopathy.

[0088] Embodiment No. 11. The method of Embodiment No. 8, wherein the diabetic retinopathy is moderately severe to severe diabetic retinopathy.

[0089] Embodiment No. 12. The method of Embodiment No. 8, wherein the diabetic retinopathy is severe diabetic retinopathy.

[0090] Embodiment No. 13. The method of any one of Embodiment Nos. 8-12, wherein the diabetic retinopathy is non-proliferative.

[0091] Embodiment No. 14. The method of any one of Embodiment Nos. 8-12, wherein the diabetic retinopathy is proliferative.

[0092] Embodiment No. 15. The method of any one of Embodiment Nos. 1-14, wherein the compound of Formula

[0093] Embodiment No. 16. The method of any one of Embodiment Nos. 1-15, wherein the administering delivers said compound of Formula I to the eye of the human patient in an amount ranging from about 5 mg to about 10 mg per day. [0094] Embodiment No. 17. The method of any one of Embodiment Nos. 1-15, wherein the administering delivers said compound of Formula I to the eye of the human patient in an amount ranging from about 4 mg to about 6 mg per day.

[0095] Embodiment No. 18. The method of any one of Embodiment Nos. 1-15, wherein the administering delivers said compound of Formula I to the eye of the human patient in an amount of about 5 mg per day.

[0096] Embodiment No. 19. The method of any one of Embodiment Nos. 1-15, wherein the administering delivers said compound of Formula I to the eye of the human patient in an amount of 5 mg per day.

[0097] Embodiment No. 20. The method of any one of Embodiment Nos. 1-15, wherein the administering delivers said compound of Formula I to the eye of the human patient in an amount ranging from about 9 mg to about 11 mg per day.

[0098] Embodiment No. 21. The method of any one of Embodiment Nos. 1-15, wherein the administering delivers said compound of Formula I to the eye of the human patient in an amount of about 10 mg per day.

[0099] Embodiment No. 22. The method of any one of Embodiment Nos. 1-15, wherein the administering delivers said compound of Formula I to the eye of the human patient in an amount of 10 mg per day.

[00100] Embodiment No. 23. The method of any one of Embodiment Nos. 1-19, wherein the ophthalmic formulation is topically administered to an eye of the human patient two times per day.

[00101] Embodiment No. 24. The method of any one of Embodiment Nos. 1-16 or 20-22, wherein the ophthalmic formulation is topically administered to an eye of the human patient four times per day.

[00102] Embodiment No. 25. The method of any one of Embodiment Nos. 1-24, wherein the ophthalmic formulation comprises a compound of Formula I in an amount of about 5% w/w.

[00103] Embodiment No. 26. The method of any one of Embodiment Nos. 1-24, wherein the ophthalmic formulation comprises a compound of Formula I in an amount of 5% w/w. [00104] Embodiment No. 27. The method of any one of Embodiment Nos. 1-26, wherein the ophthalmic formulation is an aqueous ophthalmic solution.

[00105] Embodiment No. 28. The method of any one of Embodiment Nos. 1-27, wherein the ophthalmic formulation is topically administered to the eye of the human patient in the form of an eye drop.

[00106] Embodiment No. 29. The method of Embodiment No. 28, wherein the eye drop has a volume of about 50 |1L.

[00107] Embodiment No. 30. The method of any one of Embodiment Nos. 1-29, wherein the ophthalmic formulation is topically administered to an eye of the human patient in need thereof for a duration for at least 7 consecutive days.

[00108] Embodiment No. 31. The method of any one of Embodiment Nos. 1-29, wherein the ophthalmic formulation is topically administered to an eye of the human patient in need thereof for a duration of at least 14 consecutive days.

[00109] Embodiment No. 32. The method of any one of Embodiment Nos. 1-29, wherein the ophthalmic formulation is topically administered to an eye of the human patient in need thereof for a duration of at least 28 consecutive days.

[00110] Embodiment No. 33. The method of any one of Embodiment Nos. 1-29, wherein the ophthalmic formulation is topically administered to an eye of the human patient in need thereof for a duration of at least 56 consecutive days.

[00111] Embodiment No. 34. The method of any one of Embodiment Nos. 1-29, wherein the ophthalmic formulation is topically administered to an eye of the human patient in need thereof for a duration of at least 84 consecutive days.

[00112] Embodiment No. 35. The method of any one of Embodiment Nos. 1-29, wherein the ophthalmic formulation is topically administered to an eye of the human patient in need thereof for a duration of at least 168 consecutive days.

[00113] Embodiment No. 36. The method of any one of Embodiment Nos. 1-29, wherein the ophthalmic formulation is topically administered to an eye of the human patient in need thereof daily. [00114] Embodiment No. 37. The method of any one of Embodiment Nos. 1-36, wherein the method is characterized by reducing the patient’s Diabetic Retinopathy Severity Score by at least 10 on the Diabetic Retinopathy Severity Scale of 10-90.

[00115] Embodiment No. 38. The method of any one of Embodiment Nos. 1-36, wherein the method is characterized by reducing the patient’s Diabetic Retinopathy Severity Score by at least 15 on the Diabetic Retinopathy Severity Scale of 10-90.

[00116] Embodiment No. 39. The method of any one of Embodiment Nos. 1-36, wherein the method is characterized by reducing the patient’s Diabetic Retinopathy Severity Score by at least 25 on the Diabetic Retinopathy Severity Scale of 10-90.

[00117] Embodiment No. 40. The method of any one of Embodiment Nos. 1-39, wherein the method is characterized achieving at least a 1-step reduction in the patient’s Diabetic Retinopathy Severity Score.

[00118] Embodiment No. 41. The method of any one of Embodiment Nos. 1-39, wherein the method is characterized achieving at least a 2-step reduction in the patient’s Diabetic Retinopathy Severity Score.

[00119] Embodiment No. 42. The method of any one of Embodiment Nos. 1-39, wherein the method is characterized achieving at least a 3-step reduction in the patient’s Diabetic Retinopathy Severity Score.

[00120] Embodiment No. 43. The method of any one of Embodiment Nos. 1-39, wherein the method achieves a reduction in the patient’s Diabetic Retinopathy Severity Score ranging from 1 to 4 steps.

[00121] Embodiment No. 44. The method of any one of Embodiment Nos. 1-39, wherein the method achieves a reduction in the patient’s Diabetic Retinopathy Severity Score ranging from 2 to 3 steps.

[00122] Embodiment No. 45. The method of any one of Embodiment Nos. 1-44, wherein the method is characterized by reducing the patient’s Diabetic Retinopathy Severity Score so that the patient’s Diabetic Retinopathy Severity Score is no greater than 47 on the Diabetic Retinopathy Severity Scale of 10-90. [00123] Embodiment No. 46. The method of any one of Embodiment Nos. 1-44, wherein the method is characterized by reducing the patient’s Diabetic Retinopathy Severity Score so that the patient’s Diabetic Retinopathy Severity Score is no greater than 43 on the Diabetic Retinopathy Severity Scale of 10-90.

[00124] Embodiment No. 47. The method of any one of Embodiment Nos. 1-44, wherein the method is characterized by reducing the patient’s Diabetic Retinopathy Severity Score so that the patient’s Diabetic Retinopathy Severity Score is no greater than 35 on the Diabetic Retinopathy Severity Scale of 10-90.

[00125] Embodiment No. 48. The method of any one of Embodiment Nos. 1-44, wherein the method is characterized by reducing the patient’s Diabetic Retinopathy Severity Score so that the patient’s Diabetic Retinopathy Severity Score is no greater than 20 on the Diabetic Retinopathy Severity Scale of 10-90.

[00126] Embodiment No. 49. The method of any one of Embodiment Nos. 1-48, wherein the method results in an improvement in Best Corrected Visual Acuity by at least one line in the patient’s vision measured using a Snellen vision chart.

[00127] Embodiment No. 50. The method of any one of Embodiment Nos. 1-48, wherein the method results in an improvement in Best Corrected Visual Acuity by at least two lines in the patient’s vision measured using a Snellen vision chart.

[00128] Embodiment No. 51. The method of any one of Embodiment Nos. 1-50, wherein the method is characterized by reducing the patient’s central retina thickness by at least 10%.

[00129] Embodiment No. 52. The method of any one of Embodiment Nos. 1-50, wherein the method is characterized by reducing the patient’s central retina thickness by at least 20%.

[00130] Embodiment No. 53. The method of any one of Embodiment Nos. 1-50, wherein the method is characterized by reducing the patient’s central retina thickness by at least 30%.

[00131] Embodiment No. 54. The method of any one of Embodiment Nos. 1-50, wherein the method is characterized by reducing the patient’s central retina thickness by at least 40%.

