METHODS AND FORMULATIONS FOR TREATMENT OF OCULAR DISORDERS

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of US 62/007,112 filed June 3, 2014, Cousins et al, entitled "METHODS AND FORMULATIONS FOR TREATMENT OF OCULAR DISORDERS", Atty Docket No. DU4359PROV which is hereby incorporated by reference in its entirety.

1. FIELD

[0002] The present disclosure relates generally to the treatment of disorders of the eye, and more specifically relates to methods, formulations, and drug delivery systems for the treatment of ocular diseases including posterior segment eye disorders, such as age-related macular degeneration (AMD). As such, the disclosure finds utility in the fields of ophthalmology, pharmacology, and pharmaceutical formulation.

2. BACKGROUND

2.1. Introduction

[0003] Disease and injury to the anterior surface of the eye are the leading causes of visits to physicians for medical eye care in the United States. These diseases and injuries rank among the most painful of eye conditions and can lead to disability and blindness. Major clinical problems of the surface of the eye include ocular surface drying, tear film abnormalities, and related complications; ocular surface wounds with resultant pathology and scarring; corneal dysfunction dystrophies and inherited disease; inflammatory disease; and external ocular infections. Eye diseases and injuries can have symptoms ranging from itchy, runny eyes to impaired vision. Therefore, it is important to address eye problems right away, as some diseases can progressively worsen or even trigger other serious problems.

[0004] Disease and injury to tissues of the posterior segment of the eye, including the retina and choroid, is involved in many of the most common blinding diseases in the industrialized world. AMD is the most common aging-related ophthalmic disorder today, and causes irreversible loss of vision. AMD is a progressive condition that is untreatable in up to 90% of patients, and is a leading cause of blindness in the elderly. The medical and societal burden caused by this pervasive and serious disorder is extremely high: as of 2003, the United Nations estimated the number of people with age-related macular degeneration at 20 to 25 million worldwide, and that number is expected to triple in the next twenty or thirty years. Furthermore, according to the

United Nation's recent predictions, the population of individuals over eighty is expected to increase from 69 million in 2000 to 379 million by the year 2050, exacerbating an already dire problem.

[0005] Although much research has been devoted to developing a cure for dry AMD, there is currently no FDA-approved pharmacotherapy for the disease.

3. SUMMARY OF THE DISCLOSURE

[0006] The present disclosure addresses the aforementioned need in the art by providing a method, composition, formulation, and drug delivery system for treating a posterior segment eye disorder in a patient.

[0007] In one aspect, a method is provided for treating or preventing a posterior segment eye disorder in a patient in need thereof, by administering to the patient a therapeutically effective dose of an active agent selected from a retinoid X receptor (RXR) modulator, a liver X receptor (LXR) modulator, or a combination thereof. The posterior segment eye disorder may be dry age- related macular degeneration, wet macular degeneration, other causes of choroidal neovascularization (including ocular histoplasmosis, traumatic, myopia and others), diabetic retinopathy with or without diabetic macular edema, other causes of macular edema, other causes of retinal neovascularization, retinal detachments from any cause (including tractional, exudative or rhegmatogenous), proliferative vitreoretinopathy, endophthalmitis, posterior uveitis, branch and central retinal vein occlusion, other vascular retinopathies (including hypertensive and macular telangiectasia), retinitis pigmentosa and other retinal degenerations, panuveitis, posterior uveitis, AIDS-related retinitis and endophthalmitis, and other disorders that will be discussed in detail infra. The active agent is generally administered in a pharmaceutical formulation that comprises a pharmaceutically accepted vehicle, where the formulation is adapted to a particular mode of administration. The active agent may be orally administered or systemically administered in some other manner, or the agent may be administered to the eye via topical administration, periocular or intravitreal injection, or by way of an implanted ophthalmic drug delivery system. In another aspect, a method is provided for treating or preventing a posterior segment eye disorder in a patient in need thereof, by administration of an active agent as described above, in combination with administration of a therapeutically effective amount of an additional active agent. The additional active agent may also be a therapeutic agent indicated for the same posterior segment eye disorder, or it may potentiate the activity of the initial agent, or it may be indicated for another related or unrelated eye disorder. [0008] In another aspect, a method is provided for treating or preventing a posterior segment eye disorder in a patient in need thereof, by administration of an active agent as described above, where the active agent is administered periodically, at regular intervals or as needed, throughout an ongoing dosage regimen, e.g., daily, weekly, monthly, etc., for an extended time period, e.g., two months, four months, six months, one year, two years, or longer.

[0009] In a further aspect, a method is provided for treating or preventing a posterior segment eye disorder in a patient in need thereof, by administration of an active agent as described above, where the active agent is administered in a controlled release formulation such that drug release occurs gradually and over a sustained time period, as may be accomplished with a controlled release injected formulation, a controlled release implant, or the like.

[0010] In an additional aspect, a method is provided for treating or preventing a posterior segment eye disorder in a patient in need thereof, by administering to the patient a therapeutically effec the Formula (I):

[0011] Wherein R ¹ and R ² are each independently selected from hydrogen; halo; hydroxyl; cyano; nitro; amine; carboxyl; Ci-i ₂ (e.g., C1-3) alkoxyl optionally substituted with 1 or more Ci-12 (e.g., C1-3) alkyl, C2-12 (e.g., C2-3) alkenyl, C2-12 (e.g., C2-3) alkynyl, C3-12 cycloalkyl, C2-6 heterocyclyl, C ₆ -i2 aryl, C4-12 heteroaryl, carboxyl, amine, oxo, hydroxyl, cyano and/or halo; Ci-12 (e.g., C1-3) carbonyl optionally substituted with 1 or more Ci-12 (e.g., C1-3) alkyl, C2-12 (e.g., C2-3) alkenyl, C2-12 (e.g., C2-3) alkynyl, C3-12 cycloalkyl, C2-6 heterocyclyl, C6-12 aryl, C4-12 heteroaryl, carboxyl, amine, oxo, hydroxyl, cyano and/or halo; Ci-12 (e.g., C1-3) alkoxycarbonyl optionally substituted with 1 or more Ci-12 (e.g., C1-3) alkyl, C2-12 (e.g., C2-3) alkenyl, C2-12 (e.g., C2-3) alkynyl, C3-12 cycloalkyl, C2-6 heterocyclyl, C6-12 aryl, C4-12 heteroaryl, carboxyl, amine, oxo, hydroxyl, cyano and/or halo; Ci-12 (e.g., C1-3) alkyl, C2-12 (e.g., C2-3) alkenyl or C2-12 (e.g., C2-3) alkynyl, each optionally substituted with 1 or more halo, hydroxyl, Ci i2 (e.g., C1-3) alkoxyl, Ci-12 (e.g., C1-3) carbonyl, Ci-12 (e.g., C1-3) alkoxycarbonyl, C3-12 cycloalkyl, C2-6 heterocyclyl, C6-12 aryl, C4-12 heteroaryl, carboxyl, oxo, cyano, nitro, and/or amine; C3-12 cycloalkyl, C2-6 heterocyclyl, C6-12 aryl or C4-12 heteroaryl, each optionally substituted with 1 or more halo, hydroxyl, Ci-i2 (e.g., C1-3) alkyl, C2-12 (e.g., C2-3) alkenyl, C2-12 (e.g., C2-3) alkynyl, Ci-6 (e.g., C1-3) carbonyl, C2-6 (e.g., C2-3) alkoxycarbonyl, carboxyl, cyano, nitro, azide, amine, C3-12 cycloalkyl, C2-6 heterocyclyl, C6-12 aryl, and/or C4-12 heteroaryl; wherein each of the substituents is additionally optionally substituted with 1 or more halo, hydroxyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 (e.g., C1-3) alkoxyl, Ci-6 (e.g., C1-3) alkoxycarbonyl, carboxyl, cyano, nitro and/or amine.

[0012] In another aspect, a method is provided for treating or preventing a posterior segment eye disorder in a patient in need thereof, by administering to the patient a therapeutically effective dose of an active agent having the Formula (II):

[0013] Wherein R ³ , R ⁴ and R ⁵ are each independently selected from Ci-12 (e.g., C1-3) alkyl, C2- 12 (e.g., C2-3) alkenyl or C2-12 (e.g., C2-3) alkynyl, each optionally substituted with 1 or more halo, hydroxyl, Ci-i2 (e.g., C1-3) alkoxyl, Ci-12 (e.g., C1-3) carbonyl, Ci-12 (e.g., C1-3) alkoxycarbonyl, C3- 12 cycloalkyl, C2-6 heterocyclyl, C6-12 aryl, C4-12 heteroaryl, carboxyl, oxo, cyano, nitro, and/or amine. R ⁶ is selected from hydrogen; halo; hydroxyl; cyano; nitro; amine; and carboxyl.

[0014] In some embodiments, the active agent can be one or more of the following:

1 2 3

[0015] It should be noted that IO194204 has multiple designators including AGN194204.

[0016] In yet an additional aspect, a method is provided for treating or preventing a posterior segment eye disorder in a patient in need thereof, by administration of an active agent as described above, where the posterior segment eye disorder can be dry age-related macular degeneration, wet macular degeneration, other causes of choroidal neovascularization (including ocular histoplasmosis, traumatic, myopia and others), diabetic retinopathy with or without diabetic macular edema, other causes of macular edema, other causes of retinal neovascularization, retinal detachments from any cause (including tractional, exudative or rhegmatogenous), proliferative vitreoretinopathy, endophthalmitis, posterior uveitis, branch and central retinal vein occlusion, other vascular retinopathies (including hypertensive and macular telangiectasia), retinitis pigmentosa and other retinal degenerations, panuveitis, posterior uveitis, AIDS-related retinitis and endophthalmitis, and other disorders that will be discussed in detail infra.