[00132] Embodiment No. 55. The method of any one of Embodiment Nos. 1-50, wherein the method is characterized by reducing the patient’s central retina thickness by at least 50%. [00133] Embodiment No. 56. The method of any one of Embodiment Nos. 1-55, wherein the method is characterized by reducing non-ccntral retina thickness least 10%.

[00134] Embodiment No. 57. The method of any one of Embodiment Nos. 1-55, wherein the method is characterized by reducing non-central retina thickness least 20%.

[00135] Embodiment No. 58. The method of any one of Embodiment Nos. 1-57, wherein the method is characterized by delaying the development of a vision-threatening complication.

[00136] Embodiment No. 59. The method of any one of Embodiment Nos. 1-57, wherein the method is characterized by delaying by at least 2 months the development of a vision-threatening complication.

[00137] Embodiment No. 60. The method of any one of Embodiment Nos. 1-57, wherein the method is characterized by delaying by at least 4 months the development of a vision-threatening complication.

[00138] Embodiment No. 61. The method of any one of Embodiment Nos. 1-57, wherein the method is characterized by delaying by at least 6 months the development of a vision-threatening complication.

[00139] Embodiment No. 62. The method of any one of Embodiment Nos. 58-61 , wherein the vision-threatening complication is a ncovascular vision-threatening complication.

[00140] Embodiment No. 63. The method of any one of Embodiment Nos. 58-61, wherein the vi ion-threatening complication is diabetic macular edema.

[00141] Embodiment No. 64. The method of any one of Embodiment Nos. 58-61, wherein the vision-threatening complication is center-involved diabetic macular edema.

[00142] Embodiment No. 65. The method of any one of Embodiment Nos. 58-61, wherein the vision-threatening complication is proliferative diabetic retinopathy having a severity greater than mild.

[00143] Embodiment No. 66. The method of any one of Embodiment Nos. 1-65, wherein the patient has Type 1 diabetes. [00144] Embodiment No. 67. The method of any one of Embodiment Nos. 1-65, wherein the patient has Type 2 diabetes.

[00145] Embodiment No. 68. The method of any one of Embodiment Nos. 1-67, wherein the patient does not have visually significant diabetic macular edema.

[00146] Embodiment No. 69. The method of Embodiment No. 68, wherein the method prevents the development of diabetic macular edema.

[00147] Another aspect of the invention provides the following enumerated embodiments:

[00148] Embodiment No. 1. A method of treating diabetic retinopathy in a human patient, comprising topically administering to an eye of the human patient in need thereof an ophthalmic formulation comprising a compound of Formula I in an amount of from about 71 mmol/L to about 106 mmol/L, to thereby treat the diabetic retinopathy, wherein the ophthalmic formulation is topically administered to an eye of the human patient two, three, or four times per day, which results in delivering from about 0.0071 mmol to about 0.021 mmol compound of Formula I per day to the eye of the human patient, and Formula I is represented by pharmaceutically acceptable salt thereof.

[00149] Embodiment No. 2. The method of Embodiment No. 1, wherein the diabetic retinopathy is mild diabetic retinopathy.

[00150] Embodiment No. 3. The method of Embodiment No. 1, wherein the diabetic retinopathy is moderate diabetic retinopathy.

[00151] Embodiment No. 4. The method of Embodiment No. 1, wherein the diabetic retinopathy is moderately severe to severe diabetic retinopathy.

[00152] Embodiment No. 5. The method of Embodiment No. 1, wherein the diabetic retinopathy is severe diabetic retinopathy. [00153] Embodiment No. 6. The method of any one of Embodiment Nos. 1 -5, wherein the diabetic retinopathy is non-prolifcrativc.

[00154] Embodiment No. 7. The method of any one of Embodiment Nos. 1-5, wherein the diabetic retinopathy is proliferative.

[00155] Embodiment No. 8. A method of reducing central retinal thickness in a human patient suffering from diabetic retinopathy, comprising topically administering to an eye of the human patient in need thereof an ophthalmic formulation comprising a compound of Formula I in an amount of from about 71 mmol/L to about 106 mmol/L, to thereby reduce central retinal thickness, wherein the ophthalmic formulation is topically administered to an eye of the human patient two, three, or four times per day, which results in delivering from about 0.0071 mmol to about 0.021 mmol compound of Formula I per day to the eye of the human patient, and Formula

I is represented pharmaceutically acceptable salt thereof.

[00156] Embodiment No. 9. The method of Embodiment No. 8, wherein the diabetic retinopathy is mild diabetic retinopathy.

[00157] Embodiment No. 10. The method of Embodiment No. 8, wherein the diabetic retinopathy is moderate diabetic retinopathy.

[00158] Embodiment No. 11. The method of Embodiment No. 8, wherein the diabetic retinopathy is moderately severe to severe diabetic retinopathy.

[00159] Embodiment No. 12. The method of Embodiment No. 8, wherein the diabetic retinopathy is severe diabetic retinopathy.

[00160] Embodiment No. 13. The method of any one of Embodiment Nos. 8-12, wherein the diabetic retinopathy is non-proliferative. [00161] Embodiment No. 14. The method of any one of Embodiment Nos. 8-12, wherein the diabetic retinopathy is proliferative.

[00162] Embodiment No. 15. The method of any one of Embodiment Nos. 1-14, wherein the administering delivers said compound of Formula I to the eye of the human patient in an amount ranging from about 0.0089 mmol to about 0.018 mmol per day.

[00165] Embodiment No. 18. The method of any one of Embodiment Nos. 1-16, wherein the administering delivers said compound of Formula I to the eye of the human patient in an amount ranging from about 0.0071 mmol to about 0.0106 mmol per day.

[00166] Embodiment No. 19. The method of any one of Embodiment Nos. 1-16, wherein the administering delivers said compound of Formula I to the eye of the human patient in an amount of about 0.0089 mmol per day.

[00167] Embodiment No. 20. The method of any one of Embodiment Nos. 1-16, wherein the administering delivers said compound of Formula I to the eye of the human patient in an amount of 0.0089 mmol per day. [00168] Embodiment No. 21 . The method of any one of Embodiment Nos. 1-16, wherein the administering delivers said compound of Formula I to the eye of the human patient in an amount ranging from about 0.016 mmol to about 0.020 mmol per day.

[00169] Embodiment No. 22. The method of any one of Embodiment Nos. 1-16, wherein the administering delivers said compound of Formula I to the eye of the human patient in an amount of about 0.018 mmol per day.

[00170] Embodiment No. 23. The method of any one of Embodiment Nos. 1-16, wherein the administering delivers said compound of Formula I to the eye of the human patient in an amount of 0.018 mmol per day.

[00171] Embodiment No. 24. The method of any one of Embodiment Nos. 1-20, wherein the ophthalmic formulation is topically administered to an eye of the human patient two times per day.

[00172] Embodiment No. 25. The method of any one of Embodiment Nos. 1-17 or 21-23, wherein the ophthalmic formulation is topically administered to an eye of the human patient four times per day.

[00173] Embodiment No. 26. The method of any one of Embodiment Nos. 1-25, wherein the ophthalmic formulation comprises a compound of Formula I in an amount of about 89 mmol/L.

[00174] Embodiment No. 27. The method of any one of Embodiment Nos. 1-25, wherein the ophthalmic formulation comprises a compound of Formula I in an amount of 89 mmol/L.

[00175] Embodiment No. 28. The method of any one of Embodiment Nos. 1-16, wherein the administering delivers said compound of Formula I to the eye of the human patient in an amount ranging from 0.0071 mmol to about 0.0089 mmol per day.

[00176] Embodiment No. 29. The method of any one of Embodiment Nos. 1-28, wherein the ophthalmic formulation is an aqueous ophthalmic solution.

[00177] Embodiment No. 30. The method of any one of Embodiment Nos. 1-29, wherein the ophthalmic formulation is topically administered to the eye of the human patient in the form of an eye drop. [00178] Embodiment No. 31 . The method of Embodiment No. 30, wherein the eye drop has a volume of about 50 (1L.

[00179] Embodiment No. 32. The method of any one of Embodiment Nos. 1-31, wherein the ophthalmic formulation is topically administered to an eye of the human patient in need thereof for a duration for at least 7 consecutive days.

[00180] Embodiment No. 33. The method of any one of Embodiment Nos. 1-31, wherein the ophthalmic formulation is topically administered to an eye of the human patient in need thereof for a duration of at least 14 consecutive days.

[00181] Embodiment No. 34. The method of any one of Embodiment Nos. 1-31, wherein the ophthalmic formulation is topically administered to an eye of the human patient in need thereof for a duration of at least 28 consecutive days.

[00182] Embodiment No. 35. The method of any one of Embodiment Nos. 1-31, wherein the ophthalmic formulation is topically administered to an eye of the human patient in need thereof for a duration of at least 56 consecutive days.