[0017] In some embodiments, it has been surprisingly found that the combination of an RXR modulator and an LXR modulator can provide a synergistic effect compared to each agent used in isolation. When administered to a patient in need thereof, the combination acts on ocular cells relevant to ocular diseases, thereby providing enhanced therapeutic efficacy than each agent alone. In one example, such synergistic effect acts to increase expression of LXR-regulated genes.

[0018] In a further aspect, a pharmaceutical formulation is provided for ophthalmic administration, where the formulation contains a therapeutically effective amount of an active agent selected from a retinoid X receptor (RXR) modulator, a liver X receptor (LXR) modulator, and combinations thereof, and a pharmaceutically acceptable ophthalmic vehicle. [0019] In still a further aspect, a pharmaceutical formulation is provided for ophthalmic administration, where the formulation contains a therapeutically effective amount of an active agent having the molecular structure of Formula (I) or (II) above.

[0020] In still a further aspect, a pharmaceutical formulation is provided as above, wherein the formulation comprises an injectable composition, i.e., a composition for periocular or intravitreal administration.

[0021] In yet a further aspect, a drug delivery system is provided for treating a patient with a posterior segment eye disorder, where the system provides for controlled release of an active agent into the eye of a patient with the posterior segment eye disorder, wherein the active agent is selected from a retinoid X receptor (RXR) modulator, a liver X receptor (LXR) modulator, and a combination thereof, and the system comprises a biodegradable polymeric implant, a nonbiodegradable polymeric implant, a nonpolymeric implant, an iontophoretic delivery device, an ultrasound-activated drug delivery system, a drug-releasing contact lens, a drug-coated microneedle system, a microelectromechanical system (MEMS) delivery device, or a refillable port system.

[0022] Other aspects and embodiments of the disclosure will become apparent in light of the following description and drawings.

4. BRIEF DESCRIPTION OF THE FIGURES

[0023] Figure 1. Synergistic effect of a RXR modulator, LG268, and a LXR modulator, T090, in modulating expression of specific genes, ABCA1 and ABCG1, in treated ARPE-19 cells. As compared to untreated cells, the combination of LG268 (10 μΜ) and T090 (1 μΜ) promoted significant increase in both ABCA1 and ABCG1 expression.

[0024] Figure 2. Synergistic effect of a RXR modulator, LG268, and a LXR modulator, T090, in modulating expression of specific genes, ABCA1 and ABCG1, in treated primary human RPE cells. As compared to untreated cells, the combination of LG268 (10 μΜ) and T090 (1 μΜ) promoted significant increase in both ABCA1 and ABCG1 expression.

[0025] Figure 3. ApoE expression at the RPE / choroid of normal mice receiving periocular administration of vehicle solutions. Treatment with either vehicle solution, 4.5% ethanol in water solution and 2% Labrasol in 5% dextrose in water suspension (both pH adjusted to approximately 7 - 7.4), did not alter expression of ApoE in Western blot analysis of freshly isolated RPE / choroid tissue (eye was dissected and the RPE/choroid complex was harvested for protein, run on SDS PAGE electrophoresis and processed for Apolipoprotein E (ApoE) expression, using specific antibody directed against ApoE). Increased ApoE expression by this method is apparent as "double banding" on the blot. No increase was apparent either at Day 1 following injection (left blot image) or at Day 3 following injection (right blot image). These findings affirm lack of artifactual or nonspecific increase in ApoE expression by exposure to the vehicle.

[0026] Figure 4. Single-dose pharmacodynamic study with RXR ligand PA024. Mice were treated 30 μg of PA024 drug in 4.5% ethanol in water solution, by injection of drug into the subconjunctival space, and RPE / choroid complex was harvested for Western blot analysis of ApoE expression at various time points (as described in Fig. 3). Double banding (black arrow) indicated ApoE upregulation. Data indicate increased expression soon after injection (day 2), which is sustained through day 4, indicating that single administration of PA024 in this soluble formulation produces sustained biological effects for 4 days, informing dosing frequency.

[0027] Figure 5. Multi- administration pharmacodynamic study with two distinct formulations with RXR ligand PA024 demonstrates a robust PD signal. Top lanes: Mice were treated with 30 μg of PA024 drug in a 4.5% ethanol in water solution, with repeat subconjunctival administration at days indicated in Western blot descriptions, and analysis of ApoE expression at designated days (top lanes). Data indicate good expression of ApoE (black arrows indicating "double banding") at Day 1 (after 1 dose), at Day 4 (after 2 doses) and at Day 14 (after 6 doses). Bottom lanes: Mice were treated with 120 μg of PA024 drug, with repeat subconjunctival administration at days indicated in Western blot descriptions, and analysis of ApoE expression at designated days (bottom lanes). Data indicated good expression at Day 1 and 3 (after 1 dose) and at day 7 (after 2 doses).

[0028] Figure 6. Single dose pharmacodynamic study with RXR ligand AGN194204 shows duration of biological effects. Mice were treated with 30 μg of AGN194204 drug in 4.5% ethanol in water solution administered into the subconjunctival space, and RPE / choroid complex was harvested for Western blot analysis (as described in Fig. 3). Double banding (black arrow) indicates ApoE upregulation. Data indicates increased ApoE expression at day 2 with sustained expression through day 3 - 4, informing dosing frequency in this formulation.

[0029] Figure 7. Multi- administration pharmacodynamic study with two distinct formulations with RXR ligand AGN 194204 demonstrates a robust PD signal. Top lanes: Mice were treated with 30 μg of AGN 194204 drug in a 4.5% ethanol in water solution, with repeat subconjunctival administration at days indicated in Western blot descriptions, and analysis of ApoE expression at designated days (top lanes). Data indicate good expression of ApoE (black arrows indicating "double banding") at Day 1 (after 1 dose), at Day 4 (after 2 doses) and at Day 14 (after 6 doses). Bottom lanes: Mice were treated with 120 μg of AGN 194204 drug, with repeat subconjunctival administration at days indicated in Western blot descriptions, and analysis of ApoE expression at designated days (bottom lanes). Data indicated good expression at Day 1 and 3 (after 1 dose) and at day 7 (after 2 doses).

[0030] Figure 8. Multi- administration pharmacodynamic study with RXR ligand Bexarotene demonstrates increased ApoE levels by Western blot. Left eyes of mice were treated with 120 μg of Bexarotene in an 11.5% DMSO and 4.4% gum Arabic suspension at Day 0 and Day 2. Right eyes remained untreated. RPE / choroid complex of both eyes was isolated and processed for ApoE expression by Western blot analysis. As compared to untreated right eyes, Bexarotene- treated left eyes demonstrated consistent increase in ApoE expression, assessed at Day 6.

[0031] Figure 9. Biochemical effect of Bexarotene in the ApoE4 transgenic mouse model of AMD shows increased levels of solubilized Αβ peptides by ELISA analysis of RPE / choroid tissue complexes. 120 μg of Bexarotene in 11.5% DMSO / 4.4% gum Arabic suspension was administered as described in Fig. 8 in 18 mo old ApoE4 transgenic mice that had been fed high fat + cholesterol diet for 8 weeks. These mice exhibit features of human AMD disease, including sub-RPE basal laminar deposit formation, basal RPE amyloid accumulation, and abnormal ERGs.. Bexarotene-treated eyes demonstrated major increase or mobilization of both amyloid peptides, Αβ40 and Αβ42, as compared to vehicle-treated left eyes and untreated right eyes.

[0032] Figure 10. Bexarotene treatment caused visual function improvement (Electroretinograms) in the ApoE4 mouse model of AMD (n=8). Solid black squares represent ERG values of left eye prior to treatment; solid grey circles represent ERG values of fellow right eye (untreated) prior to treatment of left eye. Open grey circles represent ERG values fellow right eye (untreated) after treatment of left eye. Open black squares represent ERG values of treated left eye after Bexarotene treatment. Bexarotene periocular treatment (administered at day 0 and day 2) demonstrates dramatic improvement in ERG amplitude, indicating that Bexarotene improves visual function in the mouse model of AMD.

[0033] Figure 11. Bexarotene treatment caused deposit regression in mouse AMD eyes (morphological outcome). Left panel is a representative electron micrograph of a mouse eye treated with Bexarotene, revealing a near normal basal RPE and Bruch's membrane (dotted line circle and bracket). Right panel is a representative electron micrograph of an untreated mouse eye treated with AMD, showing thick basal deposits and abnormal Bruch's membrane (dotted line circle and bracket).

[0034] Figure 12A-12F. Bexarotene treatment caused deposit regression in mouse AMD eyes with AMD. The data in Figures 12B-12F demonstrate 5 individual eyes in which the electron micrographs from a cross section through the mouse retina was quantified in bexarotene treated and untreated eyes. All 5 treated eyes (black bars) revealed less deposit area than the untreated fellow eye (gray bars). Cumulative frequency curves demonstrate that the majority of sections in Bexarotene-treated eyes had reduced thickness of deposits.

[0035] Figure 13. Representative transmission electron microscopy of eyes from each treatment group. Using the scoring system, the vehicle treated eye demonstrates discontinuous deposits (dashed oval) that are present but flat and with homogenous appearance, along with collagenous thickening of Bruch's membrane and loss of choriocapillaris fenestrations. In contrast, both the PA024- and AGN1942024-treated eyes had clearance of deposits with normalization of Bruch's membrane thickening and normal choriocapillaris morphology. Fellow untreated eyes showed features of pathology that were comparable to those observed in vehicle- treated eyes, affirming that the treated animals had evidence of deposit pathology at baseline.

[0036] Figure 14. Representative TEM micrographs from PA024-treated eyes and fellow eye demonstrating that pathology present in untreated fellow eye but essentially resolved in eye receiving periocular drug treatment.

[0037] Figure 15. Eyes treated with AGN194204 or PA024 had lower group median deposit severity score as compared to vehicle-treated eyes

5. DETAILED DESCRIPTION OF THE DISCLOSURE

5.1. General Definitions

[0038] While the following terms are believed to be well understood by one of ordinary skill in the art, the following definitions are set forth to facilitate explanation of the presently disclosed subject matter.

[0039] Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which the disclosure pertains. Specific terminology of particular importance to the description of the present disclosure is defined below. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0040] As used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an active agent" includes a single active agent as well as a combination or mixture of two or more different active agents, reference to "a vehicle" or "an excipient" includes not only a single vehicle or excipient but also a combination or mixture of two or more different vehicles and excipients, and the like. [0041] Throughout the present specification, the terms "about" and/or "approximately" may be used in conjunction with numerical values and/or ranges. The term "about" is understood to mean those values near to a recited value. For example, "about 40 [units]" may mean within + 25% of 40 {e.g. , from 30 to 50), within + 20%, + 15%, + 10%, + 9%, + 8%, + 7%, + 6%, + 5%, + 4%, + 3%, + 2%, ± 1 %, less than + 1 %, or any other value or range of values therein or therebelow. Furthermore, the phrases "less than about [a value]" or "greater than about [a value]" should be understood in view of the definition of the term "about" provided herein. The terms "about" and "approximately" may be used interchangeably.

[0042] As used herein, the verb "comprise" as is used in this description and in the claims and its conjugations are used in its non-limiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded.

[0043] Throughout the specification the word "comprising," or variations such as "comprises" or "comprising," will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps. The present disclosure may suitably "comprise", "consist of, or "consist essentially of, the steps, elements, and/or reagents described in the claims. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as "solely", "only" and the like in connection with the recitation of claim elements, or the use of a "negative" limitation. The terms "treating" and "treatment" as used herein refer to reduction in severity and/or frequency of symptoms, elimination of symptoms and/or underlying cause, and improvement or remediation of damage.

[0044] The term "controlled release" refers to a drug-containing formulation or fraction thereof in which release of the drug is not immediate, i.e., with a "controlled release" formulation, administration does not result in immediate release of the drug into an absorption pool. The term is used interchangeably with "nonimmediate release" as defined in Remington: The Science and Practice of Pharmacy, Nineteenth Ed. (Easton, PA: Mack Publishing Company, 1995). In general, the term "controlled release" as used herein includes sustained release, modified release and delayed release formulations. That is, "controlled release" includes "sustained release" (synonymous with "extended release"), referring to a formulation that provides for gradual release of an active agent over an extended period of time, as well as "delayed release," indicating a formulation that, following administration to a patient, provides for a measurable time delay before the active agent is released from the formulation into the body of the patient, e.g., the eye. [0045] The term "dosage form" denotes any form of a pharmaceutical composition that contains an amount of active agent sufficient to achieve a therapeutic effect with a single administration. The frequency of administration that will provide the most effective results in an efficient manner without overdosing will vary with the characteristics of the particular active agent, including both its pharmacological characteristics and its physical characteristics.

[0046] The terms "effective amount" and "therapeutically effective amount" of an agent, compound, composition or combination of the disclosure refer to an amount that is nontoxic and effective for producing a therapeutic effect upon administration to a subject.

[0047] As used herein, the term "ocular disease" means and includes any disorder, disease, or perturbed function of the eye and surrounding ocular adnexae (including conjunctiva, connective tissue, extraocular muscles, periorbital tissues, and eyelids). Ocular disorders include posterior segment eye disorder(s) such as dry age-related macular degeneration, neovascular (or "wet") macular degeneration, other causes of choroidal neovascularization (including ocular histoplasmosis, traumatic, myopia and others), diabetic retinopathy with or without diabetic macular edema, other causes of macular edema, other causes of retinal neovascularization, retinal detachments from any cause (including tractional, exudative or rhegmatogenous), proliferative vitreoretinopathy, endophthalmitis, posterior uveitis, branch and central retinal vein occlusion, other vascular retinopathies (including hypertensive and macular telangiectasia), retinitis pigmentosa and other retinal degenerations, panuveitis, glaucoma, posterior uveitis, AIDS-related retinitis and endophthalmitis, as well as anterior segment disorders, including conjunctivitis, dry eye syndrome, tear film insufficiency, corneal epithelial disease, allergic eye disease, ocular hypertension, corneal dystrophies, scleritis, iritis, and other disorders that will be discussed in detail infra.

[0048] As used herein, the term "patient" or "individual" or "subject" refers to any person or mammalian subject for whom or which therapy is desired, and generally refers to the recipient of the therapy to be practiced according to the disclosure.

[0049] By "pharmaceutically acceptable" is meant a material that is not biologically or otherwise undesirable, i.e., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. When the term "pharmaceutically acceptable" is used to refer to a pharmaceutical carrier or excipient, it is implied that the carrier or excipient has met the required standards of toxicological and manufacturing testing and/or that it is included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration. The term "pharmaceutically acceptable salts" include acid addition salts of basic agents which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or with organic acids such as acetic, oxalic, tartaric, mandelic acids, and the like. Pharmaceutically acceptable basic addition salts of acidic agents can be prepared with inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, or with organic bases such as isopropylamine, trimethylamine, histidine, procaine and the like.

[0050] "Pharmacologically active" (or simply "active") as in a "pharmacologically active" analog, refers to a compound having the same type of pharmacological activity as the parent compound and approximately equivalent in degree.

[0051] It specifically is understood that any numerical range recited herein includes all values from the lower value to the upper value. For example, if a concentration range is stated as 1 % to 50%, it is intended that values such as 2% to 40%, 10% to 30%, or 1 % to 3%, etc., are expressly enumerated in this specification. It is to be understood that these ranges comprise all subranges therein. Thus, the range "from 50 to 80" includes all possible ranges therein (e.g., 51-79, 52-78, 53-77, 54-76, 55-75, 60-70, etc.). Furthermore, all values within a given range may be an endpoint for the range encompassed thereby (e.g. , the range 50-80 includes the ranges with endpoints such as 55-80, 50-75, etc.). These are only examples of what is specifically intended, and all possible combinations of numerical values between and including the lowest value and the highest value enumerated are to be considered to be expressly stated in this application.

5.2. Chemical Definitions

[0052] As used herein, the phrase "having the formula" or "having the structure" is not intended to be limiting and is used in the same way that the term "comprising" is commonly used.

[0053] The term "acyl" refers to substituents having the formula -(CO)-alkyl, -(CO)-aryl, or - (CO)-aralkyl, and the term "acyloxy" refers to substituents having the formula -0(CO)-alkyl, - 0(CO)-aryl, or -0(CO)-aralkyl, wherein "alkyl," "aryl, and "aralkyl" are as defined above.

[0054] The term "alicyclic" is used in the conventional sense to refer to an aliphatic cyclic moiety, as opposed to an aromatic cyclic moiety, and may be monocyclic, bicyclic, or polycyclic.

[0055] The term "alkaryl" refers to an aryl group with an alkyl substituent, and the term "aralkyl" refers to an alkyl group with an aryl substituent, wherein "aryl" and "alkyl" are as defined above. Preferred aralkyl groups contain 6 to 24 carbon atoms, and particularly preferred aralkyl groups contain 6 to 16 carbon atoms. Examples of aralkyl groups include, without limitation, benzyl, 2-phenyl-ethyl, 3 -phenyl-propyl, 4-phenyl-butyl, 5-phenyl-pentyl, 4- phenylcyclohexyl, 4-benzylcyclohexyl, 4-phenylcyclohexylmethyl, 4-benzylcyclohexylmethyl, and the like. Alkaryl groups include, for example, p-methylphenyl, 2,4-dimethylphenyl, p- cyclohexylphenyl, 2,7-dimethylnaphthyl, 7-cyclooctyinaphthyl, 3-ethyl-cyclopenta-l ,4-diene, and the like. The terms "alkaryloxy" and "aralkyloxy" refer to substituents of the formula -OR wherein R is alkaryl or aralkyl, respectively, as just defined.

[0056] The term "alkenyl" as used herein refers to a linear, branched or cyclic hydrocarbon group of 2 to about 24 carbon atoms containing at least one double bond, such as ethenyl, n- propenyl, isopropenyl, n-butenyl, isobutenyl, octenyl, decenyl, tetradecenyl, hexadecenyl, eicosenyl, tetracosenyl, and the like. Generally, although again not necessarily, alkenyl groups herein contain 2 to about 18 carbon atoms, preferably 2 to 12 carbon atoms. The term "lower alkenyl" intends an alkenyl group of 2 to 4 carbon atoms.