[00183] Embodiment No. 36. The method of any one of Embodiment Nos. 1-31, wherein the ophthalmic formulation is topically administered to an eye of the human patient in need thereof for a duration of at least 84 consecutive days.

[00184] Embodiment No. 37. The method of any one of Embodiment Nos. 1-31, wherein the ophthalmic formulation is topically administered to an eye of the human patient in need thereof for a duration of at least 168 consecutive days.

[00185] Embodiment No. 38. The method of any one of Embodiment Nos. 1-31, wherein the ophthalmic formulation is topically administered to an eye of the human patient in need thereof daily.

[00186] Embodiment No. 39. The method of any one of Embodiment Nos. 1-38, wherein the method is characterized by reducing the patient’s Diabetic Retinopathy Severity Score by at least 10 on the Diabetic Retinopathy Severity Scale of 10-90. [00187] Embodiment No. 40. The method of any one of Embodiment Nos. 1-38, wherein the method is characterized by reducing the patient’s Diabetic Retinopathy Severity Score by at least 15 on the Diabetic Retinopathy Severity Scale of 10-90.

[00188] Embodiment No. 41. The method of any one of Embodiment Nos. 1-38, wherein the method is characterized by reducing the patient’s Diabetic Retinopathy Severity Score by at least 25 on the Diabetic Retinopathy Severity Scale of 10-90.

[00189] Embodiment No. 42. The method of any one of Embodiment Nos. 1-41, wherein the method is characterized achieving at least a 1-step reduction in the patient’s Diabetic Retinopathy Severity Score.

[00190] Embodiment No. 43. The method of any one of Embodiment Nos. 1-41, wherein the method is characterized achieving at least a 2-step reduction in the patient’s Diabetic Retinopathy Severity Score.

[00191] Embodiment No. 44. The method of any one of Embodiment Nos. 1-41, wherein the method is characterized achieving at least a 3-step reduction in the patient’s Diabetic Retinopathy Severity Score.

[00192] Embodiment No. 45. The method of any one of Embodiment Nos. 1-41, wherein the method achieves a reduction in the patient’s Diabetic Retinopathy Severity Score ranging from 1 to 4 steps.

[00193] Embodiment No. 46. The method of any one of Embodiment Nos. 1-41, wherein the method achieves a reduction in the patient’s Diabetic Retinopathy Severity Score ranging from 2 to 3 steps.

[00194] Embodiment No. 47. The method of any one of Embodiment Nos. 1-46, wherein the method is characterized by reducing the patient’s Diabetic Retinopathy Severity Score so that the patient’s Diabetic Retinopathy Severity Score is no greater than 47 on the Diabetic Retinopathy Severity Scale of 10-90.

[00195] Embodiment No. 48. The method of any one of Embodiment Nos. 1-46, wherein the method is characterized by reducing the patient’s Diabetic Retinopathy Severity Score so that the patient’s Diabetic Retinopathy Severity Score is no greater than 43 on the Diabetic Retinopathy Severity Scale of 10-90.

[00196] Embodiment No. 49. The method of any one of Embodiment Nos. 1-46, wherein the method is characterized by reducing the patient’s Diabetic Retinopathy Severity Score so that the patient’s Diabetic Retinopathy Severity Score is no greater than 35 on the Diabetic Retinopathy Severity Scale of 10-90.

[00197] Embodiment No. 50. The method of any one of Embodiment Nos. 1-46, wherein the method is characterized by reducing the patient’s Diabetic Retinopathy Severity Score so that the patient’s Diabetic Retinopathy Severity Score is no greater than 20 on the Diabetic Retinopathy Severity Scale of 10-90.

[00198] Embodiment No. 51. The method of any one of Embodiment Nos. 1-50, wherein the method results in an improvement in Best Corrected Visual Acuity by at least one line in the patient’s vision measured using a Snellen vision chart.

[00199] Embodiment No. 52. The method of any one of Embodiment Nos. 1-50, wherein the method results in an improvement in Best Corrected Visual Acuity by at least two lines in the patient’s vision measured using a Snellen vision chart.

[00200] Embodiment No. 53. The method of any one of Embodiment Nos. 1-52, wherein the method is characterized by reducing the patient’s central retina thickness by at least 10%.

[00201] Embodiment No. 54. The method of any one of Embodiment Nos. 1-52, wherein the method is characterized by reducing the patient’s central retina thickness by at least 20%.

[00202] Embodiment No. 55. The method of any one of Embodiment Nos. 1-52, wherein the method is characterized by reducing the patient’s central retina thickness by at least 30%.

[00203] Embodiment No. 56. The method of any one of Embodiment Nos. 1-52, wherein the method is characterized by reducing the patient’s central retina thickness by at least 40%.

[00204] Embodiment No. 57. The method of any one of Embodiment Nos. 1-52, wherein the method is characterized by reducing the patient’s central retina thickness by at least 50%. [00205] Embodiment No. 58. The method of any one of Embodiment Nos. 1-57, wherein the method is characterized by reducing non-ccntral retina thickness least 10%.

[00206] Embodiment No. 59. The method of any one of Embodiment Nos. 1-57, wherein the method is characterized by reducing non-central retina thickness least 20%.

[00207] Embodiment No. 60. The method of any one of Embodiment Nos. 1-59, wherein the method is characterized by delaying the development of a vision-threatening complication.

[00208] Embodiment No. 61. The method of any one of Embodiment Nos. 1-59, wherein the method is characterized by delaying by at least 2 months the development of a vision-threatening complication.

[00209] Embodiment No. 62. The method of any one of Embodiment Nos. 1-59, wherein the method is characterized by delaying by at least 4 months the development of a vision-threatening complication.

[00210] Embodiment No. 63. The method of any one of Embodiment Nos. 1-59, wherein the method is characterized by delaying by at least 6 months the development of a vision-threatening complication.

[00211] Embodiment No. 64. The method of any one of Embodiment Nos. 60-63, wherein the vision-threatening complication is a ncovascular vision-threatening complication.

[00212] Embodiment No. 65. The method of any one of Embodiment Nos. 60-63, wherein the vi ion-threatening complication is diabetic macular edema.

[00213] Embodiment No. 66. The method of any one of Embodiment Nos. 60-63, wherein the vision-threatening complication is center-involved diabetic macular edema.

[00214] Embodiment No. 67. The method of any one of Embodiment Nos. 60-63, wherein the vision-threatening complication is proliferative diabetic retinopathy having a severity greater than mild.

[00215] Embodiment No. 68. The method of any one of Embodiment Nos. 1-67, wherein the patient has Type 1 diabetes. [00216] Embodiment No. 69. The method of any one of Embodiment Nos. 1-67, wherein the patient has Type 2 diabetes.

[00217] Embodiment No. 70. The method of any one of Embodiment Nos. 1-69, wherein the patient does not have visually significant diabetic macular edema.

[00218] Embodiment No. 71. The method of Embodiment No. 70, wherein the method prevents the development of diabetic macular edema.

EXAMPLES

[00219] The invention now being generally described, will be more readily understood by reference to the following examples, which arc included merely for purposes of illustrating certain aspects and embodiments of the present invention, and are not intended to limit the invention.

EXAMPLE / - Treatment of Diab etie Peiinopat/iy

[00220] The ability of Compound 1 to treat diabetic retinopathy may be evaluated according to a clinical study in which Compound 1 is topically administered to patients suffering from diabetic retinopathy. Compound 1 has the chemical name (S)-3-(6-(difluoromethoxy)pyridin-3- yl)-3-(2-oxo-3-(3-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl) propyl)imidazolidin-l-yl)propanoic acid 2-amino-2-methylpropan-l-ol salt, and is depicted by the following chemical formula:

[00221] The study is to be configured as a Phase 2 clinical trial enrolling approximately 210 subjects diagnosed with moderately severe to severe non-proliferative diabetic retinopathy (NPDR) or mild proliferative diabetic retinopathy (PDR) and who are treatment naive (i.e., no prior anti-VEGF or laser (focal, grid, pan-retinal photocoagulation) administered). Subjects enrolled in the clinical trial will be randomized 2:2: 1 : 1 into the following groups: Compound 1 administered twice daily (BID), Compound 1 administered four times daily (QID), vehicle control administered BID, and vehicle control administered QTD. Subject randomization will be stratified by baseline Diabetic Retinopathy Severity Scale (DRSS) score (47 or 53 or 61). Subjects with PDR (DRSS score 61) will be capped at 20% of all randomized participants. Compound 1 is administered in the form of a solution containing 5% w/w Compound 1. Each group will self-administer one 50-pL eye drop of study solution (frequency as assigned) for 24 weeks. The study solution is an aqueous solution.

[00222] Further experimental procedures are described below.