[0057] The term "alkyl" as used herein refers to a branched or unbranched saturated hydrocarbon group typically although not necessarily containing 1 to about 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl, and the like, as well as cycloalkyl groups such as cyclopentyl, cyclohexyl, and the like. Generally, although again not necessarily, alkyl groups herein contain 1 to about 18 carbon atoms, preferably 1 to about 12 carbon atoms. The term "lower alkyl" intends an alkyl group of 1 to 6 carbon atoms. Preferred lower alkyl substituents contain 1 to 4 carbon atoms. "Substituted alkyl" refers to alkyl substituted with one or more substituent groups, and the terms "heteroatom-containing alkyl" and "heteroalkyl" refer to alkyl in which at least one carbon atom is replaced with a heteroatom, as described in further detail infra. If not otherwise indicated, the terms "alkyl" and "lower alkyl" include linear, branched, cyclic, unsubstituted, substituted, and/or heteroatom-containing alkyl or lower alkyl, respectively.

[0058] The term "aryloxy" as used herein refers to an aryl group bound through a single, terminal ether linkage, wherein "aryl" is as defined above. An "aryloxy" group may be represented as -O-aryl where aryl is as defined above. Preferred aryloxy groups contain 5 to 24 carbon atoms, and particularly preferred aryloxy groups contain 5 to 14 carbon atoms. Examples of aryloxy groups include, without limitation, phenoxy, o-halo-phenoxy, m-halo-phenoxy, p-haio- phenoxy, o-methoxy-phenoxy, m-methoxy-phenoxy, p-methoxy-phenoxy, 2,4- dimethoxyphenoxy, 3,4,5-trimethoxy-phenoxy, and the like.

[0059] The term "alkynyl" as used herein refers to a linear or branched hydrocarbon group of 2 to 24 carbon atoms containing at least one triple bond, such as ethynyl, n-propynyl, and the like. Generally, although again not necessarily, alkynyl groups herein contain 2 to about 18 carbon atoms, preferably 2 to 12 carbon atoms. The term "lower alkynyl" intends an alkynyl group of 2 to 4 carbon atoms. [0060] The term "alkoxy" as used herein intends an alkyl group bound through a single, terminal ether linkage; that is, an "alkoxy" group may be represented as -O-alkyl where alkyl is as defined above. A "lower alkoxy" group intends an alkoxy group containing 1 to 6 carbon atoms, and includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, t-butyloxy, etc. Preferred lower alkoxy substituents contain 1 to 3 carbon atoms, and particularly preferred such substituents contain 1 or 2 carbon atoms (i.e., methoxy and ethoxy). The terms "alkenyloxy" and "alkynyloxy" are defined in an analogous manner.

[0061] The term "amine" includes primary (— NH ₂ ), secondary (— NHR), tertiary (— NRR'), and quaternary (— N ⁺ RR'R") amine having one, two or three independently selected substituents R, R' , and R" such as straight chain or branched chain alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycle, and the like. The term "azide" refers to a group of formula— N ₃ . The term "nitro" refers to a group of formula— NO2.

[0062] The term "aryl" as used herein, and unless otherwise specified, refers to an aromatic substituent containing a single aromatic ring or multiple aromatic rings that are fused together, directly linked, or indirectly linked (such that the different aromatic rings are bound to a common group such as a methylene or ethylene moiety). Preferred aryl groups contain 5 to 24 carbon atoms, and particularly preferred aryl groups contain 5 to 14 carbon atoms. Exemplary aryl groups contain one aromatic ring or two fused or linked aromatic rings, e.g., phenyl, naphthyl, biphenyl, diphenylether, diphenylamine, benzophenone, and the like. "Substituted aryl" refers to an aryl moiety substituted with one or more substituent groups, and the terms "heteroatom containing aryl" and "heteroaryl" refer to aryl substituent, in which at least one carbon atom is replaced with a heteroatom, as will be described in further detail infra. If not otherwise indicated, the term "aryl" includes unsubstituted, substituted, and/or heteroatom-containing aromatic substituents.

[0063] As used herein, the term "cyano," employed alone or in combination with other terms, refers to a group of formula— CN, wherein the carbon and nitrogen atoms are bound together by a triple bond.

[0064] The term "cyclic" refers to alicyclic or aromatic substituents that may or may not be substituted and/or heteroatom containing, and that may be monocyclic, bicyclic, or polycyclic.

[0065] The terms "halo" and "halogen" are used in the conventional sense to refer to a chloro, bromo, fluoro, or iodo substituent.

[0066] The term "heteroatom-containing" as in a "heteroatom-containing alkyl group" (also termed a "heteroalkyl" group) or a "heteroatom-containing aryl group" (also termed a "heteroaryl" group) refers to a molecule, linkage or substituent in which one or more carbon atoms are replaced with an atom other than carbon, e.g., nitrogen, oxygen, sulfur, phosphorus or silicon, typically nitrogen, oxygen or sulfur, preferably nitrogen or oxygen. Similarly, the term "heteroalkyl" refers to an alkyl substituent that is heteroatom-containing, the term "heterocyclic" refers to a cyclic substituent that is heteroatom-containing, the terms "heteroaryl" and heteroaromatic" respectively refer to "aryl" and "aromatic" substituents that are heteroatom- containing, and the like. Examples of heteroalkyl groups include alkoxyaryl, alkylsulfanyl substituted alkyl, N-alkylated amino alkyl, and the like. Examples of heteroaryl substituents include pyrrolyl, pyrrolidinyl, pyridinyl, quinolinyl, indolyl, pyrimidinyl, imidazolyl, 1,2,4- triazolyl, tetrazolyl, etc., and examples of heteroatom-containing alicyclic groups are pyrrolidino, morpholino, piperazino, piperidino, etc.

[0067] "Hydrocarbonyl" refers to univalent hydrocarbonyl radicals containing 1 to about 30 carbon atoms, preferably 1 to about 24 carbon atoms, more preferably 1 to about 18 carbon atoms, most preferably about 1 to 12 carbon atoms, including linear, branched, cyclic, saturated, and unsaturated species, such as alkyl groups, alkenyl groups, aryl groups, and the like. "Substituted hydrocarbonyl" refers to hydrocarbonyl substituted with one or more substituent groups, and the term "heteroatom-containing hydrocarbonyl" refers to hydrocarbyl in which at least one carbon atom is replaced with a heteroatom. Unless otherwise indicated, the term "hydrocarbonyl" is to be interpreted as including substituted and/or heteroatom-containing hydrocarbonyl moieties.

[0068] "Optional" or "optionally" means that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not. For example, the phrase "optionally substituted" means that a nonhydrogen substituent may or may not be present on a given atom, and, thus, the description includes structures wherein a non-hydrogen substituent is present and structures wherein a nonhydrogen substituent is not present. Similarly, the phrase an "optionally present" bond as indicated by a dotted line in the chemical formulae herein means that a bond may or may not be present.

[0069] By "substituted" as in "substituted alkyl," "substituted aryl," and the like, as alluded to in some of the aforementioned definitions, is meant that in the alkyl, aryl, or other moiety, at least one hydrogen atom bound to a carbon (or other) atom is replaced with one or more non-hydrogen substituents. Examples of such substituents include, without limitation: functional groups such as halo, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy, C5-C24 aryloxy, acyl (including C2-C24 alkylcarbonyl (-CO-alkyl) and C6-C24 arylcarbonyl (-CO-aryl)), acyloxy (- O-acyl), C2-C24 alkoxycarbonyl (-(CO)-O-alkyl), C6-C24 aryloxycarbonyl (-(CO)-O-aryl), halocarbonyl (-CO)-X where X is halo), C2-C24 alkylcarbonato (-O-(CO)-O-alkyl), C6-C24 arylcarbonato (-O-(CO)-O-aryl), carboxy (-COOH), carboxylato (-COO-), carbamoyl (-(CO)- NH ₂ ), mono-(Ci-C ₂ 4 alkyl)-substituted carbamoyl (-(CO)-NH(Ci-C ₂ 4 alkyl)), di-(Ci-C ₂ 4 alkyl)- substituted carbamoyl (-(CO)-N(Ci-C ₂ 4 alkyl) ₂ ), mono-(C6-C ₂ 4 aryl)- substituted carbamoyl (- (CO)-NH-aryl), di-(C6-C ₂₄ aryl)-substituted carbamoyl (-(CO)-N(aryl) ₂ ), di-N-(Ci-C ₂₄ alkyl), N- (C6-C24 aryl)-substituted carbamoyl, thiocarbamoyl (-(CS)-NH ₂ ), carbamido (-NH-(CO)-NH ₂ ), cyano(-C≡N), isocyano (-N ⁺ ≡C -), cyanato (-0-C≡N), isocyanato (-0— N ⁺ ≡C -), isothiocyanato (- S-C≡N), azido (-N=N ⁺ ≡N ^" ), formyl (-(CO)-H), thioformyl (-(CS)-H), amino (-NH ₂ ), mono-(Ci- C24 alkyl)-substituted amino, di-(Ci-C ₂ 4 alkyl)-substituted amino, mono-(C5-C ₂ 4 aryl)-substituted amino, di-(C5-C ₂ 4 aryl)-substituted amino, C2-C24 alkylamido (-NH-(CO)-alkyl), C6-C24 arylamido (-NH-(CO)-aryl), imino (-CR=NH where R is hydrogen, C1-C24 alkyl, C5-C24 aryl, Ce- C24 alkaryl, C6-C24 aralkyl, etc.), alkylimino (-CR=N(alkyl), where R is hydrogen, C1-C24 alkyl, C5-C24 aryl, C6-C24 alkaryl, C6-C24 aralkyl, etc.), arylimino (-CR=N(aryl), where R is hydrogen, C1-C24 alkyl, C5-C ₂ 4aryl, Ce- C24 alkaryl, C6-C24 aralkyl, etc.), nitro (-NO2), nitroso (-NO), sulfo (- SO2-OH), sulfonate (-SO2-O-), C1-C24 alkylsulfanyl (-S-alkyl; also termed "alkylthio"), arylsulfanyl (-S-aryl; also termed "arylthio"), C1-C24 alkylsulfinyl (-(SO)-alkyl), C5-C24 arylsulfinyl (-(SO)-aryl), C1-C24 alkylsulfonyl (-S0 ₂ -alkyl), C5-C24 arylsulfonyl (-S0 ₂ -aryl), phosphono (-P(0)(OH) ₂ ), phosphonato (-P(0)(0-) ₂ ), phosphinato (-P(0)(0-)), phospho (-PO2), and phosphino (-PH2); and the hydrocarbyl moieties C1-C24 alkyl (preferably C1-C18 alkyl, more preferably C1-C12 alkyl, most preferably C1-C6 alkyl), C2-C24 alkenyl (preferably C2-C18 alkenyl, more preferably C2-C12 alkenyl, most preferably C2-C6 alkenyl), C2-C24 alkynyl (preferably C2- Ci8 alkynyl, more preferably C2-C12 alkynyl, most preferably C2-C6 alkynyl), C5-C24 aryl (preferably Cs-Cw aryl), C6-C24 alkaryl (preferably C6-C18 alkaryl), and C6-C24 aralkyl (preferably C6-C18 aralkyl).