Experimental Procedures

[00223] Human subjects will be screened for potential enrollment and, if qualified, enrolled in the study. Inclusion criteria and exclusion criteria for the study arc set forth below.

[00224] Subjects enrolled in the trial shall have Type 1 or Type 2 diabetes under adequate control as evidenced by glycosylated hemoglobin (HbAlc) less than or equal to 10.0% and diagnosed with moderately severe to severe NPDR or mild PDR, as defined by the DRSS scores of 47, 53, and 61, with the PDR population capped at no more than 20% of all randomized participants. Participants will not have center-involved diabetic macular edema (Cl-DME) at the screening and baseline examinations but may have non-center-involved diabetic macular edema (non-CI-DME). Participants must have (i) a Best corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study (ETDRS) letter score in the study eye of >69 letters (Snellen equivalent 20/40) and (ii) a central subfield thickness (CST) < 300 pm.

[00225] Only one eye will be designated as the study eye in every participant. For participants who meet eligibility criteria in both eyes during the screening phase, the eye with the higher reading center confirmed DRSS should be selected. If both eyes have the same score, the eye with the clearest lens and ocular media will be selected. If there is no objective basis for selecting the study eye, factors such as ocular dominance (better focus ability), other ocular pathology and participant preference should be considered in making the selection. The final selection will be done by the investigator at baseline and must not be changed during the course of the study.

[00226] No other ocular topic drugs (eye drops) should be taken during the study unless prescribed by the treating study physician and after discussion with the sponsor and medical monitor. If topical therapy (eye drops) is prescribed, the application of such therapy should not occur within 10 minutes (before or after) of instillation of study therapy. Other therapies for retinal disease (i.e., oral, topical, an d/or intravitreal injected drugs like steroids or anti VEGFs) are not permitted, unless applied as rescue therapy. Such intake will be recorded. Contact lens wear is strictly prohibited from the time of screening throughout the study. If participant has current contact lens use at screening, contact lens use should be discontinued immediately, and a 14 day ocular surface stabilization period is needed between screening and baseline.

[00227] Concomitant medications are to be recorded.

[00228] Subjects enrolled in the clinical trial will be randomized 2:2: 1 : 1 into the following groups: Compound 1 administered twice daily (BID), Compound 1 administered four times daily (QID), vehicle control administered BID, and vehicle control administered QID. Subject randomization will be stratified by baseline Diabetic Retinopathy Severity Scale (DRSS) score (47 or 53 or 61). Subjects with PDR (DRSS score 61) will be capped at 20% of all randomized participants. Compound 1 is administered in the form of a solution containing 5% w/w Compound 1. Each group will self-administer one 50-pL eye drop of study solution topically to the eye (frequency as assigned) for 24 weeks.

Inclusion Criteria

[00229] Participants are eligible to be included in the study only if all the following criteria apply:

1. Men or women >18 years of age with type 1 or 2 diabetes mellitus who have moderately severe to severe non-proliferative diabetic retinopathy (NPDR) [diabetic retinopathy severity scale (DRSS) score of 47 or 53], or mild proliferative diabetic retinopathy (PDR) [(diabetic retinopathy severity scale (DRSS) score of 61): NVE < 0.5 DA in 1+ quadrants], confirmed by the central reading center, in whom pan-retinal photocoagulation (PRP) and/or anti-VEGF intravitreal therapy (IVT) can be safely deferred for at least 6 months per the investigator. In respect to DRSS score of 61, patients with < one neovascularization elsewhere (NVE) > 1 disk diameter (DD) from disc definitely present will be included. Any presence of FPD or FPE will be excluded. (ETDRS report number 12 in Ophthalmology (1991) vol. 98(5 Suppl), pages 823- 33). 2. Best corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study (ETDRS) letter score in the study eye of >69 letters (approximate Snellen equivalent of 20/40 or better).

3. Treatment naive (i.e., no previous anti-VEGF or steroid treatment or laser or PRP treatment within 1,000 pm diameter of the foveal center/treatment for macular edema or diabetic retinopathy in the study eye).

4. Willing and able to return for all study visits and comply with study-related procedures.

5. Able to adhere to the study dosing requirements.

6. Understands and signs the written informed consent form.

Exclusion Criteria

[00230] Participants are excluded from the study if any of the following criteria apply:

1. Presence of diabetic macular edema (DME) threatening the center of the macula in the study eye (within 1,000 pm diameter of the foveal center).

2. Any prior focal or grid laser photocoagulation or any prior PRP in the study eye.

3. Eyes with DRSS score 61 due to fibrous proliferations at disc or fibrous proliferations elsewhere. a. DRSS score 61 with neovascularization elsewhere (NVE) only is allowed. Any sign of fibrosis proliferation is exclusionary.

4. Any prior systemic anti-vascular endothelial growth factor (VEGF) treatment or intravitreal (IVT) anti-VEGF treatment in the study eye.

5. Any prior intraocular steroid injection in the study eye - inclusive of Iluvien and Retisert

• History of Ozurdcx and Triamcinolone use prior to 12 months before study enrollment is allowed.

6. Current anterior segment neovascularization (ASNV), vitreous hemorrhage, or tractional retinal detachment visible at the screening assessments in the study eye.

7. Uncontrolled glaucoma or ocular hypertension in the study eye defined as an IOP >25 millimeter of mercury (mmHg) regardless of concomitant treatment with lOP-lowering medications. 8. Hypertension defined as systolic >180 mmHg or >160 mmHg on 2 consecutive measurements (during the same visit) or diastolic >100 mmHg.

9. Screening glycated hemoglobin (HbAlc) blood test >10.0%.

10. Renal failure (stage 4 or end-stage), dialysis, or history of renal transplant.

11. History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that might affect interpretation of the results of the study or render the subject at high risk for treatment complications.

12. Initiation of intensive insulin treatment (a pump or multiple daily injections) within 4 months prior to randomization or plans to do so in the next 4 months.

13. Epiretinal membrane, posterior hyaloidal traction, and/or vitreomacular traction in the study eye as determined to be significant by the Investigator.

14. Previous pars plana vitrectomy in the study eye.

15. Any intraocular surgery in the study eye within 90 days (3 months) prior to study enrollment.

16. Yttrium aluminum garnet (YAG) laser treatment in the study eye within 90 days (3 months) prior to study enrollment.

17. Concomitant use of any topical ophthalmic medications in the study eye, including dry eye or glaucoma medications, unless on a stable dose for at least 90 days (3 months) prior to study enrollment and expected to stay on stable dose throughout study participation. Topical eyedrops are not allowed within +10 minutes of study drop application.

18. Contact lens use from time of screening throughout the study.

19. Central corneal changes from dry eye that are visually significant and/or Sjogren’s syndrome.

20. Visually significant Fuchs endothelial dystrophy or other diagnosed conditions of comeal compromise including Anterior Basement Membrane Dystrophy, or any corneal dystrophy affecting central vision (peripheral processes are not exclusionary).

21. Chronic or recurrent uveitis in the study eye.

22. Ongoing ocular infection or inflammation in either eye. 23. A history of cataract surgery complicated by vitreous loss in the study eye.

24. Congenital eye malformations in the study eye.

25. A history of penetrating ocular trauma in the study eye.

26. Cognitive impairment that, in the opinion of the investigator, could compromise compliance with the requirements of the study.

27. Females of childbearing potential (i.e., who are not postmenopausal for at least 1 year or surgically sterile for at least 6 weeks prior to Visit 1 - Screening/Randomization) who are lactating, or who are pregnant as determined by a positive serum pregnancy test at Visit 1 - Screening/Randomization. Women of childbearing potential must agree to use acceptable methods of birth control throughout the study.

• Women who are breastfeeding or who have a positive serum hCG/urine pregnancy test at the screening or BL Visit.

28. Females and males of childbearing potential unwilling or unable to utilize the following acceptable methods of birth control: tubal ligation, transdermal patch, intrauterine dcviccs/systcms, oral/implantablc/injcctablc or contraceptives, diaphragm or cervical cap with spermicide, or vasectomized partner for females; condoms with spermicidal agent and vasectomy for males; or sexual abstinence for males and females.

29. Participation in any other investigational device or drug clinical research study within 12 weeks of Visit 1 - Screening/Randomization and during the duration of enrollment.

30. Contraindication to the study medications or fluorescein dye.

31. Other ocular pathologies that, in the investigator’s opinion, would interfere with the participant’s vision in the study eye.

32. Ocular media of insufficient quality to obtain fundus photographs, fluorescein angiography, and OCT images in the study eye.

33. CST of > 300 pm. Rescue Therapy

[00231] Rescue therapy may be administered in the following situation: patients meeting one or all the following criteria would qualify for rescue with anti-VEGF therapy and/or PRP laser after consultation with the Medical Monitor:

• Worsening DRSS score to 65 or higher as confirmed by the central reading center,

• Decrease in BCVA of > 10 ETDRS letters from baseline associated with DME at any visit,

• Decrease in BCVA of 5 to 9 ETDRS letters from baseline at two consecutive visits 4 weeks apart associated with DME,

• Increase in CST of > 75 microns from baseline associated with DME,

• Any condition that, in the clinical opinion of the investigator, warrants rescue therapy after consultation with the Medical Monitor.

Evaluation of Efficacy and Safety - Endpoints and Measurement Procedures

[00232] The primary outcome measure is the proportion of participants treated with Compound 1 who have improved by >2 steps from baseline as determined by central reading center assessment using the Diabetic Retinopathy Severity Scale (DRSS). The primary endpoint for assessing safety is the proportion of participants who develop treatment-emergent adverse events through week 24.

[00233] Secondary outcome measures for efficacy that will be tested are as follows:

• Proportion of participants developing worse than mild PDR (DRSS 65 and above) at Week 24.

• Proportion of participants who develop ASNV at Week 24.

• Time to development of PDR worse than mild (DRSS 65 and above).

• Proportion of participants who develop CI-DME at Week 24.

Time to development of CI-DME. Proportion of participants with a change in DRSS step at Week 24 compared to baseline. A change in DRSS step is defined as diabetic retinopathy worsening or improving by 1, 2, or > 3 steps.

• Proportion of participants with mild PDR (DRSS score 61 ) at baseline who regress to NPDR (DRSS score < 53) by Week 24.

• Mean and median change in DRSS score from baseline to Week 24.

• Mean and median change in BCVA (ETDRS letters) from baseline to Week 24.

• Lines gained/lost in BCVA (± 5, 10, and 15 ETDRS letters) at Week 24.

• Mean and median change in area under the curve (AUC) for change in BCVA from baseline to Week 24.

• Mean and median change in CST from baseline to Week 24.

• AUC for change in CST from baseline to 24 weeks.

• Proportion of participants who met the rescue criteria.

• Time to meet rescue therapy criteria.

[00234] Exploratory outcomes measures include: o Proportion of participants who have non-CLDME (which is DME found outside 1,000 pm diameter of the foveal center) at baseline that is resolved (no non-CI- DME) at Week 24. o Proportion of participants who do not have non-CI-DME at baseline that develop non-CLDME by Week 24. o Time to development of non-CI-DME (in those participants who do not have non CI DME at baseline). o Time to resolve non-CI-DME (in those participants who do have non-CI-DME at baseline). o Change in area of retinal non-perfusion from baseline to Week 24 seen on widefield fluorescein angiography (FA). o Proportion of participants with intact foveal avascular zone (FAZ) seen on widcficld FA at Week 24. o Optical coherence tomography angiography (OCTA) endpoints within the 6 mm area:

■ Change from baseline to Week 24 in FAZ area.

■ Change from baseline to Week 24 in non-perfusion area.

■ Change from baseline to Week 24 in vessel caliber.

■ Ischemic Index at Week 24 compared to baseline.

■ Proportion of participants with new neovascularization at Week 24.

■ Proportion of participants with new intraretinal microvascular anomalies (IRMA) at Week 24.

■ Change in vessel density from baseline to Week 24 in the superficial and deep layers. o Optical Coherence Tomography (OCT) endpoints:

■ Change in Total Macular Volume (TMV) from baseline to Week 24 for 1 , 3, and 6 mm regions.

■ Proportion of participants with appearance or disappearance of subretinal fluid or cysts in the 9 subfields at Week 24.

Collection of Information to Assess Efficacy

[00235] A schedule of activities and data to be collect are provided in Table 1 below.

TABLE 1. Schedule of activities (through week 24 - primary endpoint) 1 . Patients who are withdrawn from the study before week 24/visit 8 will be asked to return to the clinic to complete the visit 8 assessments.

2. Patients will continue to receive study treatment based on exam findings, AE review, and verification that rescue criteria is not met.

3. Cornea health assessment following installation of fluorescein stain, including epithelium and endothelium, for signs of toxicity.

4. Intraocular pressure should be measured at approximately the same time of day from visit to visit, if possible.

5. An FP must be performed once a patient has been diagnosed with PDR, ASNV, or CI-DME in the study eye, and before rescue treatment is given.

8. May be performed at Visit 1 or 2. Including height, weight, and body temperature.

9. Vital signs (blood pressure and heart rate) will be measured after the patient has been sitting for 5 minutes at the screening visit. From baseline through end of study only blood pressure and heart rate will be measured.

10. Adverse events will be collected from the time the informed consent form (ICF) is signed until early termination or the end of study visit. If a patient withdraws from the study, ongoing AEs will be followed to the end of study visit or until the patient withdraws consent.

11. All samples collected for laboratory assessments will be obtained prior to administration of study drug.

12. At visits at which FA is performed, urinalysis samples will be collected before FA in order to avoid false elevations in urine protein values.

13. For women of childbearing potential, a negative screening serum pregnancy test at Visit 1 is required before randomization. All women of childbearing potential will have a urine pregnancy test at each treatment visit starting at visit 2 (day 1); a negative urine pregnancy test is required before treatment is continued (randomized treatment, rescue treatment).

[00236] Ophthalmology examinations will be done for the study eye and/or both eyes as described in the table above. Color fundus photography ( CFP)

[00237] The anatomical state of the retinal vasculature will be evaluated by an ophthalmologist from posterior segment examination and CFP. All digital CFP images need to be taken by a certified technician following an acquisition protocol for modified 7-standard fields stereoscopic color fundus photographs or 4-wide field imaging of the central reading center at the visits indicated in Table 1 above.

[00238] All CFPs will be transmitted to the central reading center for ETDRS diabetic retinopathy severity scale (DRSS, see Table 2 below) grading and storage. The images of the screening visit of both eyes will be used as part of the eligibility assessment regarding the severity of diabetic retinopathy.

[00239] CFPs may, in addition, be evaluated for additional, exploratory, endpoints. This may include assessment of microaneurysm turnover (Nunes S, et al. in Ophthalmologica (2009) vo. 223(5), pages 292-7.) or measurement of diameters of retinal vessels as described previously (Lundberg K. et al. in Retina (2013) vol. 33(10). Pages 2089-95.). This may involve transmission of CFP to additional central reading centers.

Diabetic Retinopathy Severity’ Scale

[00240] The Diabetic Retinopathy Severity Scale (DRSS) is presented in Table 2 below. A patient’s score on the DRSS is determined by analysis of color fundus photography images of the patient’s retina, and comparing the anatomical state of the retinal vasculature to the descriptions in Table 2. For example, if diabetic retinopathy is absent in the patient’s retina, then the patient is assigned a DRSS score of 10. If the patient is observed to have mild NPDR, then the patient is assigned a DRSS score of 35.

TABLE 2.

Level Severity

10 DR absent

20 Microaneurysms only

35 Mild NPDR

43 Moderate NPDR 47 Moderately severe NPDR

53 Severe NPDR

61 Mild PDR

65 Moderate PDR

71 High-risk PDR

75 High-risk PDR

81 Advanced PDR: fundus partially obscured, center of macula attached

85 Advanced PDR: posterior fundus obscured, or center of macula detached 90 Cannot grade, even sufficiently for level 81 or 85

ETDRS = Early Treatment Diabetic Retinopathy Study; DR = diabetic retinopathy; NPDR = non-proliferative DR; PDR = proliferative diabetic retinopathy

Modified from (Staurenghi G. et al. The British journal of Ophthalmology (2018), page 102).

[00241] Changes in a patient’s severity of disease under the DRSS can be characterized. For example, a change in severity from a first severity category in Table 2 to an adjacent severity category in Table 2 is referred to a l-step change in DRSS score. For example, a change in severity from Mild NPDR to Moderate NPDR is a l-step change in DRSS score. A change in severity from a first severity category in Table 2 to a severity category in Table 2 that is two echelons higher or lower in severity (e.g., a change in severity from Mild NPDR to Moderately severe NPDR) is referred to a 2-step change in DRSS score. A change in severity from a first severity category in Table 2 to a severity category in Table 2 that is three echelons higher or lower in severity (e.g., a change in severity from Mild NPDR to Severe NPDR) is referred to a 3- step change in DRSS score. A change in severity from a first severity category in Table 2 to a severity category in Table 2 that is four echelons higher or lower in severity (e.g., a change in severity from Mild NPDR to Mild PDR) is referred to a 4-step change in DRSS score. Best corrected visual acuity (BCVA)

[00242] Visual function will be assessed using a modified ETDRS protocol starting at 4 meters (AREDS in Control Clin Trials (1999) vol. 20(6), page 573-600). Visual Acuity examiners must be qualified to ensure consistent measurement of BCVA.