[0070] In addition, the aforementioned functional groups may, if a particular group permits, be further substituted with one or more additional functional groups or with one or more hydrocarbonyl moieties such as those specifically enumerated above. Analogously, the abovementioned hydrocarbonyl moieties may be further substituted with one or more functional groups or additional hydrocarbonyl moieties such as those specifically enumerated.

[0071] When the term "substituted" appears prior to a list of possible substituted groups, it is intended that the term apply to every member of that group. For example, the phrase "substituted alkyl, alkenyl, and aryl" is to be interpreted as "substituted alkyl, substituted alkenyl, and substituted aryl. " Analogously, when the term "heteroatom-containing" appears prior to a list of possible heteroatom-containing groups, it is intended that the term apply to every member of that group. For example, the phrase "heteroatom-containing alkyl, alkenyl, and aryl" is to be interpreted as "heteroatom-containing alkyl, substituted alkenyl, and substituted aryl. " [0072] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they optionally encompass substituents resulting from writing the structure from right to left, e.g., -CH2NH- optionally also recites -NHCH2-.

[0073] In accordance with a convention used in the art, the group:

[0074] —I ^<

[0075] is used in structural formulae herein to depict a bond that is the point of attachment of the moiety or substituent to the core or backbone structure.

[0076] For compounds described herein, groups and substituents thereof may be selected in accordance with permitted valence of the atoms and the substituents, such that the selections and substitutions result in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.

[0077]

5.3. Active Agents

[0078] In one embodiment, the active agent is a modulator of the retinoid X receptor (RXR) and/or the liver X receptor (LXR), i.e., the agent is a compound or composition that stimulates, blocks, or inhibits the biological activity of the retinoid- associated nuclear receptor RXR and/or the LXR.

[0079] RXR modulators either increase or decrease the ability of the RXR to activate transcription of genes including those that control cellular differentiation and proliferation. The term "RXR modulator" as used herein encompasses prodrugs and precursors as well as RXR modulators per se, i.e., compounds that are therapeutically inactive as administered but that are converted to an active RXR modulator in the body, following administration. The agent may or may not in addition be a modulator of the retinoic acid receptor (RAR), although in a preferred embodiment the agent is not an RAR modulator but rather is RXR-selective.

[0080] Within the group of RXR modulators, selective or non-selective agonists of the RXR, including partial agonists, are generally preferred for use in conjunction with the methods and formulations of the present disclosure. It should be noted that when the term "agonist" is used herein, it is intended to include partial agonists. In the presence of an RXR agonist, it is generally accepted that the receptor undergoes a conformational change that results in an increase in the transcriptional regulation activity of RXR, RXR homodimers, and/or RXR heterodimers. RXR is known to form a dimer either with itself, in which case the dimer is an "RXR homodimer," or with another receptor such as the thyroid receptor, the vitamin D receptor, or the peroxisome proliferator-activated receptor, in which case the dimer is an "RXR heterodimer," and an RXR agonist as provided herein increases the transcriptional regulation activity of any of the foregoing.

[0081] Examples of RXR agonists that can be administered in the context of the present disclosure include, without limitation, those compounds and compositions described in U.S.

[0082] Patent Nos. 5,399,586 to Davies et al, 5,466,861 to Dawson et al, 5,780,676 to Boehm et al, 5,801,253 to Klaus et al., 5,837,725 to Dawson et al., 5,962,731 to Boehm et al., 6,320,074 to Boehm et al, 7,348,359 to Gardinier et al, U.S. Patent No. 4,326,055 to Loeliger; U.S. Patent No. 4,578,498 to Frickel et al, and Japanese Application Publication Nos. 2010280585 and 2013177329, as well as those compounds and compositions described in Boehm et al. (1994) /. Med. Chem. 38:3146-3155, Boehm et al. (1994) /. Med. Chem. 37:2930-2941, Antras et al. (1991) /. Biol. Chem. 266: 1157-1161 , Salazar-Olivo et al. (1994) Biochem. Biophys. Res. Commun. 204(10): 257-263, and Safanova (1994) Mol. Cell. Endocrin. 104:201-211. Such compounds may be prepared according to methods known in the art as described in the aforementioned references, as well as in M. L. Dawson and W. H. Okamura, Chemistry and Biology of Synthetic Retinoids, Chapters 3, 8, 14 and 16 (Florida: CRC Press, Inc., 1990); M. L. Dawson and P. D. Hobbs, The Retinoids, Biology, Chemistry and Medicine, M. B. Sporn et al, Eds. (2nd ed.), pp. 5-178 (New York, NY: Raven Press, 1994); Liu et al. (1984) Tetrahedron 40: 1931-1969; Strickland et al. (1983) Cancer Res. 43:5268-5272; Mayer et al. (1980) Eur. J. Med. Chem. 15:9-15; Allegretto et al. (1995) /. Biol. Chem. 270:23906-23909; Bissonette et al. (1995) Mol. Cell. Bio. 15:5576-5585; Beard et al. (1995) /. Med. Chem. 38:2820-2829; Koch et al. (1996) /. Med. Chem. 39:3229-3234; Kakuta et al. (2010) ACS Med. Chem. Lett. :521-525; and Kakuta et al. (2013) /. Med. Chem. 56: 1865-1877.

[0083] An exemplary group of RXR agonists useful in conjunction with the present disclosure is represented by the general structure of formula (I) or (II).

[0084] Additional active agents that can be used in conjunction with the present disclosure are modulators of the liver X receptor, particularly LXR agonists and partial agonists. Examples of such compounds are set forth, generically and by subgroup, in U.S. Patent Application Publication No. 2012/0115912 by Landreth, particularly at pages 26-31. In some embodiments, suitable LXR agonist can be selected from 22(R)-hydroxycholesterol, acetyl-podocarpic dimer, N,N-dimethyl- 3beta-hydroxy-cholenamide (DMHCA), methyl-3 -hydroxy-5a,6a-epoxycholanate (Yan, W., et al, (2010) Pharmacology 86: 306-312 ), 3-[3-[[[2-chloro-3-(trifluoromethyl-)phenyl]methyl](2,2- diphenylethyl)amino]propoxy]benzeneacetic acid (GW 3965) and N-(2,2,2-trifluoroethyl)-N-[4- [2,2,2-trifluoro- 1 -hydroxy- 1 -(trifluoromethyl)ethyl] phenyl] -benzenesulfonamide (T0901317). [0085] It will be appreciated that other RXR modulators and LXR modulators may be synthesized by modification of naturally occurring compounds, by modification of known synthetic compounds, or by using synthetic methods known to those of ordinary skill in the art of synthetic organic chemistry and/or described in the pertinent texts and literature. Any such compound that is currently known or that is discovered or invented hereinafter is considered to be within the scope of the disclosure and thus suitable for use as the active agent to be administered in the present methods of treating and preventing posterior segment eye disorders.

[0086] When referring to an active agent, whether specified as a particular compound (e.g., bexarotene) or a compound class (e.g., an RXR agonist), the term used to refer to the agent is intended to encompass not only the specified molecular entity but also its pharmaceutically acceptable, pharmacologically active analogs and derivatives, including, but not limited to, salts, esters, amides, prodrugs, conjugates, active metabolites, hydrates, crystalline forms, enantiomers, stereoisomers, and other such compounds.

5.4. Isomers

[0087] Compounds described herein may exist in one or more particular geometric, optical, enantiomeric, diastereomeric, epimeric, atopic, stereoisomer, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r- forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and 1-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; a and β-forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and half chair-forms; and combinations thereof, hereinafter collectively referred to as "isomers" (or "isomeric forms").

[0088] In one embodiment, a compound described herein may be an enantiomerically enriched isomer of a stereoisomer described herein. For example, the compound may have an enantiomeric excess of at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%.

[0089] Compounds may be prepared in racemic form or as individual enantiomers or diastereomers by either stereospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers or diastereomers by standard techniques, such as the formation of stereoisomeric pairs by salt formation with an optically active base, followed by fractional crystallization and regeneration of the free acid. The compounds may also be resolved by formation of stereoisomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column. The enantiomers also may be obtained from kinetic resolution of the racemate of corresponding esters using lipase enzymes. [0090] Note that specifically included in the term "isomer" are compounds with one or more isotopic substitutions. For example, H may be in any isotopic form, including ¾ ² H (D), and ³ H (T); C may be in any isotopic form, including ¹² C, ¹³ C, and ¹⁴ C; O may be in any isotopic form, including ¹⁶ 0 and ¹⁸ 0; and the like.

5.5. Salts

[0091] A compound described herein can be in the form of a salt, e.g., a pharmaceutically acceptable salt. Neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of this disclosure. Examples of pharmaceutically acceptable salts are discussed in Berge et al, (1977) "Pharmaceutically Acceptable Salts." /. Pharm. Sci. Vol. 66, pp. 1-19.

[0092] For example, if the compound is has an acidic functional group that can be deprotonated (e.g., -COOH to -COO-), then a salt form may be formed with a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na ⁺ and K ⁺ , alkaline earth cations such as Ca ²⁺ and Mg ²⁺ , and other cations such as ammonium ion (i.e., NH4 ^"1" ). Examples of suitable organic cations include, but are not limited to, substituted ammonium ions (e.g., NH3R1 ^"1" , NH2R2 ^"1" , NHR3 ^"1" , NR ₄ ⁺ ). Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine.

[0093] If the compound has a basic functional group that can be protonated (e.g., -NH2 toNH3 ⁺ ), then a salt form may be formed with a suitable anion. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.

[0094] Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, gluchep tonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric. Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.

[0095] Unless otherwise specified, a reference to a particular compound also includes salt forms thereof.

5.6. Chemically Protected Forms

[0096] Functional groups present in the molecular structure of active agents useful herein may or may not be protected, and it is intended that both protected and unprotected forms be encompassed herein. A functional group is "protected" if the group is in modified form to preclude undesired reactions at the protected site. Suitable protecting groups for compounds herein will be apparent to those of ordinary skill in the art ad/or described in the pertinent texts and literature; see, e.g., the level of skill in the art, and with reference to standard textbooks, such as Greene et ah, Protective Groups in Organic Synthesis (New York: Wiley, 1999), incorporated by reference herein.

5.7. Prodrugs and Other Modifications

[0097] In addition to salt forms, the present disclosure may also provide compounds that are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds described herein. Prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present disclosure when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0098] A compound described herein can also be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and include those that increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism, and/or alter rate of excretion. Examples of these modifications include, but are not limited to, esterification with polyethylene glycols, derivatization with pivolates or fatty acid substituents, conversion to carbamates, hydroxylation of aromatic rings, and heteroatom substitution in aromatic rings.

5.8. Indications, Formulations, and Administration

[0099] The method of the disclosure involves treatment or prevention of an ophthalmic disorder in a patient by administering to the patient a therapeutically effective amount of an active agent as described herein. The active agent may be administered to the patient by itself or more typically in a formulation, dosage form (e.g., a unit dosage form), or drug delivery system, such as an implant or the like. As noted above, patients who benefit from the present method are those who are prone to or afflicted with an ophthalmic disorder, generally although not necessarily involving the posterior segment of the eye. An active agent as described herein may be administered in the context of monotherapy, or it may be combined with another active agent as described herein (i.e., in the same structural family or functional class) and/or with a different class of active agent. With combination therapy, the active agents may be administered separately, in separate formulations or dosage forms, or simultaneously, either in one dosage form or in two or more different dosage forms.

[00100] Pharmaceutical formulations, dosage forms, and drug delivery systems suitable for use in conjunction with the present disclosure contain a "therapeutically effective" amount of the active agent or agents, i.e., an amount effective to achieve the intended purpose. Determination of a therapeutically effective amount for a particular active agent is well within the capability of those skilled in the art of ophthalmology and ocular pharmacotherapy. A "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result, such as improved pathology of age-related macular degeneration or another disorder of the eye. A therapeutically effective amount of a compound may vary according to factors such as the mode of administration, disease state, age, sex, and weight of the subject, and the ability of the compound to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response. Doses for oral administration can range from about 0.1 mg/kg/day to about 100 mg/kg/day while doses suitable for topical or injectable administration are typically in the range of about 0.01 mg/ml to about 100 mg/ml. A therapeutically effective amount is also one in which any toxic or detrimental effects of the compound are outweighed by the therapeutically beneficial effects. See also Table 2 below for ocular specific doses.

[00101] Also disclosed herein is a formulation for intraocular injection for a 10 mg / mL solution of active pharmaceutical ingredient (API) is formulated with 10 mM phosphate; 0.015% polysorbate 80; 0.84% sodium chloride; pH 6.5; for a total vehicle concentration of 295 mOsm (milli-osmoles). The API is processed to particles of uniform size (10 - 20 micron size) and is micronized by roller milling technique. In one embodiment, 10 + 1 mg/ml API is formulated with 10 + 1 mM phosphate; 0.015 + .008% polysorbate 80; 0.84+ 0.16% sodium chloride; pH 6.5 + 0.5; 295 + 30 mOsm. In another embodiment, 10 + 0.5 mg/ml API is formulated with 10 + 0.5 mM phosphate; 0.015 + .002% polysorbate 80; 0.84+ 0.02% sodium chloride; pH 6.5 + 0.1 ; 295 + 15 mOsm. [00102] Administration of an active agent to treat or prevent an ophthalmic disorder may be carried out using any appropriate mode of administration. Thus, administration can be, for example, systemic (e.g., oral), or it may be topical, periocular, or intravitreal. For orally active drugs, systemic administration via the oral route may be preferred for some drugs, although the frequency of dosing necessary to maintain therapeutic blood levels of drug in the target tissue of the eye can result in non-specific absorption and undesirable systemic side effects. For these reasons, oral drug administration will typically be limited to active agents that have limited systemic side effects and high therapeutic indices, and that are well tolerated when administered via the oral route.

[00103] In the treatment and prevention of ocular disorders, topical drug delivery is generally viewed as the preferred route of administration for many drugs, as systemic, e.g., oral, delivery may be problematic for the reasons outlined above. Topical formulations are convenient for the patient to use, thus minimizing problems with patient compliance. In addition, the preparation of topical ophthalmic formulations such as eye drops, ointments, and the like is normally straightforward and does not, typically, involve complex or costly manufacturing techniques. Generally, topical drug delivery to the eye is carried out by administration of a formulation containing a pharmaceutically acceptable vehicle and one or more excipients. Depending on the hydrophilicity and solubility characteristics of a particular active agent, the formulation may be aqueous, partially aqueous, or nonaqueous, and the ophthalmic vehicle selected will depend on the particular type of formulation. For example, a topically administrable composition can be formulated as aqueous solution for a water-soluble drug, or as an ophthalmic suspension for a drug with lower aqueous solubility. In the former case, the vehicle is aqueous, and in the latter case, the vehicle will be only partially aqueous. Formulations for topical administration to the eye may also be in the form of an ointment, in which case the pharmaceutically acceptable carrier is composed of an ointment base. Preferred ointment bases have a melting or softening point close to body temperature, and any ointment bases commonly used in ophthalmic preparations may be advantageously employed. Common ointment bases include petrolatum and mixtures of petrolatum and mineral oil.

[00104] Topical formulations, however, are normally preferred for treating and preventing disorders of the anterior segment of the eye, e.g., disorders of the cornea, conjunctiva, and sclera, but are not typically preferred for treating and preventing disorders of the posterior segment of the eye, e.g., disorders of the retina, choroid, vitreous humor, and optic nerve. The leading causes of vision impairment and blindness are posterior segment-linked disorders, and it is thus imperative to ensure that an active agent can reach the target tissue at therapeutic levels. Posterior segment- linked disorders include, without limitation, age-related macular degeneration, macular edema (including diabetic macular edema), proliferative vitreoretinopathy, endophthalmitis, posterior uveitis, branch and central retinal vein occlusion, retinitis pigmentosa, retinal detachment, diabetic retinopathy, retinal degeneration, vascular retinopathy, uveitis, AIDS-related retinitis, choroidal and retinal neovascularization, and macular telangiectasia. When the formulation is administered topically, it is preferred that the formulation and/or mode of administration be modified so as to increase the retention time of the drug in the eye. For example, an ophthalmic permeation enhancer may be incorporated into the formulation, or a punctal plug can be used in conjunction with topical administration, or the like. Punctal plugs, as is known in the art, are devices that are inserted into the tear duct (or "puncta") of the eye to prevent drainage of liquid. Punctal plugs may be gradually soluble in aqueous fluid and thus temporary (as is the case with collagen plugs, for instance) or they may be inert and thus permanent (a silicone plug such as that available from FCI Ophthalmics as Snug Plugs™ is one example).

[00105] In one embodiment, the selected active agent is administered to treat or prevent an a posterior segment eye disorder using either the periocular or intravitreal routes, with the formulation, dosage form, or delivery system adapted to the selected mode of administration. Both periocular and intravitreal administration overcome the occasional disadvantages that can be associated with systemic or topical drug administration, as alluded to earlier herein. Periocular administration encompasses four distinct types of injection into the eye, i.e., subconjunctival, sub- tenon, retrobulbar, and peribulbar. Active agents administered by periocular injection can reach the targeted tissue in the posterior segment of the eye by at least one of three pathways: transcleral; systemic circulation through the choroid; and the anterior pathway through the tear film, cornea, aqueous humor, and the vitreous humor. Of the four periocular routes, subconjunctival injection is generally preferred insofar as the potentially rate limiting conjunctival epithelial barrier is avoided. In contrast with periocular injections, intravitreal injections bypass the choroid and blood-retinal barriers by direct administration into the vitreous.