Fluorescein angiography ( FA )

[00243] The anatomical state of the retinal vasculature of the study eye and the fellow eye (only at BL and EOS) will be evaluated by FA (widefield preferred). All FAs will be conducted by a qualified technician following an acquisition protocol of the central reading center. The angiographic images will be evaluated by a study ophthalmologist for individual safety decisions. All FA images will be archived electronically at the site as part of the source documentation and sent to the central reading center for evaluation and storage.

[00244] At screening a standardized set of FA images will be sent to the central reading center for evaluation and eligibility assessment.

Optical coherence tomography ( OCT}

[00245] Structural OCT (widefield preferred) will be performed by using spectral domain devices. The specific device models accepted for the study will be defined by the central reading center. OCTs will be performed at every visit by qualified technicians following an acquisition protocol of the central reading center. OCTs will also be used for local safety assessment. Newly found clinically relevant pathologies should be reported as adverse event. All obtained images will be sent to the central reading center for evaluation and central reading center data will be used for the final analysis.

[00246] At screening a standardized set of OCT images will be sent to the central reading center for evaluation and eligibility assessment. Beside central retinal thickness within the central 1 mm (CST) and whole macular volume also the presence of center involving macular edema will be assessed. SD-OCT will be also assessed for several exploratory outcome parameters and morphologic predictive biomarkers.

Optical coherence tomography angiography ( OCTA )

[00247] OCTA is optional at sites that have an OCTA. The OCTA needs to be performed by a qualified technician following an acquisition protocol of the central reading center at Visit 1 and 8 as scheduled in Table 1 . The specifications of this OCTA can be found in the acquisition protocol of the central reading center. Images obtained via OCTA will be sent to the Central Reading Center for evaluation. Several quantitative and qualitative parameters including the foveal avascular zone and area of nonperfusion, which have been shown to be associated with diabetic retinal severity will be assessed.

Slit lamp biomicroscopy ( anterior and posterior segment)

[00248] The slit lamp examination (anterior and posterior segment) will be performed according to local medical practice and applicable medical standards at the site at every visit as stated in Table 1. Abnormal findings are to be recorded in the eCRF as either medical history or adverse event as applicable.

Tonometry (intraocular pressure (IOP) measurement)

[00249] Intraocular pressure is to be measured at every visit with any locally approved noncontact tonometer.

[00250] If there is no non-contact tonometer available at the site, applanation tonometry (Goldmann, Tonopen, or other locally approved alternatives) may be used. In any case, where both methods are available, the non-contact method is to be used. In cases in which Goldmann applanation tonometry (GAT) is used, assessment of corneal health using fluorescein stain should be performed prior to tonometer applanation.

[00251] The same method of IOP measurement must be used throughout the study for each individual participant and should be performed at approximately the same time of day if possible. Values, including time of day, and measuring type are to be recorded in the eCRF.

Vision-threatening complications

[00252] Vision-threatening complication (VTC) is defined as the composite outcome of proliferative diabetic retinopathy (PDR) (inclusive of participants who have vitreous hemorrhage or fractional retinal detachment believed to be due to PDR) and/or anterior segment neovascularization (ASNV) (participants with neovascularization of the iris [at least 2 cumulative clock hours], and/or definitive neovascularization of the iridocorneal angle) and/or CI-DME. Vision Threatening Complications include PDR/ASNV identified by investigators and Diabetic Retinopathy Scale Score (DRSS) >61. [00253] Vision-threatening complications are defined as occurrence of any of the following adverse events:

• More than mild PDR

• Iris neo-vascularization

• Center-involved DME.

[00254] The assessment will be continued after treatment discontinuation until end of study.

EXAMPLE 2 - Treatment of Diab etie Petinopathy

[00255] The ability of Compound 1 to treat diabetic retinopathy may be evaluated according to a clinical study in which Compound 1 is topically administered to patients suffering from diabetic retinopathy. Compound 1 has the chemical name (5)-3-(6-(difluoromethoxy)pyridin-3- yl)-3-(2-oxo-3-(3-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl) propyl)imidazolidin-l-yl)propanoic acid 2-amino-2-methylpropan-l-ol salt, and is depicted by the following chemical formula:

[00256] The study is to be configured as a Phase 2 clinical trial enrolling approximately 210 subjects diagnosed with moderately severe to severe non-proliferative diabetic retinopathy (NPDR) or mild proliferative diabetic retinopathy (PDR) and who are treatment naive (i.e., no prior anti-VEGF or laser (focal, grid, pan-retinal photocoagulation) administered). Subjects enrolled in the clinical trial will be randomized 2:2: 1 : 1 into the following groups: Compound 1 administered twice daily (BID), Compound 1 administered four times daily (QID), vehicle control administered BID, and vehicle control administered QID. Subject randomization will be stratified by baseline Diabetic Retinopathy Severity Scale (DRSS) score (47 or 53 or 61). Subjects with PDR (DRSS score 61) will be capped at 20% of all randomized participants. Compound 1 is administered in the form of a solution containing 5% w/w Compound 1. Each group will self-administer one 50-pL eye drop of study solution (frequency as assigned) for 24 weeks. The study solution is an aqueous solution. [00257] Further experimental procedures are described below.

Experimental Procedures

[00258] Human subjects will be screened for potential enrollment and, if qualified, enrolled in the study. Inclusion criteria and exclusion criteria for the study are set forth below.

[00259] Subjects enrolled in the trial shall have Type 1 or Type 2 diabetes under adequate control as evidenced by glycosylated hemoglobin (HbAlc) less than or equal to 12.0% and diagnosed with moderately severe to severe NPDR or mild PDR, as defined by the DRSS scores of 47, 53, and 61, with the PDR population capped at no more than 20% of all randomized participants. Participants must have (i) a Best corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study (ETDRS) letter score in the study eye of >69 letters (Snellen equivalent 20/40) (ii) a central subfield thickness (CST) < 325 pm, and (iii) presence of a normal foveal contour.

[00260] Only one eye will be designated as the study eye in every participant. For participants who meet eligibility criteria in both eyes during the screening phase, the eye with the higher reading center confirmed DRSS should be selected. If both eyes have the same score, the eye with the clearest lens and ocular media will be selected. If there is no objective basis for selecting the study eye, factors such as ocular dominance (better focus ability), other ocular pathology and participant preference should be considered in making the selection. The final selection will be done by the investigator at baseline and must not be changed during the course of the study.

[00261] No other ocular topic drugs (eye drops) should be taken during the study unless prescribed by the treating study physician and after discussion with the sponsor and medical monitor. If topical therapy (eye drops) is prescribed, the application of such therapy should not occur within 10 minutes (before or after) of instillation of study therapy. Other therapies for retinal disease (i.e., oral, topical, and/or intravitreal injected drugs like steroids or anti VEGFs) are not permitted, unless applied as rescue therapy. Such intake will be recorded. Contact lens wear is strictly prohibited from the time of screening throughout the study. If participant has current contact lens use at screening, contact lens use should be discontinued immediately, and a 14 day ocular surface stabilization period is needed between screening and baseline. [00262] Concomitant medications are to be recorded.

[00263] Subjects enrolled in the clinical trial will be randomized 2:2: 1 : 1 into the following groups: Compound 1 administered twice daily (BID), Compound 1 administered four times daily (QID), vehicle control administered BID, and vehicle control administered QID. Subject randomization will be stratified by baseline Diabetic Retinopathy Severity Scale (DRSS) score (47 or 53 or 61). Subjects with PDR (DRSS score 61) will be capped at 20% of all randomized participants. Compound 1 is administered in the form of a solution containing 5% w/w Compound 1. Each group will self-administer one 50-pL eye drop of study solution topically to the eye (frequency as assigned) for 24 weeks.

Inclusion Criteria

[00264] Participants are eligible to be included in the study only if all the following criteria apply:

1. Men or women >18 years of age with type 1 or 2 diabetes mellitus who have moderately severe to severe non-proliferative diabetic retinopathy (NPDR) [diabetic retinopathy severity scale (DRSS) score of 47 or 53], or mild proliferative diabetic retinopathy (PDR) [(diabetic retinopathy severity scale (DRSS) score of 61): NVE < 0.5 DA in 1+ quadrants], in whom pan- retinal photocoagulation (PRP) and/or anti-VEGF intravitreal therapy (IVT) can be safely deferred for at least 6 months per the investigator.

2. Best corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study (ETDRS) letter score in the study eye of >69 letters (approximate Snellen equivalent of 20/40 or better).

3. Normal foveal contour.

4. Treatment naive (i.e., no previous anti-VEGF or steroid treatment or laser).

5. Willing and able to return for all study visits and comply with study-related procedures.

6. Able to adhere to the study dosing requirements.

7. Understands and signs the written informed consent form.

Exclusion Criteria

[00265] Participants are excluded from the study if any of the following criteria apply: 1. CST of> 325 pm. Fluid in the central subfield is allowed so long as CST is < 325 pm.

2. Any prior focal or grid laser photocoagulation or any prior PRP in the study eye as it pertains to treatment of DME or DR (peripheral retinal hole treated with laser is allowed).

3. Eyes with DRSS score 61 due to fibrous proliferations at disc or fibrous proliferations elsewhere. a. DRSS score 61 with neovascularization elsewhere (NVE) only is allowed. Any sign of fibrosis proliferation is exclusionary.

4. Any prior systemic anti-vascular endothelial growth factor (VEGF) treatment or intravitreal (IVT) anti- VEGF treatment in the study eye.

5. Any prior intraocular steroid injection in the study eye - inclusive of ILUVIEN® and RETISERT®

• History of Ozurdex® and triamcinolone use prior to 12 months before study enrollment is allowed.

6. Current anterior segment neovascularization (ASNV), vitreous hemorrhage, or tractional retinal detachment visible at the screening assessments in the study eye.

7. Uncontrolled glaucoma or ocular hypertension in the study eye defined as an IOP >25 millimeter of mercury (mmHg) regardless of concomitant treatment with lOP-lowering medications.

8. Hypertension defined as systolic >180 mmHg or >160 mmHg on 2 consecutive measurements (during the same visit) or diastolic >100 mmHg.

9. Screening glycated hemoglobin (HbAlc) blood test >12.0%.

10. Renal failure (stage 4 or end-stage), dialysis, or history of renal transplant.

11. History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that might affect interpretation of the results of the study or render the subject at high risk for treatment complications. 12. Initiation of intensive insulin treatment (a pump or multiple daily injections) within 4 months prior to randomization or plans to do so in the next 4 months.

13. Epiretinal membrane, posterior hyaloidal traction, and/or vitreomacular traction in the study eye as determined to be significant by the Investigator.

14. Previous pars plana vitrectomy in the study eye.

15. Any intraocular surgery in the study eye within 90 days (3 months) prior to study enrollment.

16. Yttrium aluminum garnet (YAG) laser treatment in the study eye within 90 days (3 months) prior to study enrollment.

17. Concomitant use of any topical ophthalmic medications in the study eye, including dry eye or glaucoma medications, unless on a stable dose for at least 90 days (3 months) prior to study enrollment and expected to stay on stable dose throughout study participation. Topical eyedrops are not allowed within +10 minutes of study drop application.

18. Contact lens use from time of screening throughout the study.

19. Central corneal changes from dry eye that are visually significant and/or Sjogren’s syndrome.

20. Visually significant Fuchs endothelial dystrophy or other diagnosed conditions of comeal compromise including Anterior Basement Membrane Dystrophy, or any corneal dystrophy affecting central vision (peripheral processes arc not exclusionary).

21. Chronic or recurrent uveitis in the study eye.

22. Ongoing ocular infection or inflammation in either eye.

23. A history of cataract surgery complicated by vitreous loss in the study eye.

24. Congenital eye malformations in the study eye.

25. A history of penetrating ocular trauma in the study eye.

26. Cognitive impairment that, in the opinion of the investigator, could compromise compliance with the requirements of the study.

27. Females of childbearing potential (i.e., who are not postmenopausal for at least 1 year or surgically sterile for at least 6 weeks prior to Visit 1 - Screening/Randomization) who are lactating, or who are pregnant as determined by a positive serum pregnancy test at Visit 1 - Screening/Randomization. Women of childbearing potential must agree to use acceptable methods of birth control throughout the study.

• Women who are breastfeeding or who have a positive serum hCG/urine pregnancy test at the screening or BL Visit.

28. Females and males of childbearing potential unwilling or unable to utilize the following acceptable methods of birth control: tubal ligation, transdermal patch, intrauterine devices/systems, oral/implantable/injectable or contraceptives, diaphragm or cervical cap with spermicide, or vasectomized partner for females; condoms with spermicidal agent and vasectomy for males; or sexual abstinence for males and females.

29. Participation in any other investigational device or drug clinical research study within

12 weeks of Visit 1 - Screening/Randomization and during the duration of enrollment.

30. Contraindication to the study medications or fluorescein dye.

31. Other ocular pathologies that, in the investigator’s opinion, would interfere with the participant’s vision in the study eye.

32. Ocular media of insufficient quality to obtain fundus photographs, fluorescein angiography, and OCT images in the study eye.

33. Concomitant use of Semaglutide (WegovyTM, Ozempic®, Rybelsus®) or Thiazolidinediones (Actos®, Avandia®) within 12 months prior to Visit 1 (allowed if a stable dose has been established for at least 1 year of use) a. Plans to start concomitant use of Semaglutide or Thiazolidinediones during the study duration is exclusionary.

Rescue Therapy

[00266] Rescue therapy may be administered in the following situation: patients meeting one or all the following criteria would qualify for rescue with anti-VEGF therapy and/or PRP laser after consultation with the Medical Monitor:

• Worsening DRSS score to 65 or higher as confirmed by the central reading center,

• Decrease in BCVA of > 10 ETDRS letters from baseline associated with presence of new fluid or an increase in fluid in the central subfield compared to baseline at any visit, • Decrease in BCVA of 5 to 9 ETDRS letters from baseline at two consecutive visits 4 weeks apart associated with presence of new fluid or an increase in fluid in the central subfield compared to baseline,

• Increase in CST of > 75 microns from baseline associated with presence of new fluid or an increase in fluid in the central subfield compared to baseline,

• Any condition that, in the clinical opinion of the investigator, warrants rescue therapy after consultation with the Medical Monitor.

Evaluation of Efficacy and Safety - Endpoints and Measurement Procedures

[00267] The primary outcome measure is the proportion of participants treated with Compound 1 who have improved by >2 steps from baseline as determined by central reading center assessment using the Diabetic Retinopathy Severity Scale (DRSS). The primary endpoint for assessing safety is the proportion of participants who develop treatment-emergent adverse events through week 24.

[00268] Secondary outcome measures for efficacy that will be tested are as follows:

• Proportion of participants developing worse than mild PDR (DRSS 65 and above) at Week 24.

• Proportion of participants who develop ASNV at Week 24.

• Time to development of PDR worse than mild (DRSS 65 and above).

• Proportion of participants who develop CI-DME at Week 24.

• Time to development of CI-DME.

• Proportion of participants with a change in DRSS step at Week 24 compared to baseline. A change in DRSS step is defined as diabetic retinopathy worsening or improving by 1, 2, or > 3 steps.

• Proportion of participants with mild PDR (DRSS score 61) at baseline who regress to NPDR (DRSS score < 53) by Week 24.

• Mean and median change in DRSS score from baseline to Week 24.

• Mean and median change in BCVA (ETDRS letters) from baseline to Week 24. Lines gained/lost in BCVA (± 5, 10, and 15 ETDRS letters) at Week 24.

• Mean and median change in area under the curve (AUC) for change in BCVA from baseline to Week 24.

• Mean and median change in CST from baseline to Week 24.

• AUC for change in CST from baseline to 24 weeks.

• Proportion of participants who met the rescue criteria.

• Time to meet rescue therapy.

[00269] Exploratory outcomes measures include: o Change in Macular Volume (MV) from baseline to Week 24 for 1, 3, and 6 mm regions. MV will be defined as the sum of the 9 subfield measurements as provided by the imaging center. o Change in area of retinal non-perfusion from baseline to Week 24 seen on widefield fluorescein angiography (FA). o Proportion of participants with intact foveal avascular zone (FAZ) seen on widefield FA at Week 24. o Optical coherence tomography angiography (OCTA) endpoints within the 6 mm area:

■ Change from baseline to Week 24 in FAZ area.

■ Change from baseline to Week 24 in non-perfusion area.

■ Change from baseline to Week 24 in vessel caliber.

■ Ischemic Index at Week 24 compared to baseline.

■ Proportion of participants with new neovascularization at Week 24.

■ Proportion of participants with new intraretinal microvascular anomalies (IRMA) at Week 24.

■ Change in vessel density from baseline to Week 24 in the superficial and deep layers. Collection of Information to Assess Efficacy

[00270] A schedule of activities and data to be collect are provided in Table 1 below.

TABLE 1. Schedule of activities (through week 24 - primary endpoint) Non-Ocular Assessments:

1. Patients who are withdrawn from the study before week 24/visit 8 will be asked to return to the clinic to complete the visit 8 assessments.

2. Patients will continue to receive study treatment based on exam findings, AE review, and verification that rescue criteria is not met.