[00106] Controlled release formulations - preferably sustained formulations— for topical, periocular, and intravitreal administration are generally preferred to ensure that the active agent is continuously reaching the target tissue of the eye. These systems additionally reduce the frequency of drug administration, assist in overcoming blood-ocular tissue barriers, and can enhance the stability of a formulation. A variety of controlled release compositions, dosage forms, and drug delivery systems such as ocular implants have been developed. See, e.g., Kuno and Fujii (May/June 2012) Retina Today, pp. 54-59; Gaudana et al. (2010) AAPS Journal 12(3):348-360; Haders (July/August 2008) Drug Delivery Technology 8(7):48-53; Kompella et al. (2010) Therapeutic Delivery 1(3): 435-456; del Amo and Urtti (2008) Drug Discovery Today 13(3/4): 135-143; Thrimawithana et al. (2011) Drug Discovery Today 16(5/6): 271-277; Abdelkadar and Alany (2012) Current Drug Delivery 9: 421-430; and Gaudana et al. (2009) Pharmaceutical Research 26(5): 1197-1216. For instance, injectable formulations, including formulations designed for either periocular or intravitreal injection, can be manufactured so as to contain surface-modified nanospheres to enhance diffusion, e.g., nanospheres having covalently or otherwise attached surface hydrophilic groups (such as low molecular weight polyethylene glycol), or nanospheres treated so as to have surface anionic groups. See Kim et al. (2009) Pharm Res. 26(5): 1197-1216. Colloidal formulations that provide for controlled release of active agent have also been prepared, including compositions containing drug-loaded liposomes, microparticles, and nanoparticles. The surfaces of the agent containing particles may be electrically neutral, or they may be ionized; cationic surfaces are usually preferred to enhance the passage through the negatively charged corneal epithelial mucosa. Cationic liposomes are one possibility. Chitosan-coated nanoparticles are also in use, insofar as the amino groups of chitosan have a pKa of about 6.5, in turn meaning that the surface amino groups are protonated at physiological pH. The active agent may also be formulated in a lipid-based composition, typically a w/o or o/w surfactant-containing emulsion.

[00107] Excipients for topically administrable and injectable ophthalmic formulations typically include, by way of illustration, thickeners, isotonic agents, buffering agents, preservatives, release rate-controlling excipients, and solubility modulators. Examples of thickeners include cellulosic polymers such as methylcellulose (MC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropyl-methylcellulose (HPMC), and sodium carboxymethylcellulose (NaCMC); other swellable hydrophilic polymers such as polyvinyl alcohol (PVA), hyaluronic acid or a salt thereof (e.g., sodium hyaluronate); and crosslinked acrylic acid polymers commonly referred to as "carbomers" (and available from B.F. Goodrich as Carbopol® polymers). The preferred amount of any thickener is such that a viscosity in the range of about 15 cps to 25 cps is provided, as a formulation having a viscosity in the aforementioned range is generally considered optimal for both comfort and retention of the formulation in the eye. Any suitable isotonic agents and buffering agents commonly used in ophthalmic formulations may be used, providing that the osmotic pressure of the solution does not deviate from that of lachrymal fluid by more than 2-3% and that the pH of the formulation is maintained in the range of about 6.5 to about 8.0, preferably in the range of about 6.8 to about 7.8, and optimally at a pH of about 7.4. Preferred buffering agents include carbonates such as sodium and potassium bicarbonate. Solubility modulators for facilitating the incorporation of water-insoluble drugs into ophthalmic formulations are known in the art and include complexing agents such as cyclodextrins, surfactants (e.g., polyoxyethylated nonionic surfactants; see Jiao (2008) Advanced Drug Delivery Reviews 60: 1663-1673), and gums such as gum arabic, guar gum, hydroxypropyl guar gum, xanthan gum, locust bean gum, and agar gum.

[00108] Ocular implants that provide for controlled release of active agent in the eye include both nonbiodegradable drug delivery systems as well as drug delivery systems that will gradually hydrolyze, dissolve, or otherwise degrade in the eye. In general, suitable sites for these ocular delivery systems will be the same as those sites that are appropriate to receive the active agent by periocular or intravitreal injection, although implants may also be placed in the conjunctival cul- de-sac, or inferior fornix. Nonbiodegradable implants are typically formulated from an inert, biocompatible, nonhydrolyzable polymer that provides for long-term sustained release of active agent, on the order of at least one month, three months, six months, one year, or even two years. One such implant is that available from Surmodics Inc. as the I-Vation system, in which a titanium coil implant is coated with the active agent and two esterified acrylic polymers, poly (methyl methacrylate) (PMMA) and ethylene-vinyl acetate (EVA). Biodegradable drug delivery systems may be made from gradually hydrolyzing, dissolving, or otherwise biodegrading polymers such as those in the poly-a-hydroxy acid family, e.g., polylactic acid, polyglycolic acid, and poly(lactide-co-glycolide), a copolymer thereof.

[00109] Still other controlled release delivery systems include refillable micropumps (in a MEMS -based drug delivery devices such as that under development by Replenish Inc.) and refillable port drug delivery systems (such as that under development by Genentech and ForSight Vision 4 Inc.), drug-coated microneedles (see Jiang et al. (2007) Invest. Ophthalmol. Vis. Sci. 48(9):4038043, and systems for co-delivering the active agent with microparticles of an enzyme that hydrolyzes the collagenous and extracellular matrix of the sclera (Jiang et al. (2009) Pharm. Res. 26(2):395-403.

[00110] Additional delivery systems useful in conjunction with the present method, particularly with respect to delivery to the posterior segment of the eye, include ultrasound-mediated drug delivery (see Zderic et al. (2004) Cornea 23(8):804-l l); ocular iontophoresis (see Guadana et al. (2010) AAPS 12(3):348-360; and drug-releasing, drug-loaded contact lenses such as the PLGA/poly(2-hydroxyethyl methacrylate) lenses described by Nash, "Drug-Dispensing Contact Lens Could Replace Imprecise Eye Drops," in Scientific American (August 12, 2009).

[00111] The disclosure is generally directed to methods for treating or preventing a posterior segment eye disorder, such as AMD. [00112] The retina is a complex multilayered structure, but may be viewed as composed of two functional parts: first, the photosensitive layer of rods and cones and neural connections that gather light and convert it to nerve impulses transmitted via the optic nerve; second, the underlying retinal pigment epithelium and its basal layer called Bruch's membrane, which together maintain the structural integrity of the barrier between the retina and the choroid, the main source of blood supply to the outer half of the retina.

[00113] The macula is the central area of the retina, composed primarily of cone cells and typically in the range of about 1 mm to 5 mm in diameter. The fovea is at the center of the macula, contains the largest concentration of cone cells in the eye, and is the thinnest region of the retina. It is the fovea that is responsible for central, high resolution vision. In a healthy eye, this area is free of blood vessels and is referred to as the capillary-free zone.

[00114] Macular degeneration refers to the progressive destruction of the macula, and while some macular degeneration occurs in younger individuals, the term generally refers to age-related macular degeneration (AMD or ARMD). The two forms of AMD are "wet" AMD (also referred to as neovascular AMD) and "dry" AMD (also referred to as atrophic or nonneovascular AMD), depending on the respective presence or absence of new blood vessels that have invaded the retina.

[00115] AMD begins with the appearance of drusen in the macula, i.e., macromolecular deposits between the retinal pigment epithelium and the choroid. While some people with drusen can still have good vision, it is fairly common for people with drusen to develop advanced AMD, as large and numerous drusen can disturb the pigmented cell layer under the macula. Visual acuity can drastically decrease, or there can be a gradual loss of central vision, with blurring in the region of focus. It can become difficult to discern colors or even distinguish dark from light, and recovery of visual function after exposure to bright light becomes slow. Currently, no medical or surgical treatment is available for this condition.

[00116] Dry AMD can often lead to wet AMD, in which abnormal blood vessel growth in the macula leads to bleeding, leaking, and scarring, causing irreversible damage to the photoreceptors and rapid loss of vision.

[00117] Effective therapies for AMD may also be useful in the treatment or prevention of other ocular disorders. The disclosure may therefore also provide methods of treating or preventing other disorders of the retina as well as disorders of the choroid, vitreous humor, and optic nerve. Such disorders include, for example, macular edema (including diabetic macular edema), proliferative vitreoretinopathy, endophthalmitis, posterior uveitis, branch and central retinal vein occlusion, retinitis pigmentosa, retinal detachment, diabetic retinopathy, retinal degeneration, vascular retinopathy, uveitis, AIDS-related retinitis, choroidal and retinal neovascularization, and macular telangiectasia.

[00118] Preferred methods, devices, and materials are described, although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure. All references cited herein are incorporated by reference in their entirety.

[00119] The following Examples further illustrate the disclosure and are not intended to limit the scope. In particular, it is to be understood that this disclosure is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims.

6. EXAMPLES

6.1. Compound Synthesis

[00120] The following RXR agonists have been described in Japanese Application Publication Nos. 2010280585 and 2013177329 which are hereby incorporated by reference in their entirety. Specifically, the half maximal effective concentration (ECso) of these compounds generally ranges from 10-200 nM. Compounds 1-3 were synthesized and characterized as described by Ohsawa et al., 2010. Ohsawa, et al. (2010) Modification at the Lipophilic Domain of RXR Agonists Differentially Influences Activation of RXR Heterodimers. ACS Medicinal Chemistry Letters 1 (9), 521-525. Compounds 4-6 were synthesized and characterized as described by Ohsawa et al., 2013. Ohsawa et al. (2013) Mechanism of Retinoid X Receptor Partial Agonistic Action of l-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-lH-b enzotriazole-5-carboxylic Acid and Structural Development To Increase Potency. Journal of Medicinal Chemistry 56 (5),

1865-1877.