3. Cornea health assessment following installation of fluorescein stain, including epithelium and endothelium, for signs of toxicity.

4. Intraocular pressure should be measured at approximately the same time of day from visit to visit, if possible.

5. An FP and FA must be performed once a patient has been diagnosed with worse than mild PDR, ASNV, or new onset or worsening CI-DME in the study eye, and before rescue treatment is given. FA is fluorescein angiography.

8. May be performed at Visit 1 or 2. Including height, weight, and body temperature.

9. Vital signs (blood pressure and heart rate) will be measured after the patient has been sitting for 5 minutes at the screening visit. From baseline through end of study only blood pressure and heart rate will be measured.

10. Adverse events will be collected from the time the informed consent form (ICF) is signed until early termination or the end of study visit. If a patient withdraws from the study, ongoing AEs will be followed to the end of study visit or until the patient withdraws consent.

11. All samples collected for laboratory assessments will be obtained prior to administration of study drug. 12. At visits at which FA is performed, urinalysis samples will be collected before FA in order to avoid false elevations in urine protein values.

13. For women of childbearing potential, a negative screening serum pregnancy test at Visit 1 is required before randomization. All women of childbearing potential will have a urine pregnancy test at each treatment visit starting at visit 2 (day 1); a negative urine pregnancy test is required before treatment is continued (randomized treatment, rescue treatment).

[00271] Ophthalmology examinations will be done for the study eye and/or both eyes as described in the table above.

Color fundus photography ( CFP)

[00272] The anatomical state of the retinal vasculature will be evaluated by an ophthalmologist from posterior segment examination and CFP. All digital CFP images need to be taken by a certified technician following an acquisition protocol for modified 7-standard fields stereoscopic color fundus photographs or 4-wide field imaging of the central reading center at the visits indicated in Table 1 above.

[00273] All CFPs will be transmitted to the central reading center for ETDRS diabetic retinopathy severity scale (DRSS, see Table 2 below) grading and storage. The images of the screening visit of both eyes will be used as part of the eligibility assessment regarding the severity of diabetic retinopathy.

[00274] CFPs may, in addition, be evaluated for additional, exploratory, endpoints. This may include assessment of microaneurysm turnover (Nunes S, et al. in Ophthalmologica (2009) vo. 223(5), pages 292-7.) or measurement of diameters of retinal vessels as described previously (Lundberg K. et al. in Retina (2013) vol. 33(10). Pages 2089-95.). This may involve transmission of CFP to additional central reading centers.

Diabetic Retinopathy Severity’ Scale

[00275] The Diabetic Retinopathy Severity Scale (DRSS) is presented in Table 2 below. A patient’s score on the DRSS is determined by analysis of color fundus photography images of the patient’s retina, and comparing the anatomical state of the retinal vasculature to the descriptions in Table 2. For example, if diabetic retinopathy is absent in the patient’s retina, then the patient is assigned a DRSS score of 10. If the patient is observed to have mild NPDR, then the patient is assigned a DRSS score of 35.

TABLE 2.

Level Severity

10 DR absent

20 Microaneurysms only

35 Mild NPDR

43 Moderate NPDR

47 Moderately severe NPDR

53 Severe NPDR

61 Mild PDR

65 Moderate PDR

71 High-risk PDR

75 High-risk PDR

81 Advanced PDR: fundus partially obscured, center of macula attached

85 Advanced PDR: posterior fundus obscured, or center of macula detached

90 Cannot grade, even sufficiently for level 81 or 85

ETDRS = Early Treatment Diabetic Retinopathy Study; DR = diabetic retinopathy; NPDR = non-proliferative DR; PDR = proliferative diabetic retinopathy

Modified from (Staurenghi G. et al. The British journal of Ophthalmology (2018), page 102).

[00276] Changes in a patient’s severity of disease under the DRSS can be characterized. For example, a change in severity from a first severity category in Table 2 to an adjacent severity category in Table 2 is referred to a l-step change in DRSS score. For example, a change in severity from Mild NPDR to Moderate NPDR is a l-step change in DRSS score. A change in severity from a first severity category in Table 2 to a severity category in Table 2 that is two echelons higher or lower in severity (c.g., a change in severity from Mild NPDR to Moderately severe NPDR) is referred to a 2-step change in DRSS score. A change in severity from a first severity category in Table 2 to a severity category in Table 2 that is three echelons higher or lower in severity (e.g., a change in severity from Mild NPDR to Severe NPDR) is referred to a 3- step change in DRSS score. A change in severity from a first severity category in Table 2 to a severity category in Table 2 that is four echelons higher or lower in severity (e.g., a change in severity from Mild NPDR to Mild PDR) is referred to a 4-step change in DRSS score.

Best corrected visual acuity (BCVA)

[00277] Visual function will be assessed using a modified ETDRS protocol starting at 4 meters (AREDS in Control Clin Trials (1999) vol. 20(6), page 573-600). Visual Acuity examiners must be qualified to ensure consistent measurement of BCVA.

Fluorescein angiography ( FA )

[00278] The anatomical state of the retinal vasculature of the study eye and the fellow eye (only at BL and EOS) will be evaluated by FA (widefield preferred). All FAs will be conducted by a qualified technician following an acquisition protocol of the central reading center. The angiographic images will be evaluated by a study ophthalmologist for individual safety decisions. All FA images will be archived electronically at the site as part of the source documentation and sent to the central reading center for evaluation and storage.

[00279] At screening a standardized set of FA images will be sent to the central reading center for evaluation and eligibility assessment.

Optical coherence tomography ( OCT}

[00280] Structural OCT (widefield preferred) will be performed by using spectral domain devices. The specific device models accepted for the study will be defined by the central reading center. OCTs will be performed at every visit by qualified technicians following an acquisition protocol of the central reading center. OCTs will also be used for local safety assessment. Newly found clinically relevant pathologies should be reported as adverse event. All obtained images will be sent to the central reading center for evaluation and central reading center data will be used for the final analysis. [00281] At screening a standardized set of OCT images will be sent to the central reading center for evaluation and eligibility assessment. Beside central retinal thickness within the central 1 mm (CST) and whole macular volume also the presence of center involving and non-center involving macular edema will be assessed. SD-OCT will be also assessed for foveal contour and several exploratory outcome parameters and morphologic predictive biomarkers.

Optical coherence tomography angiography ( OCTA )

[00282] OCTA is optional at sites that have an OCTA. The OCTA needs to be performed by a qualified technician following an acquisition protocol of the central reading center at Visit 1 and 8 as scheduled in Table 1. The specifications of this OCTA can be found in the acquisition protocol of the central reading center. Images obtained via OCTA will be sent to the Central Reading Center for evaluation. Several quantitative and qualitative parameters including the foveal avascular zone and area of nonperfusion, which have been shown to be associated with diabetic retinal severity will be assessed.

Slit lamp biomicroscopy ( anterior and posterior segment}

[00283] The slit lamp examination (anterior and posterior segment) will be performed according to local medical practice and applicable medical standards at the site at every visit as stated in Table 1. Abnormal findings are to be recorded in the eCRF as either medical history or adverse event as applicable.

Tonometry (intraocular pressure (IOP} measurement)

[00284] Intraocular pressure is to be measured at every visit with any locally approved noncontact tonometer.

[00285] If there is no non-contact tonometer available at the site, applanation tonometry (Goldmann, Tonopen, or other locally approved alternatives) may be used. In any case, where both methods are available, the non-contact method is to be used. In cases in which Goldmann applanation tonometry (GAT) is used, assessment of corneal health using fluorescein stain should be performed prior to tonometer applanation.

[00286] The same method of IOP measurement must be used throughout the study for each individual participant and should be performed at approximately the same time of day if possible. Values, including time of day, and measuring type are to be recorded in the eCRF. Vision-threatening complications

[00287] Vision-threatening complication (VTC) is defined as the composite outcome of proliferative diabetic retinopathy (PDR) (inclusive of participants who have vitreous hemorrhage or tractional retinal detachment believed to be due to PDR) and/or anterior segment neovascularization (ASNV) (participants with neovascularization of the iris [at least 2 cumulative clock hours], and/or definitive neovascularization of the iridocorneal angle) and/or Cl-DME. Vision Threatening Complications include PDR/ASNV identified by investigators and Diabetic Retinopathy Scale Score (DRSS) >61. CI-DME is defined as the presence of fluid in the central subfield in participants who have no fluid at baseline or CST> 325 pm.

[00288] Vision-threatening complications are defined as occurrence of any of the following adverse events:

• More than mild PDR

• Iris neo-vascularization

• Center-involved DME.

[00289] The assessment will be continued after treatment discontinuation until end of study.

INCORPORATION BY REFERENCE

[00290] The entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes.

EQUIVALENTS

[00291] The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.