1 2 3

6.2. Synergistic Effect of LXR and RXR Agonists

[00121] Using the human RPE cell line ARPE 19 (Figure 1) or primary RPE cells derived from an anonymous human donor (Figure 2), four conditions were tested: vehicle, the RXR agonist LG268, the LXR agonist T0901317, or both. Compounds were added into cultured cells, and several days later, mRNA was recovered and analyzed by quantitative PCR for increased mRNA content for two LXR-regulated genes (ABCA1 and ABCG1). The results demonstrate that either LG268 alone or T0901317 alone increases expression of both genes. However, the combination of both agonists produced a dramatic increase in gene expression, much greater than the additive effect of either alone, indicating the two drugs are synergistic. Thus, the combination of RXR- specific and LXR-specific agonists, acting on ocular cells relevant to ocular diseases, is synergistic compared to agonists of the specific receptors used in isolation, in terms of increased expression of LXR-regulated genes and therapeutic efficacy. See the brief description of the figures for additional experimental methods.

6.3. Experimental Methods and Animal Study Design

[00122] Gene expression studies: Bioactivity for RXR and LXR agonist compounds was assessed by quantitative reverse transcriptase polymerase chain reaction (RT-PCR) analysis of retinal pigment epithelium cells treated with specific compounds. ARPE- 19 cells (a type of retinal pigment epithelium cell) or primary RPE cells were grown to confluence on collagen / laminin substrate, using maintenance medium (DMEM) supplemented with 10% fetal bovine serum, as previously described (Marin-Castano ME (2006) Invest Ophthalmol Vis Sci 47:4098-4112). Cells were then treated with vehicles or compounds, LG100268 (LG268, 10 μΜ) - RXR agonist, T090 (1 μΜ) - LXR agonist, either individually or in combination as specified in Figures 1 and 2. Following treatment for 18 hours, cells were washed with phosphate-buffered saline and recovered at 4°C. Total RNA was extracted from freshly isolated cells using the RNeasy Mini Kit (Qiagen, Valencia, CA) and genomic DNA was removed using a DNAse Kit (Ambion / Applied Biosystems, Foster City, CA). RNA was quantified using an RNA-specific fluorescent kit (Quant- iT, RiboGreen, Molecular Probes, Eugene, OR), and cDNA were prepared using an iScript cDNA synthesis kit (Bio-Rad, Hercules, CA). Primers for ABCG1 and ABCA1 were custom-designed with the aid of Vector NTI software (Invitrogen, Carlsbad, CA) and obtained from Integrated DNA Technologies (Coralville, IA). Gene expression levels were determined on a Bio-Rad iCycler using iQ SYBR Green Supermix (Bio-Rad) and were normalized to 36B4 expression. Fold-change was determined by the ΔΔ Ct method, determining the difference in gene expression in drug-treated cells, as compared to vehicle.

[00123] Western blot analysis (Figures 3 - 8): Following recovery of eyes, the RPE - choroid tissue complex was dissected, harvested and processed at 4°C in a modified radioimmunoprecipitation assay (RIP A) buffer, and protein concentration determined using Bio- Rad protein assay. Proteins were resolved using SDS-PAGE and transferred to a nitrocellulose membrane, which were blocked with PBS-Tween (0.05%)-5% nonfat dry milk solution for 1 h. The membrane was subsequently incubated with antibodies to ApoE or tubulin control for normalization, overnight at 4°C. Blots were washed in PBS-Tween (0.1%) and incubated with secondary antibodies conjugated to horseradish peroxidase (Bio-Rad) for 1 hr., room temperature. Following additional washes, immunoreactive proteins were detected using ECL chemiluminescence (Amersham Pharmacia Biotech) and recorded by fluorography on Hyperfilm (Amersham Pharmacia Biotech) according to manufacturer's instructions.

[00124] Experimental design for Bexarotene animal studies (Figure 9 -12 ): The study design was as follows: ApoE4 transgenic mice, 93 to 97 wks. Old were placed on high fat + cholesterol diet for 8 weeks to induce drusen and vision impairment. Bexarotene was formulated in 11.5% DMSO / 4.4 % gum Arabic suspension for subconjunctival administration to the left eye; the right eye served as an untreated control. Mice (n=8) underwent baseline ERG for both eyes to affirm reduction in amplitudes following high-fat diet. Mice were then treated with 100 μg Bexarotene suspension at day 0 and day 2, and post-treatment ERG was measured at day 6. Mice were euthanized and mouse eyes were recovered for analysis, either by ELISA for amyloid beta or by histology for transmission electron microscopy. Mice (n=4) treated with 11.5% DMSO / 4.4% gum Arabic suspension vehicle served as control.

[00125] ELISA analysis for amyloid beta (Αβ) peptides (Figure 9): Following recovery of eyes, the RPE -choroid tissue complex was dissected, harvested, and processed at 4°C and analyzed with ELISA kits specific for Αβ-40 and for Αβ-42, as previously described (Ding JD, et al., (2011) PNAS 108:E279-E287). [00126] Electroretinogram: ERGs were recorded using the Espion E ² system (Diagnosys, LLC), as previously described (Ding JD, et al, (2011) PNAS 108:E279-E287). Personnel responsible for ERGs and assessment of pathology were masked as to the identity of the treatment groups.

[00127] Transmission electron microscopy: Mouse eyes were embedded with a mixture of Epon and Spurr resins and polymerized at 60°C for 36-48 h. Thin sections of -80 nm were cut, mounted, on copper grids, counterstained with uranyl acetate and Sato's lead, and examined on a Tecnai G2 TWIN transmission electron microscope (FEI). The cumulative frequency of sections with various subRPE thickness was then quantified across the mouse eye to assess the extent of thick subRPE deposit formation across the retinal sections.

[00128] Experimental design for RXR-agonist mouse studies: The study design was as follows: ApoE4 transgenic mice, 93 to 97 wks. Old were placed on high fat + cholesterol diet for 12 weeks to induce drusen and vision impairment. PA024 or AGN 194204 were formulated in 4.5% ethanol in water solution (pH 7.4) for subconjunctival administration. Mice were treated with unilateral, periocular administration to the right eye, of one of the following, each in fully soluble solution: vehicle control (4.5% ethanol solution, pH adjusted to 7.4), PA024 (0.03 mg / 0.05 mL), or AGN194204 (0.03 mg / 0.05 mL). Mice in each group received a total of 7 administrations to the right eye over two weeks, with each administration performed under gas anesthesia. Left eyes served as untreated controls. Mice were sacrificed and eyes were processed for transmission electron microscopy (TEM) as described above. TEM micrographs were evaluated using a peer-reviewed and validated deposit scoring system (Invest Ophthalmol Vis Sci. 2006 Feb;47(2):729-37) to qualitatively assess the degree of deposit-associated disease pathology. Multiple TEM sections were sampled across the retina for each animal, and a median value was assessed for each eye. From the total data set of animals in each group, a median value was calculated for eyes in each group, following treatment. Results are shown in Figures 13, 14 and 15. The scoring in Figure 13 and 15 used the methodology described in Espinosa-Heidmann DG, Suner IJ, Catanuto P, Hernandez EP, Marin-Castano ME, Cousins SW. (2006) Cigarette smoke- related oxidants and the development of sub-RPE deposits in an experimental animal model of dry AMD, Invest Ophthalmol Vis Sci. 47(2):729-737. Table 1 shows the scoring scheme. [00129] Table 1. Deposit scoring system

severe = 7-10; very severe > 10; max =15.

6.4. Toxicity Associated with RXR drugs

[00131] Toxicity at high doses included (1) focal corneal stromal haze and conjunctival chemosis (single injection); (2) Epithelial compromise and corneal ulceration, conjunctival chemosis (edema), conjunctival hemorrhage, conjunctival hemorrhage, fibrosis, eyelid swelling and erythema (all evident after multiple injections); and (3) Suppression of ERG b-wave. Preferred formulations are shown below in Table 2.

[00132] Table 2. Therapeutic range and dose associated with toxicity for suspension formulations

[00133] It should be understood that the above description is only representative of illustrative embodiments and examples. For the convenience of the reader, the above description has focused on a limited number of representative examples of all possible embodiments, examples that teach the principles of the disclosure. The description has not attempted to exhaustively enumerate all possible variations or even combinations of those variations described. That alternate embodiments may not have been presented for a specific portion of the disclosure, or that further undescribed alternate embodiments may be available for a portion, is not to be considered a disclaimer of those alternate embodiments. One of ordinary skill will appreciate that many of those undescribed embodiments, involve differences in technology and materials rather than differences in the application of the principles of the disclosure. Accordingly, the disclosure is not intended to be limited to less than the scope set forth in the following claims and equivalents.

6.5. INCORPORATION BY REFERENCE

[00134] All references, articles, publications, patents, patent publications, and patent applications cited herein are incorporated by reference in their entireties for all purposes. However, mention of any reference, article, publication, patent, patent publication, and patent application cited herein is not, and should not be taken as an acknowledgment or any form of suggestion that they constitute valid prior art or form part of the common general knowledge in any country in the world. It is to be understood that, while the disclosure has been described in conjunction with the detailed description, thereof, the foregoing description is intended to illustrate and not limit the scope. Other aspects, advantages, and modifications are within the scope of the claims set forth below. All publications, patents, and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference.